Drug Facts for Your Personal Formulary: Muscarinic Receptor Agonists and
Antagonists (continued)
Drugs
Therapeutic Uses
Clinical Pharmacology and Tips
Muscarinic Receptor Antagonists
Glycopyrrolate
• Duodenal ulcer
• Sialorrhea
• Antimuscarinic adverse effects and contraindications similar to atropine
• Fewer CNS effects as glycopyrrolate is a quaternary amine and therefore
unable to cross the blood-brain barrier
Dicyclomine, hyoscyamine
Diarrhea-predominant irritable bowel
syndrome (IBS)
• Antimuscarinic adverse effects and contraindications similar to atropine
(including constipation-dominant IBS)
• Evidence for efficacy is limited
Trihexyphenidyl, benztropine
• Parkinson disease
• Antimuscarinic adverse effects and contraindications similar to atropine
• Mainly used to treat the tremor in Parkinson disease
• Not recommended for elderly or demented patients
Drug Facts for Your Personal Formulary: Muscarinic Receptor Agonists and
Antagonists
Drugs
Therapeutic Uses
Clinical Pharmacology and Tips
Muscarinic Receptor Agonists
Methacholine
• Diagnosis of bronchial airway
hyperreactivity
• Muscarinic effects: GI cramps, diarrhea, nausea, vomiting; lacrimation, salivation,
sweating; urinary urgency; vision problems; bronchospasm
• Do not use in patients with GI obstruction, urinary retention, asthma/COPD
Carbachol
• Glaucoma (topical administration)
• Systemic muscarinic effects minimal with proper topical application, otherwise
similar to methacholine
Bethanechol
• Ileus (postoperative, neurogenic)
• Urinary retention
• Similar to methacholine
• Take on empty stomach to minimize nausea/vomiting
Pilocarpine
• Glaucoma (topical administration)
• Xerostomia due to
• Sjögren syndrome
• Head and neck irradiation
• Systemic muscarinic effects minimal with proper topical application, otherwise
similar to methacholine
Cevimeline
• Xerostomia due to
• Sjögren syndrome
• Similar to methacholine
Muscarinic Receptor Antagonists
Atropine
• Acute symptomatic
bradycardia (e.g., AV block)
• Cholinesterase inhibitor intoxication
• Aspiration prophylaxis
• Antimuscarinic adverse effects: xerostomia, constipation, blurred vision,
dyspepsia, and cognitive impairment
• Contraindicated in patients with urinary tract obstruction (especially in benign
prostatic hyperplasia), GI obstruction, and angle-closure glaucoma
Scopolamine
• Motion sickness
• CNS effects (drowsiness, amnesia, fatigue)
Homatropine,
cyclopentolate,
tropicamide
Ipratropium,
tiotropium,
aclidinium,
Pirenzepine,
umeclidinium
telenzepine
Oxybutynin,
trospium,
darifenacin,
solifenacin,
tolterodine,
fesoterodine
• Ophthalmological examination
(cycloplegia and mydriasis
induction)
• COPD
• Rhinorrhea (ipratropium)
• Antimuscarinic adverse effects are minimal with proper topical application
• Peptic ulcer disease (not in U.S.)
• Antimuscarinic adverse effects and contraindications similar to atropine
• Overactive bladder, enuresis,
neurogenic
bladder
• Minimal absorption as quaternary amine ⇒fewer antimuscarinic adverse
effects, otherwise similar to atropine
• Antimuscarinic adverse effects and contraindications similar to atropine
• CNS-related antimuscarinic effects less likely with trospium (quaternary amine),
darifenacin and solifenacin (some selectivity for M3 receptors), fesoterodine
(prodrug of tolterodine), and tolterodine (preference for muscarinic receptors in
the bladder)
Drug Facts for Your Personal Formulary: Anticholinesterase Agents
Drugs
Therapeutic Uses
Major Toxicity and Clinical Pearls
Noncovalent Reversible Inhibitors
Edrophonium
Tacrine
Donepezil
Propidium
Fasciculin
Galantamine
• Edrophonium can be used to diagnose
myasthenia gravis
• Tacrine, donepezil and galantamine used for
Alzheimer disease
• Edrophonium and tacrine: bind reversibly to choline subsite
nearTrp86 and Glu202
• Edrophonium has a short duration of action because of rapid
renal elimination; effects are limited to the peripheral nervous
system.
• Donepezil and tacrine: higher affinity for AChE, more
hydrophobic, can cross BBB.
• Tacrine: high incidence of hepatotoxicity
• Donepezil binds with higher affinity to the active center gorge of
AChE.
• Propidium & fasciculin: bind peripheral anionic site on AChE
• Pyridostigmine, neostigmine and ambenonium
are used for treatment of myasthenia gravis
• Neostigmine is used for paralytic ileus and atony
of the urinary bladder
• Rivastigmine, a very lipid soluble alternative for
treating Alzheimer disease
• Pyridostigmine used prophylactically in nerve gas
attacks
• Drugs with carbamoyl ester linkage: AChE substrates that block
by carbamylation of AChE active center serine, are hydrolyzed
slowly; regarded as hemi-substrate blockers
• Neostigmine and pyridostigmine are poorly absorbed after oral
administration
• Pyridostigmine: available in sustained release tablets; oral dose
much higher than parenteral dose
• Rivastigmine can cross the BBB, has longer duration of action,
and is available in oral and epidermal patch formulations
Carbamate Inhibitors
“Reversible”
Carbamate Inhibitors
Physostigmine
Neostigmine
Pyridostigmine
Ambenonium
Rivastigmine
Drug Facts for Your Personal Formulary: Anticholinesterase Agents (continued)
Drugs
Therapeutic Uses
Major Toxicity and Clinical Pearls
• Garden insecticides
• Symptoms of poisoning resemble those of organophosphates
but are more readily reversed and less toxic
Echothiophate
• Treatment of glaucoma
• Instilled locally in the eye
• Stable in aqueous solution
Nerve Agents
DFP Tabun
Sarin
Soman
Cyclosarin
VX
• Alkylphosphates are the most potent synthetic
toxins
• React covalently with the active site serine
• Potent and irreversible inactivators of ChE
• Recent documented use in terrorism
• Form a stable conjugate with the active site serine by
phosphorylation/phosphonylation
• Hydrolyzed by hepatic carboxyesterases and paraoxonases
• Low MW, hydrophobic, rapidly penetrates into CNS from
pulmonary inhalation
• Tabun, sarin, and cyclosarin are volatile and extremely toxic
“nerve gases”
• VX is absorbed through the skin, has slower onset, but high
toxicity
• 2-PAM and related aldoximes are used to reactivate
organophosphate-ChE conjugates
• Resistance to organophosphate-AChE reactivation is enhanced
through “aging” that results from loss of one alkyl group
Pesticides
Parathion
Methylparathion
Malathion
Diazonin
Chlorpyrifos
• Insecticides largely agricultural
• Malathion is used topically in the treatment of
pediculosis in cases of permethrin resistance
• Lethal dose of malathion in mammals is 1g/kg
• Diazinon and chlorpyrifos are used widely in
agriculture
• Metabolism of these thion pesticides to the corresponding oxon
confers pesticide activity and toxicity, more rapid rate in insects
• Malathion: detoxified by plasma carboxylesterases, a detoxification
reaction that is more rapid in mammals and birds than insects,
yielding a further margin of safety
Carbamate Inhibitors
Carbamate insecticides
Carbaryl
Propoxur
Aldicarb
Organophosphates
CHAPTER 10
Antidotal therapy for Organophosphate Exposure
Cholinesterase reactivators
2-PAM
HI-6
Obidoxime
• Quaternary pyridinium aldoxime reactivators
indicated for insecticide and nerve gas poisoning
• Improved agents in development
• Reactivates organophosphate-AChE conjugate by attacking the
conjugated phosphorus to form phospho-oxime and regenerate the
active enzyme
• Dose is infused IV or IM with autoinjector; dosing should be
repeated frequently
• Early treatment helps insure that the oxime reaches the
phosphorylated enzyme prior to complete “aging”
• Reactivators do not cross the blood-brain barrier and do not
reactivate CNS AChE
Anticholinergic agents
Atropine
• Blocks symptoms mediated through muscarinic
receptors
• Given by parenterally in 2-4mg doses every few min until
muscarinic symptoms disappear
Benzodiazepines
Diazepam
Midazolam
• Minimize seizures and associated neuronal toxicity
• Administered parenterally post-exposure
Drug Facts for Your Personal Formulary: Agents Acting at the NMJ and
Autonomic Ganglia; Antispasmodics; Nicotine
Drug
Therapeutic Uses
Clinical Pharmacology and Tips
Nicotinic ACh Receptor Agonists
SuccinylcholineUS
(Nm agonist)
Induction of neuromuscular blockade in
surgery and during intubation
Dexamethonium
(depolarizer)
• Not used clinically in the U.S.
Nicotine
(Nn agonist)
• Smoking cessation
• Low dose induces postganglionic depolarization
• High doses induce ganglionic transmission blockade
Varenicline
(Nn [α4β2 subtype])
• Smoking cessation
• FDA warning about mood and behavioral
changes
• Partial nicotinic receptor agonist preventing nicotine stimulation and
decreasing craving
• Potential for neuropsychiatric events, may cause seizures with alcohol use;
excreted largely unchanged in urine
• Induces rapid depolarization of motor end plate, inducing phase I block
• Resistant to and augments AChE inhibition; induces fasciculations, then flaccid
paralysis
• Influenced by anesthetic agent, type of muscle, and rate of administration
• Leads to phase II block after prolonged use
• Metabolized by butyrylcholinestarase; not safe for infants and children
• Contraindications: history of malignant hyperthermia, muscular dystrophy
Competitive Nicotinic ACh Receptor Antagonists (Nondepolarizing Neuromuscular Blocking Agents)
d-Tubocurarine a,L
MivacuriumS
• Induction of neuromuscular blockade in
surgery
and during intubation
• All neuromuscular blocking agents are
administered parenterally
• No longer used clinically in the U.S. or Canada
• Produces partial blockade of ganglionic ACh transmission that can produce
hypertension and reflex tachycardia
• Can induce histamine release
• Short acting due to rapid hydrolysis by plasma cholinesterase
• Use with caution in patients with renal or hepatic insufficiency
PancuroniumL
• Shows antimuscarinic receptor activity
• Renal and hepatic elimination
• Vagolytic activity may cause tachycardia, hypertension, and increased cardiac
output
RocuroniumI
•
•
•
•
VecuroniumI
• Amino steroid
• Not stable in solution
• Hepatic and renal elimination
Metocurinea,L
• Three times more potent than tubocurarine
• Less histamine release
AtracuriumI
• Preferred agent for patients with renal failure
CisatracuriumI
• Susceptible to Hofmann elimination and ester hydrolysis
• Same dosage for infants > 1 month, children, and adults
• More potent than atracurium, Hofmann elimination, no histamine release
(unlike atracurium)
Doxacuriuma,L
Pipecuronium
Amino steroid
Stable in solution
More rapid onset than vecuronium and cisatracurium
Hepatic elimination
• Renal elimination
a,L
• Hepatic metabolism; renal elimination
Drug Facts for Your Personal Formulary: Serotonergic Ligands
Drugs
Therapeutic Uses
Clinical Pharmacology and Tips
5HT3 Receptor Antagonists • Antiemetic agents • Additional detail in Chapters 50 and 51
Ondansetron
Dolasetron
Granisetron
Palonosetron
• Antiemetics
• Treatment of nausea
• Associated with asymptomatic electrocardiogram changes, including prolongation of PT
and QTc intervals
Cilansetron
Alosetron
• Antiemetics
• Treatment of nausea
• Irritable bowel syndrome
• Most useful in irritable bowel syndrome when diarrhea is the principal symptom
5HT2C Receptor Agonists • Weight loss
Lorcarserin
• Promotes weight loss
through decreased food
consumption and increased
satiety
• Hallucinogenic at supraclinical doses, likely caused by 5HT2A agonist activity that can
occur with higher doses
• Hallucinogenic properties resulted in a class IV schedule designation
• Acute treatment of migraine
• Most effective in acute settings; should be used as soon as possible after onset of attack
• Usually dosed orally; onset, 1–3 h
• Use with caution in patients with cardiovascular issues; contraindicated in patients with
ischemic heart disease and coronary artery vasospasm
• Drug interactions: CYP3A4 inhibitors ↑ CP andt½ of eletriptan, naratriptan; MAO inhibitors
↑levels of almo-, riza-, suma-, and zolmitriptan.
• Side effects: dizziness, somnolence, neck and chest pain
• May cause fetal harm; not recommended during pregnancy and nursing; reduce dose in
renal and hepatic impairment; do not administer within 24 h of other triptans, ergots,
SSRIs/SNRIs
• Beware serotonin syndrome, especially in combination with SSRIs and SNRIs
The Triptans: 5HT1B/1D Receptor Agonists • Migraine
Almotriptana
Eletriptan
Frovatriptan
Naratriptan
Rizatriptan
Sumatriptanb
Zolmitriptan
The Ergot Alkaloids • Interact with multiple 5HT receptor isoforms • Broad therapeutic utility
LSD
• No longer employed clinically
• Potent hallucinogen
• Positron emission tomographic imaging reveals similar activation patterns between
schizophrenic patients experiencing hallucinations and LSD-induced hallucinations
• 5HT2A receptor activation is believed to mediate the hallucinogenic effect of LSD
Methysergide
• Acute treatment of migraine
• Treatment of vascular headaches
• Restricted to use in patients with frequent, moderate, or infrequent, severe migraine attacks
• Erratic drug absorption
• Potential for inflammatory fibrosis with prolonged use, including pleuropulmonary and
endocardial fibrosis
Ergonovine
Methylergonovine
• Prevention of postpartum
hemorrhage
• Increasing dose results in prolonged duration and increased force of uterine contraction
• Sustained contracture can result at high doses
5HT1A Receptor Partial Agonists and SSRIs • Anxiolytics and antidepressants • Additional detail in Chapter 15
Buspirone
Treatment of anxiety
• Mimics antianxiety effects of benzodiazepines but does not interact with GABAA receptors
• Partial agonist of the 5HT1A receptor
Fluoxetine
Fluvoxamine
Paroxetine
Citalopram
Escitalopram
Sertraline
Vilazodone
• Antidepressants
• Also used to treat anxiety, panic
disorder, obsessive-compulsive
disorder, fibromyalgia, and
neuropathic pain
•
•
•
•
Selectively inhibit the serotonin transporter (SSRIs)
Most widely used treatments for major depressive disorder
Sexual dysfunction is a common side effect with SSRIs
Precaution: serotonin syndrome
MSAAs • Treatment of sexual dysfunction • Activity at multiple receptor isoforms
Flibanserin
• Treatment of
HSDD/FSIAD in
premenopausal
women
• Potent 5HT1A receptor agonist and 5HT2 receptor family antagonist
• Exerts both agonist and antagonist activity at 5HT receptors ==> MSAA designation
(multifunctional serotonin agonist and antagonist)
Dopamine Receptor Agonists • Little to no subtype specificity
Dopamine
• Congestive heart failure
• Sepsis
• Cardiogenic shock
• Only used acutely via intravenous administration
Bromocriptine
Cabergoline
• PD (see Chapter 22)
• Hyperprolactinemia
• Ergot derivatives with D2 agonist activity and D1 antagonist activity
• Limited utility due to high potential for cardiac valvulopathies via 5HT2B stimulation
• Bromocriptine and cabergoline can be used at low doses to treat hyperprolactinemia
Apomorphine
Pramipexole
Ropinirole
Rotigotine
• PD (see Chapter 22 for more
details)
• RLS
•
•
•
•
Nonergot alkaloids with broader DA receptor agonist activity
Less efficacious than L-dopa in PD; often used as adjunct therapy in advanced PD
Use in early PD can lead to poor impulse control
Pramipexole, ropinirole, and rotigotine are used to treat RLS
Dopamine Receptor Antagonists • Antipsychotics • Emerging subtype specificity of ligands (Additional detail in Chapter 16)
Chlorpromazine
Haloperidol
• Schizophrenia (see Chapter 16)
• Classified as typical antipsychotics
• Agents block D2 receptors but are not completely selective
• Improvements are most notable in positive symptoms of schizophrenia
Clozapine
• Schizophrenia (see Chapter 16)
• Classified as atypical antipsychotics
• Mixed 5HT2A–D2 receptor blockade
• Fewer extrapyramidal side effects than typical antipsychotics
Aripiprazole
Brexpiprazole
Cariprazine
• Schizophrenia (see Chapter 16)
• D2 partial agonists with varied profiles at 5HT receptors
• Improved side effect profile over many other antipsychotics
DAT Ligands • High potential for abuse • Interact with the dopamine transporter
Bupropion
• Depression
• Smoking cessation
• Also inhibits NET
• ↑ risk of suicidal ideation in pediatric/young adult patients taking this medication
Cocaine
• Rarely used therapeutically
• Schedule II classification
• Limited clinical utility as a topical anesthetic in eye and nasal surgeries
Methylphenidate
Methamphetamine
Amphetamine
• ADHD, ADD
• Narcolepsy
• Obesity
• Can worsen psychosis; use with extreme caution in patients with bipolar disorder
• Schedule II drug classification due to psychostimulant properties if misused
Drug Facts for Your Personal Formulary: Depression and Anxiety Disorders
Drugs
Therapeutic Uses
Clinical Pharmacology and Tips
Selective Serotonin Reuptake Inhibitors
Citalopram
Escitalopram
Fluoxetine
Fluvoxamine
Paroxetine
Sertraline
Vilazodone
•
•
•
•
Anxiety and depression disorders
Obsessive-compulsive disorder, PTSD
SERT selective; little effect on NET
Vilazodone also acts as 5HT1A
partial agonist
•
•
•
•
•
•
Side effects include GI disturbances
May cause sexual dysfunctions
May increase risk of suicidal thoughts or behavior
Serotonin syndrome with MAOIs
Some CYP interactions
Vilazodone is not associated with sexual dysfunction or weight gain
•
•
•
•
Side effects include nausea and dizziness
May increase risk of suicidal thoughts or behavior
May cause sexual dysfunctions
Duloxetine and milnacipran contraindicated in uncontrolled narrow-angle or
angle-closure glaucoma
Serotonin-Norepinephrine Reuptake Inhibitors
Venlafaxine
Desvenlafaxine
Duloxetine
Milnacipran
Levomilnacipran
• Anxiety and depression,
ADHD, autism, fibromyalgia,
PTSD, menopause
symptoms
• Inhibitors of SERT and NET
276
Drug Facts for Your Personal Formulary: Depression and Anxiety Disorders
(continued)
Drugs
Therapeutic Uses
Clinical Pharmacology and Tips
Tricyclic Antidepressants
CHAPTER 15
Amitriptyline
Clomipramine
Doxepin
Imipramine
Trimipramine
Nortriptyline
Maprotiline
Protriptyline
Desipramine
Amoxapine
• Block SERT, NET, α1, H1, and M1
receptors
• Major depression
• Generally replaced by newer antidepressants with fewer side effects
• Numerous side effects: orthostatic hypertension, weight gain, GI
disturbances, sexual dysfunction, seizures, irregular heart beats
• Should not be used within 14 days of taking MAOIs
• Suicidal thoughts or behavior
• Resistant major
depression and psychotic
disorders
• Schizophrenia
• Bipolar depression
• See Chapter 16 for details
• Metabolic syndrome and weight gain
Atypical Antipsychotics
Aripiprazole
Brexpiprazole
Lurasidone
Olanzapine
Quetiapine
Risperidone
Monoamine Oxidase Inhibitors
Isocarboxazid
Phenelzine
Selegiline
Tranylcypromine
• Inhibit MAOA and MAOB to prevent
NE, DA, and 5HT breakdown
• Major depression disorders
resistant to other
antidepressants
• Many side effects, including weight gain and sexual dysfunction; replaced
by newer antidepressants
• Suicidal thoughts
• Slow elimination
• May cause hypertensive crisis if taken with tyramine-containing foods/beverages
• Selegiline at lower doses is selective for MAOB (found in serotonergic neurons)
• Selegiline, as a transdermal patch, is approved for treatment of depression
• Depression
• Smoking cessation (bupropion)
• Insomnia (low-dose trazodone)
•
•
•
•
•
Atypical Antidepressants
Bupropion Trazodone
Nefazodone
Mirtazapine
Mianserin (not
marketed in the U.S.)
Vortioxetine
Bupropion is a DAT inhibitor used to help quit smoking; no weight gain side effect
Mirtazapine, trazodone, and nefazodone are 5HT2 receptor antagonists
Mirtazapine and trazodone may cause drowsiness and should be taken at bedtime
Risk of hepatic failure with nefazodone
Vortioxetine: SERT inhibitor, 5HT agonist,
and 5HT antagonist
1A
3
• Suicidal thoughts or behavior
• Do not use within 14 days of taking MAOI
Drug Facts for Your Personal Formulary: Antipsychotic and Mood-Stabilizing Agents
Drugs
Therapeutic Uses
Clinical Pharmacology and Tips
First-Generation Antipsychotics • Low-potency D2 antagonists
Chlorpromazine
• Schizophrenia
• Acute mania
• High M1, H1, and α1 adrenergic affinities increase rates of anticholinergic side effects,
sedation and weight gain, and hypotension, respectively
• Less QTc prolongation at high plasma levels than thioridazine
• High risk of metabolic adverse effects
• Photosensitivity
First-Generation Antipsychotics • Medium- and high-potency D2 antagonists
Haloperidol
• Schizophrenia
• Acute mania
•
•
•
•
Higher rates of EPSs, akathisia, hyperprolactinemia
Limited anticholinergic side effects, sedation, weight gain, and hypotension
Avoid intravenous use due to QTc prolongation
Chlorpromazine 100 mg oral equivalence: 2 mg
Fluphenazine
• Schizophrenia
• Acute mania
• Higher rates of EPSs, akathisia, hyperprolactinemia
• Limited anticholinergic side effects, sedation, weight gain, and hypotension
• Chlorpromazine 100 mg oral equivalence: 2 mg
Trifluoperazine
• Schizophrenia
• Acute mania
• Higher rates of EPSs, akathisia, hyperprolactinemia
• Limited anticholinergic side effects, sedation, weight gain, and hypotension
• Chlorpromazine 100 mg oral equivalence: 5 mg
Thiothixene
• Schizophrenia
• Acute mania
• Higher rates of EPSs, akathisia, hyperprolactinemia
• Limited anticholinergic side effects, sedation, weight gain, and hypotension
• Chlorpromazine 100 mg oral equivalence: 5 mg
Perphenazine
• Schizophrenia
• Acute mania
• Modest rates of EPSs, akathisia
• Limited anticholinergic side effects, sedation, weight gain, and hypotension
• Chlorpromazine 100 mg oral equivalence: 10 mg
Loxapine
• Schizophrenia
• Acute mania
• Modest rates of EPS, akathisia
• Limited anticholinergic side effects, sedation, weight gain, and hypotension
• Chlorpromazine 100 mg oral equivalence: 10 mg
Second-Generation Antipsychotics • 5HT2A and D2 antagonists
Asenapine
• Schizophrenia
• Acute mania
• Only available in ODT formulation due to 98% first-pass effect if swallowed
• Administer sublingually: avoid water for 10 min to achieve maximum oral-buccal
absorption (avoiding water for 2 min achieves 80% of maximum absorption)
• Low risk of metabolic adverse effects
Clozapine
• Refractory schizophrenia
• Refractory mania
• Must register patient and prescriber due to mandatory hematological monitoring
• High M1, H1, and α1 adrenergic affinity increases rates of anticholinergic side effects,
sedation and weight gain, and hypotension, respectively
• High risk of metabolic adverse effects
• Significant constipation; avoid other anticholinergic agents, manage aggressively
• Sialorrhea; manage with locally administered agents (sublingual atropine 1% drops or
ipratropium 0.06% spray)
Iloperidone
• Schizophrenia
• High α1 adrenergic affinity; titrate to minimize orthostasis
• Low risk of metabolic adverse effects
Lurasidone
• Schizophrenia
• Bipolar depression
(monotherapy and adjunct)
• Low risk for anticholinergic side effects, sedation and weight gain, and hypotension,
respectively
• Low risk of metabolic adverse effects
• Absorption increased 100% by administration with 350 kcal food
Olanzapine
• Schizophrenia
• Acute mania
• Bipolar depression (in
combination with fluoxetine)
• High risk of metabolic adverse effects
• Anticholinergic effects at high dosages
Paliperidone
• Schizophrenia
• Moderate risk of metabolic adverse effects
• High rates of hyperprolactinemia
Quetiapine
• Schizophrenia
• Acute mania
• Bipolar depression
(monotherapy)
• Unipolar depression (adjunct)
• High risk of metabolic adverse effects at full therapeutic dosages for schizophrenia
• High H1 and α1 adrenergic affinities increase rates of sedation and hypotension, respectively
• Low rates of EPSs, akathisia, and hyperprolactinemia
Risperidone
• Schizophrenia
• Acute mania
• Moderate risk of metabolic adverse effects
• High rates of hyperprolactinemia
Drug Facts for Your Personal Formulary: Antipsychotic and Mood-Stabilizing
Agents (continued)
Drugs
Therapeutic Uses
Clinical Pharmacology and Tips
Second-Generation Antipsychotics • 5HT2A and D2 antagonists
CHAPTER 16
Sertindole
• Schizophrenia
• Not available in the U.S.
• Restricted use in Europe, with extensive monitoring for QTc prolongation
• Low risk of metabolic adverse effects
Ziprasidone
• Schizophrenia
• Acute mania
• Low risk of metabolic adverse effects
• Absorption increased 100% by administration with 500 kcal food
• Improved tolerability at starting doses > 80 mg/d with food
Second-Generation Antipsychotics • D2 partial agonists
Aripiprazole
• Schizophrenia
• Acute mania
• Unipolar depression
(adjunct)
• Low risk of metabolic adverse effects
• Lowers serum prolactin
• Akathisia noted in depression trials—can be lessened with starting dose of 2.0–2.5 mg
at bedtime
Brexpiprazole
• Schizophrenia
• Unipolar depression (adjunct)
• Low risk of metabolic adverse effects
• Lowers serum prolactin
Cariprazine
• Schizophrenia
• Acute mania
• Low risk of metabolic adverse effects
• Lowers serum prolactin
Second-Generation Antipsychotics • D2 and D3 antagonists
Amisulpride
• Schizophrenia
• Unipolar depression (adjunct,
at low dosages)
• Higher rates of EPSs
• Higher rates of hyperprolactinemia
• Low risk of metabolic adverse effects
5HT2A Inverse Agonist Without D2 Binding
Pimavanserin
Parkinson disease psychosis
(PDP)
•
•
•
•
Potent 5HT2A inverse agonist with no D2 affinity
Monotherapy efficacy data for psychosis available only for PDP
Only one dose available: 34 mg once daily, with or without food
↓ dose by 50% with concurrent strong 3A4 inhibitors; may lose efficacy with strong 3A4
inducers
• Clinical effects may not be seen for 2-6 weeks
Mood Stabilizers • Acute mania and/or bipolar maintenance
Lithium
• Acute mania
• Bipolar maintenance
• Unipolar depression
(adjunct)
•
•
•
•
•
•
•
Reduces suicidality more than other treatments
Renally cleared
Higher risk for weight gain
Monitor TSH, renal function tests, levels
May cause tremor, hair loss
Therapeutic serum level: acute mania 1.0–1.5 mEq/mL
Therapeutic serum level: maintenance 0.6–1.0 mEq/mL
Valproate (divalproex)
• Acute mania
• Bipolar maintenance
•
•
•
•
•
•
•
Can be loaded in acute mania: 30 mg/kg over 24 h
Highly protein bound
Higher risk for weight gain
May cause thrombocytopenia, leukopenia, hyperammonemia, tremor, hair loss
Monitor CBC, liver function tests, levels
Therapeutic serum level: acute mania 100–120 μg/mL
Therapeutic serum level: maintenance 60–100 μg/mL
Carbamazepine
• Acute mania
• Bipolar maintenance
•
•
•
•
•
•
•
Less effective than lithium and valproic acid
Highly protein bound
HLA testing for those from east Asia to identify high risk of Stevens-Johnson syndrome
May cause hyponatremia, leukopenia
Strong inducer of CYP3A4 and P-glycoprotein
Avoid rapid titration to minimize risk of sedation, ataxia
Therapeutic serum level 6–12 μg/mL
Lamotrigine
• Bipolar maintenance
• Prolonged titration to minimize risk of Stevens-Johnson syndrome
• 50% dosage reduction required if patient on valproic acid or divalproex
Drug Facts for Your Personal Formulary: Antiseizure Agents
Drugs
Therapeutic Uses
(Seizure Types)
Clinical Pharmacology and Tips
Sodium Channel Modulators • Enhance fast inactivation
Phenytoin
Focal
• Aware
• With impaired awareness
Generalized
• Tonic-clonic
•
•
•
•
•
•
Carbamazepine
Focal
• Aware
• With impaired awareness
• Focal to bilateral tonicclonic
Generalized
• Tonic-clonic
Focal
• Aware
• With impaired awareness
• Induces CYP enzymes (e.g., CYP2C, CYP3A) and UGT
• Active metabolite (10,11-epoxide)
• Side effects: drowsiness, vertigo, ataxia, blurred vision, increased seizure frequency
Lamotrigine
Focal
• Aware
• With impaired awareness
Generalized
• Absence
• Tonic-clonic
• Reduced half-life in the presence of phenytoin, carbamazepine, or phenobarbital
• Increased concentration in the presence of valproate
• Also used in Lennox-Gastaut syndrome
Oxcarbazepine
Focal
• Aware
• With impaired awareness
•
•
•
•
Rufinamide
Focal
• Aware
• With impaired awareness
• Can be used in Lennox-Gastaut syndrome
Eslicarbazepine
Once-daily dosing only available with extended-release formulation
Intravenous use with fosphenytoin
Nonlinear pharmacokinetics
May interfere with drugs metabolized by CYP2C9/19
Induces CYPs (e.g., CYP3A4)
Side effects: gingival hyperplasia, facial coarsening; hypersensitivity (rare)
Prodrug, metabolized to eslicarbazepine
Short half-life
Less-potent enzyme induction (vs. carbamazepine)
Side effects: lower incidence of hypersensitivity reactions (vs. carbamazepine)
Sodium Channel Modulators • Enhance slow inactivation
Lacosamide
Focal
• Aware
• With impaired awareness
Calcium Channel Blockers • Block T-type calcium channels
Ethosuximide
Generalized
• Absence
• Side effects: gastrointestinal complaints, drowsiness, lethargy, dizziness, headache, hypersensitivity/skin
reactions
• Titration can reduce side-effect occurrence
Zonisamide
Focal
• Aware
• With impaired awareness
• Side effects: somnolence, ataxia, anorexia, fatigue
Calcium Channel Modulators • α2δ ligands
Gabapentin
Focal
• Aware
• With impaired awareness
• Side effects: somnolence, dizziness, ataxia, fatigue
Pregabalin
Focal
• Aware
• With impaired awareness
• Side effects: dizziness, somnolence
• Linear pharmacokinetics
• Low potential for drug-drug interactions
GABA-Enhancing Drugs • GABAA receptor allosteric modulators (benzodiazepines, barbiturates)
Clonazepam
Generalized
• Absence
• Myoclonic
• Side effects: drowsiness, lethargy, behavioral disturbances
• Abrupt withdrawal can facilitate seizures
• Tolerance to antiseizure effects
Clobazam
Lennox-Gastaut syndrome
Generalized
• Atonic
• Tonic
• Myoclonic
• N-Desmethyl-clobazam, clobazam’s active metabolite, is increased in patients with poor CYP2C19
metabolism
• Side effects: somnolence, sedation
• Tapered withdrawal recommended
Drug Facts for Your Personal Formulary: Antiseizure Agents (continued)
Drugs
Therapeutic Uses
(Seizure Types)
Clinical Pharmacology and Tips
GABA-Enhancing Drugs • GABAA receptor allosteric modulators (benzodiazepines, barbiturates) (continued)
CHAPTER 17
Diazepam
Status epilepticus
•
•
•
•
Short duration of action
Side effects: drowsiness, lethargy, behavioral disturbances
Abrupt withdrawal can facilitate seizures
Tolerance to antiseizure effects
Phenobarbital
Focal
• Focal to bilateral tonicclonic Generalized Tonic-clonic
• Induces CYPs (e.g., CYP3A4) and UGT
• Side effects: sedation, nystagmus, ataxia; irritability and hyperactivity (children); agitation and
confusion
(elderly); allergy, hypersensitivity (rare)
Primidone
Focal
• Focal to bilateral tonicclonic Generalized
• Tonic-clonic
• Induces CYP enzymes (e.g., CYP3A4)
• Not commonly used
GABA-Enhancing Drugs • GABA uptake/GABA transaminase inhibitors
Tiagabine
Focal
• Aware
• With impaired awareness
• Metabolized by CYP3A
• Side effects: dizziness, somnolence, tremor
Stiripentol
Generalized
• Tonic-clonic
(Dravet syndrome)
• Used in Dravet syndrome
• Inhibits CYP3A4/2C19
Vigabatrin
Focal
• With impaired awareness
• Used in infantile spasms, especially when caused by tuberous sclerosis
• Side effects: can cause progressive and bilateral vision loss
Glutamate Receptor Antagonists • AMPA receptor antagonists
Perampanel
Focal
• Aware
• With impaired awareness
• Metabolized by CYP3A
• Side effects: anxiety, confusion, imbalance, visual disturbance, aggressive behavior, suicidal thoughts
Potassium Channel Modulators • KCNQ2-5–positive allosteric modulator
Ezogabine
Focal
• Aware
• With impaired awareness
• Side effects: blue pigmentation of skin and lips, dizziness, somnolence, fatigue, vertigo, tremor,
attention disruption, memory impairment, retinal abnormalities, urinary retention, QT
prolongation (rare)
Synaptic Vesicle 2A Modulators
Levetiracetam
Focal
• Aware
• With impaired awareness
Generalized
• Myoclonic
• Tonic-clonic
Brivaracetam
Focal
• Aware
• With impaired awareness
• Side effects: somnolence, asthenia, ataxia, dizziness, mood changes
Mixed Mechanisms of Action
Topiramate
Focal
• Aware
• With impaired awareness
Generalized
• Tonic-clonic
• Used in Lennox-Gastaut syndrome
• Side effects: somnolence, fatigue, cognitive impairment
Valproate
Focal
• Aware
• With impaired awareness
• Focal to bilateral tonicclonic
Generalized
• Absence
• Myoclonic
• Tonic-clonic
• Side effects: transient gastrointestinal symptoms, sedation, ataxia, tremor, hepatitis (rare)
• Inhibits CYP2C9, UGT
Drug Facts for Your Personal Formulary: Drugs for Neurodegenerative Disease
Drugs
Therapeutic Uses
Clinical Pharmacology and Tips
Anti-Parkinson: l-DOPA (DA precursor); Carbidopa (inhibits AADC, reduces peripheral conversion of l-DOPA to DA)
Carbidopa/levodopa
• Most effective symptomatic therapy for PD
• Therapeutic window narrows after several years of treatment:
wearing off, dyskinesias, on/off phenomenon
• Available as immediate-release tablets and orally disintegrated tablets
Carbidopa/levod
opa sustained
release
• Patients with PD with motor fluctuations on
regular carbidopa/levodopa
• Bioavailability of immediate-release form, 75%
Carbidopalevodopa
extendedrelease capsules
(RYTARY)
• Patients with PD with motor fluctuations on
regular carbidopa/levodopa
• Mixture of immediate- and extended-release beads
Carbidopa-levodopa
intestinal gel (DUOPA)
• Patients with PD with motor fluctuations on
regular carbidopa/levodopa
• Requires placement of gastrostomy tube with jejunal extension
• Useful for wearing off issues
Anti-Parkinson: DA agonists (longer acting than l-DOPA; can produce psychosis, impulse control disorder, sleepiness)
Ropinirole
• PD
• Restless legs syndrome
Pramipexole
• PD
• Restless legs syndrome
Rotigotine
• PD
• Restless legs syndrome
Apomorphine
• Rescue therapy for acute intermittent
treatment
of off episodes
• Selective D2 receptor class agonist
• Available in immediate release (3 times daily) and sustained release (once
daily)
• Selective D2 receptor class agonist
• Available in immediate release (3 times daily) and sustained release (once
daily)
• D2 and D1 receptor class agonist
• Transdermal formulation
• Subcutaneous formulation
• Emetogenic, requires concurrent antiemetic
• Contraindicated with 5HT3 antagonists
Anti-Parkinson: COMT Inhibitors (reduce peripheral conversion of levodopa, increasing t½ and CNS dose)
Entacapone
• Adjunctive PD therapy given with each
dose of levodopa, for wearing off
• Short t½, inhibits peripheral COMT
Tolcapone
• Adjunctive PD therapy given with each
dose of levodopa, for wearing off
• Long t½, inhibits central and peripheral COMT
• May be hepatotoxic; use only in patients not responding satisfactorily to
other
treatments; monitor liver function
Carbidopa/levodopa/
entacapone
• PD, especially for wearing off on levodopa
alone
• Fixed-dose combination formulation
Anti-Parkinson: MAO-B Inhibitors (reduce oxidative metabolism of dopamine in the CNS)
Rasagiline
• PD, either as initial monotherapy or adjunct to
levodopa
•
•
•
•
•
Adjunct to reduce wearing off
Many drug interactions
Should not be given with meperidine
When administered with CYP1A2 inhibitors, Cp of rasagiline may double
Risk of serotonin syndrome
Selegiline
• PD, as adjunctive therapy in patients with
deteriorating response to levodopa
•
•
•
•
•
•
Generates amphetamine metabolites, which can cause anxiety and insomnia
MAO-B selectivity lost at doses > 30–40 mg/d
Many drug interactions
Should not be given with meperidine
Risk of serotonin syndrome
Available in immediate release, orally disintegrating tablet, or transdermal patch
Amantadine
• Early, mild PD
• Levodopa-induced dyskinesias
• Influenza
• Unclear mechanism of antiparkinsonian effects
• Effective against dyskinesia
Trihexyphenidyl
• PD, as adjunctive therapy
• Muscarinic receptor antagonist
• Anticholinergic side effects
Benztropine
• PD, as adjunctive therapy
• Muscarinic receptor antagonist
Anti-Parkinson: Other
Anti-Alzheimer: Acetylcholinesterase Inhibitors (boost cholinergic neurotransmission; first line treatment)
Donepezil
• Mild, moderate, severe AD dementia
• GI symptoms: main dose-limiting side effect
• Bradycardia/syncope less common
Rivastigmine
• Mild-moderate AD dementia
• Mild-moderate PD dementia
• Transdermal formulation available, with lower risk of GI side effects
• Also inhibits BuChE
Galantamine
• Mild-moderate AD dementia
• GI symptoms: main dose-limiting side effect
• Bradycardia/syncope less common than GI side effects
Anti-Alzheimer: Low-Affinity Uncompetitive NMDA Antagonist
Memantine
• Moderate, severe AD dementia
• Reduces excitotoxicity through use-dependent blockade of NMDA receptors
• Chorea in HD
• Reversible VMAT2 inhibitor: depletes presynaptic catecholamines
• Adverse effects: hypotension, depression with suicidality
• Adjust dose for CYP2D6 status; 2D6 inhibitors (e.g., paroxetine, fluoxetine,
quinidine, bupropion) ↑ exposure ~3 fold
• Contraindications: concurrent or recent MAO inhibitor or reserpine
Riluzole
Extends survival in ALS up to 3 months
• Uncertain mechanism of action: inhibits glutamate release, blocks sodium
channels and glutamate receptors
Edaravone
Reduces progression in early stages of ALS
• Intensive intravenous administration regimen
Anti-Spastic Agents
Baclofen
• GABAB receptor agonist
• Sedation and CNS depression
Tizanidine
• α2 adrenergic receptor agonist
• Causes drowsiness; treatment is initiated with low dose and titrated upward
• See Chapter 19
• May contribute to respiratory depression
• Not used in ALS, but for treating muscle spasm
in stroke or spinal injury and for treating
malignant hyperthermia
• May cause hepatotoxicity
Anti-Huntington
Tetrabenazine
Deutetrabenazine
Anti-ALS
Benzodiazepin
es (e.g.,
Dantrolene
clonazepam)
Drug Facts for Your Personal Formulary: Sedative-Hypnotic Agents
Drug
Therapeutic Uses
Clinical Pharmacology and Tips
Benzodiazepines-synergistic with other CNS depressants, esp. ethanol; see Table 19–2.
Alprazolam
Anxiety disorders, agoraphobia
Withdrawal symptoms may be especially severe
Chlordiazepoxide
Anxiety disorders, alcohol withdrawal, preanesthetic
medication
Adjunctive treatment of seizures associated with
Lennox- Gastaut syndrome, other epilepsy and
anxiety disorders
Long-acting and self-tapering because of active metabolites
Clonazepam
Seizure disorders, adjunctive treatment in acute mania
and certain movement disorders
Tolerance develops to anticonvulsant effects
Clorazepate
Anxiety disorders, seizure disorders
Prodrug; activity due to formation of nordazepam during absorption
Diazepam
Anxiety disorders, alcohol withdrawal, status
epilepticus, skeletal muscle relaxation,
preanesthetic
medication
Insomnia
Prototypical benzodiazepine
Clobazam
Estazolam
Active metabolite has long half-life
Decrease dose and titrate in CYP2C19 poor metabolizers
Tolerance develops to anticonvulsant effects
Contains triazolo ring; adverse effects may be similar to
those of triazolam
Drug Facts for Your Personal Formulary: Sedative-Hypnotic Agents (continued)
CHAPTER 19
Drug
Therapeutic Uses
Clinical Pharmacology and Tips
Flurazepam
Insomnia
Active metabolites accumulate with chronic use
Lorazepam
Anxiety disorders, alcohol withdrawal, preanesthetic
medication
Preanesthetic and intraoperative medication
Metabolized solely by conjugation
Midazolam
Oxazepam
Anxiety disorders, alcohol withdrawal
Metabolized solely by conjugation
Quazepam
Insomnia
Active metabolites accumulate with chronic use
Temazepam
Insomnia
Metabolized mainly by conjugation
Triazolam
Insomnia
Rapidly inactivated; may cause disturbing daytime side effects
Rapidly inactivated
“Z” Compounds-nonbenzodiazepines with agonist effects at the benzodiazepine site of GABAA receptors; have largely
replaced benzodiazepines for treating insomnia.
Zaleplon
Insomnia
Very short elimination half-life
Zolpidem
Insomnia
Short-term (2–6 week) treatment of insomnia
Eszopiclone
Insomnia
S(+) enantiomer of zopiclone
Benzodiazepine Antagonist
Flumenazil
Benzodiazepine overdose (benzodiazepine and βcarboline antagonist
Headache, dizziness; do not use in tricyclic antidepressant poisoning
(seizures!)
Miscellaneous and Emerging Agents
Ramelteon
Insomnia
Melatonin receptor agonist; significant first-pass effect
Tasimelteon
Circadian rhythm disorder in blind patients
Melatonin receptor agonist
Suvorexant
Insomnia
Orexin receptor antagonist; needs at least 7 h after 10-mg dose before
awakening
Doxepin
Depression, insomnia
Tricyclic antidepressant; sedating effects likely occur through H1 receptor
antagonism; beware of abnormal behavior, suicide ideation, depression; use
half dose in the elderly
Propofol
Induction/maintenance of anesthesia, procedural sedation
Rapid recovery
Pregabalin
(β-isobutyl–
GABA)
Nerve/muscle pain, fibromyalgia, seizures
Schedule V substance, abuse potential; some concern for suicide
ideation and angioedema
Barbiturates-synergistic with other CNS depressants, esp. ethanol; induce CYPs; respiratory depressants; see Table 19–3.
Amobarbital
Insomnia, preoperative sedation, emergency management
of seizures
• IM and IV
• Short-acting (3-8 h)
Butabarbital
Insomnia, preoperative sedation, daytime sedation
• Oral
• Fast onset of action
• Short-acting (3-8 h)
Mephobarbital
(not licensed for
use in U.S.)
Seizure disorders, daytime sedation
• Oral
• Short-acting (3-8 h)
Methohexital
Induction and maintenance of anesthesia
• IV
• Ultra short-acting (5-15 min)
Pentobarbital
Insomnia, preoperative and procedural sedation,
emergency management of seizures
• Oral, IM, IV, or rectal
• Administer Na+ salt parenterally
• Short-acting (3-8 h)
Phenobarbital
Seizure disorders, status epilepticus, daytime sedation
• Oral, IM, IV
• First-line anticonvulsant (see chapter 17); administer Na+ salt
parenterally
• Long-acting (days)
Secobarbital
Insomnia, preoperative sedation
• Oral
• Short-acting (3-8 h)
Thiopental
Induction and maintenance of anesthesia, preoperative
sedation, emergency management of seizures,
intracranial hypertension
• IV single dose provides brief period of anesthesia
• Ultra short-acting (5-15 min)
Drug Facts for Your Personal Formulary: Opioid Agonists and Antagonists
Drug
Therapeutic Use
Clinical Pharmacology and Tips
Agonists: See Table 20-7 for CDC guidelines for prescribing opioids for chronic pain
Morphine
Hydromorphone
Oxycodone
Hydrocodone
• Potent μ agonists
• Strong analgesic in moderate-to-severe pain states.
• Morphine is a useful adjunct in pulmonary edema
and general anesthesia.
• ↓GI motility ⇒constipation
• Hydrocodone, oxycodone formulated with NSAIDs
• Hydrocodone, oxycodone, and fentanyl are more
potent than morphine
• Among licit agents, LA/ER agents often preferred by
abusers
Fentanyl
• Potent μ agonist
• Administered orally (buccal tablet, sublingual
tablet/spray, oral lozenge), intravenous
(push/infusion), intramuscular, topical, topical
neuraxial
• iontophoretic,
Similar to fentanyl
• Rapid onset, short duration of action
• Slightly longer effective t1/2 than sufentanil, alfentanil,
and remifentanil
Meperidine
• Potent μ agonist
• Rapid onset, intermediate duration of action
• Not for extended use due to accumulation of seizureinducing metabolite
Methadone
• Potent MOR agonist
• Rapid onset, long duration of action
• Used in maintenance/rehab programs
• Long t1/2, ~ 27 h ⇒potential for accumulation with
too frequent repeated delivery
• Anticholinergic effects
Sufentanil
Alfentanil
Remifentanil
• Rapid onset, short duration of action
• Administered intravenously
• Sufentanil and alfentanil also given epidurally
• Remifentanil: ultrashort acting
Drug Facts for Your Personal Formulary: Opioid Agonists and Antagonists
(continued)
Therapeutic Use
Clinical Pharmacology and Tips
Codeine
• Weak prodrug for morphine
• Useful for mild-to-moderate pain
• Less efficacious than morphine but will antagonize
strong μ agonists
• Administered orally
• Useful antitussive effects
• Formulated with NSAIDs
Levorphanol
•
•
•
•
• Long elimination t1/2, ~ 14h ⇒ potential for accumulation
with too frequent repeated delivery
• Adverse effects: delirium, hallucinations
CHAPTER 20
Drug
Affinity at the MOR, KOR, and DOR
5HT/NE reuptake inhibitor; NMDA receptor antagonist
Rapid onset, modest duration of analgesia
Administered orally
Peripherally Restricted Agonist
Loperamide
• Mu opioid agonist
• Effective antidiarrheal
• Administered orally
• Loperamide crosses BBB poorly, can be formulated
with simethicone
• Mu opioid agonist
• Effective antidiarrheal
• Administered orally
• Diphenoxylate will cross the BBB, so it is formulated with
atropine, the anticholinergic effects of which (weakness,
nausea) discourage abuse.
Agonist Restricted by Coformulation
Diphenoxylate
Partial Agonists; Agonist/Antagonist Combinations
Buprenorphine
• Partial agonist at MOR; KOR antagonist
• Mild-to-moderate pain (ceiling effect)
• Administered by intramuscular, intravenous, sublingual,
transdermal, buccal film
• Coformulated with naloxone for use in abuse
management
• Delivery to a patient on a full opiate agonist may initiate
withdrawal (may be done therapeutically in management of
heroin addiction)
Butorphanol
Nalbuphine
Pentazocine
• KOR agonist/MOR antagonist
• Analgesia to mild-to-moderate pain
• Delivery to patient on a full opiate agonist may initiate
withdrawal
• Ceiling effect
• Pentazocine is also formulated with naloxone.
• Weak μ agonist and a 5HT/NE uptake inhibitor
• Analgesia for moderate pain
• Available as a fixed-dose combination with
acetaminophen
• Weak μ agonist and a 5HT/NE uptake inhibitor
• Analgesia for moderate pain
• Potential for seizures
• Serotonin syndrome risk
• As an adjunct to other opioids for chronic pain
Dextromethorphan
• ↓ Cough reflex; receptor mechanisms unclear
• Administered orally
• Available as an extended-release formulation
• Serotonin syndrome risk
• Has no analgesic or addictive properties
Codeine
• See codeine listing, above
• See codeine listing, above
Naloxone
•
•
•
•
•
Antagonist at MOR/DOR/KOR
Rapid onset, moderately short acting
Rapidly reverses central and peripheral opiate effects
Used in treating opioid overdose
Autoinjector available for emergency administration
• t1/2 ~ 64 min
• Renarcotization may occur with long-lasting agonists
as naloxone is metabolized
• May induce moderate hyperalgesia
• Known as narcan; used by emergency medical
technicians to revive comatose opioid abusers
Naltrexone
Nalmefene
•
•
•
•
Antagonist at MOR/DOR/KOR
Rapid onset, longer acting than naloxone
Reverses central and peripheral opiate effects
Used in treating alcohol and opiate dependence
• Naltrexone: formulated with bupropion for managing obesity
and with morphine for severe pain; contraindicated in hepatitis
and liver failure (Black- Box Warning: excessive doses cause
hepatocellular injury)
• Start naltrexone only after 7–10 days of abstinence
from opioids
• Long-term use of naltrexone ⇒ hypersensitivity to opioids
Other Agonists
Tramadol
Tapentadol
• Serotonin syndrome risk
Central Antitussives
Antagonists
Peripherally Restricted Antagonists
Methylnaltrexone
• Antagonist at MOR/DOR/KOR
• Reverses peripheral opiate effects (e.g., opiate-induced
constipation) but not analgesia
Alvimopan
• Antagonist at MOR/DOR/KOR
• Penetrates poorly into CNS
• FDA approved for ileus
• Does not cross BBB, thus not useful in treating
addiction or reversing CNS effects of opioids
• Reverses peripheral opiate effects
Drug Facts for Your Personal Formulary: General Anesthetics and Therapeutic
Gases
Drugs
Therapeutic Uses
Clinical Pharmacology and Tips
Propofol
Etomidate
Ketamine
Thiopental
• Anesthetic induction
• Rapid-onset and short-duration
anesthetics used in procedures for rapid
return to preoperative mental status
• Highly lipophilic ⇒ entry to brain and spinal cord, accumulation in fatty tissues
• Propofol dosage: ↓ in elderly due to reduced clearance, ↑ in young children due to
rapid clearance
• PRIS: rare complication associated with prolonged and high-dose propofol
infusion in young or head-injured patients
• Etomidate: preferred for patients at risk of hypotension or MI; produces
hypnosis, no analgesic effects; ↑ EEG activity, associated with seizures
• Ketamine: suited for patients at risk for hypotension and asthma and for pediatric
procedures; increases HR, BP, CO, CBF, and ICP; emergence delirium, hallucinations,
vivid dreams limit use
Barbiturates
Methohexital
Thiopental
• Anesthetic induction
• Respiratory and EEG depressants
• Methohexital: more rapid clearance than other barbiturates
• Thiopental: action terminated by redistribution; good safety record; not available in the
U.S.
• Intra-arterial injection of thiobarbiturates ⇒ severe inflammatory and potentially
necrotic reaction
Isoflurane
• Maintenance of anesthesia
• Commonly used inhalational
anesthetic
•
•
•
•
•
Highly volatile at RT; not flammable in air or O2
↓ Ventilation and RBF; ↑ CBF
Induces hypotension and ↑ coronary blood flow, thus ↓ myocardial O2 consumption
↓ Baroreceptor function
Excreted unchanged by the lungs
Enflurane
• Maintenance of anesthesia
•
•
•
•
Volatile at RT; store in tightly sealed bottles
Slow induction and recovery
↓ Arterial BP due to vasodilation and ↓ myocardial contractility
Possible effects: ↑ ICP, seizure activity
Sevoflurane
• Preferred agent for anesthetic
induction
• Used for outpatient anesthesia (not
irritating airway; induction and
recovery are rapid)
•
•
•
•
•
Reacts exothermically with desiccated CO2 absorbent
Ideal induction agent (pleasant smell, rapid onset)
↓ AP pressure and CO; potent bronchodilator
Preferred for patients with myocardial ischemia
Compound A, product of interaction of sevoflurane with the CO2-absorbent soda lime,
is nephrotoxic
Parenteral Anesthetics
CHAPTER 21
Inhalational Anesthetics
Desflurane
Halothane
Nitrous oxide (N2O)
Xenon
• Used for outpatient surgery
(rapid onset, rapid recovery)
• Maintenance of anesthesia
• Weak anesthetic agent used for
its significant analgesic effects
• Analgesic and anesthetic effects
• Highly volatile at RT; store in tightly sealed bottles
• Nonflammable in mixtures of air or O2
• An airway irritant
• Highly volatile at RT, light sensitive; store in tightly sealed amber bottles with thymol
(preservative)
• Possible hepatic toxicity has limited its use and is no longer available in the U.S.
• Colorless and odorless gas at RT; used as adjunct to other anesthetics.
• Will expand volume of air-containing cavities; thus, avoid use in obstructions of ear and
bowel, and in intraocular and intracranial air bubbles, etc.
• To avoid diffusional hypoxia, administer 100% O2 rather than air when discontinuing N2O
• Can increase CBF and ICP
• Clinical use of N2O is controversial due to potential metabolic effects related to
increased homocysteine and changes in DNA and protein synthesis
• Rapid induction and emergence from anesthesia
• In CNS: NMDA receptor antagonist, TREK channel agonist
• Well tolerated in older patients
Anesthetic Adjuncts • Augment anesthetic effects of general anesthesia
Benzodiazepines
Midazolam, diazepam,
lorazepam
Used for anxiolysis, amnesia,
preanesthetic sedation, and sedation
during procedures not requiring
general anesthesia
• Midazolam most commonly used, followed distantly by diazepam and lorazepam
(see Chapters 15 and 19)
α2 Adrenergic agonists
Dexmedetomidine
• Short-term (<24 h) sedation of critically
ill adults
• Sedation prior to and during surgical
or medical procedures in
nonintubated patients
• Activation of the α2A adrenergic receptor by dexmedetomidine ⇒ sedation and
analgesia
• Side effects: hypotension and bradycardia due to decreased catecholamine release in the
CNS; nausea and dry mouth
Anesthetic Adjuncts • Augment anesthetic effects of general anesthesia (continued)
Analgesics
Opioids
Fentanyl, Sufentanil,
Alfentanil, Remifentanil,
Meperidine, Morphine
• To reduce anesthetic requirement
and minimize hemodynamic
changes due to painful stimuli
NSAIDs
Acetaminophen
Neuromuscular Blocking
Agents
Succinylcholine (Depolarizing)
Atracurium, Vecuronium,
et al. (Nondepolarizing,
Competitive)
• Skeletal muscle relaxant
• Opioids are the primary analgesics during perioperative period; the choice of
opioid is based on duration of action (see Chapter 20)
• Opioids often are administered intrathecally and epidurally for management of acute
and chronic pain
• NSAIDs and acetaminophen are used for minor surgical procedures to control
postoperative
pain
• Action of nondepolarizing muscle relaxants usually is antagonized, once muscle
paralysis is no longer desired, with an AChE inhibitor (e.g., neostigmine or
edrophonium; see Chapter 10), in combination with a muscarinic receptor
antagonist
THERAPEUTIC GASES
Used primarily to reverse or
prevent the development of
hypoxia
• Excessive O2 ↓ ventilation
• Monitoring and titration are required to avoid complications and side effects
• HR and CO are slightly ↓ when 100% O2 is breathed
• High flows of dry O2 can dry out and irritate mucosal surfaces of the airway and the
eyes; humidified O2 should be used with prolonged therapy (>1 h)
• O2-enriched atmosphere constitutes a fire hazard; take precautions
Oxygen
•
Carbon dioxide
• Insufflation during endoscopic
procedures
• Flooding the surgical field
during cardiac surgery
• Adjusting pH during
cardiopulmonary bypass
• CO2 is highly soluble, noncombustible, denser than air.
• ↑ Pco2 ⇒respiratory acidosis
• Effects on CV system: combination of direct CNS and reflex sympathetic effects; net
effect: ↑ in CO, HR, and BP
Nitric oxide
• Inhaled NO is used to dilate
pulmonary vasculature in
persistent pulmonary
hypertension of the newborn
•
•
•
•
Helium
• Pulmonary function testing, treatment
of respiratory obstruction, laser
airway surgery
• As a label in imaging studies
• Mixtures of He and O2 reduce the work of breathing
• Potential as a cytoprotective agent
• For diving at depth
Hydrogen sulfide
• Potential
protection
hypoxia
therapeutic use for
against effects of
Cell-signaling molecule; induces vasodilation
Pulmonary toxicity can occur with levels > 50-100 ppm
Use lowest NO concentration required for therapeutic effect
Monitor blood methemoglobin levels intermittently during inhalation therapy
Drug Facts for Your Personal Formulary: Local Anesthetics
Drugs
Therapeutic Uses or Duration
Clinical Pharmacology and Tips
Lidocaine
• Superficial anesthesia of mucous
membranes
• 2%–10% solution
• ~30 min duration
• Maximal healthy adult dose, ~4 mg/kg
Cocaine
• Superficial anesthesia of mucous
membranes of nose, mouth, ear
• 1%–4% solution
• ~30 min duration
• Maximal healthy adult dose, ~1–3 mg/kg (maximum 400 mg); pediatric
dose, < 1 mg/kg
• Vasoconstriction + anesthesia
Eutectic mixtures, oil, or cream:
Lidocaine (2.5%)/prilocaine (2.5%)
(EMLA)
or
Lidocaine (7%)/tetracaine (7%)
(PLIAGIS)
• Superficial anesthesia of cutaneous
structures
• Effective to ~5-mm depth
• Requires 30–60 min of contact to establish effective anesthesia
• Should not be used on mucous membranes or abraded skin due to
rapid absorption
• Consult package insert for maximum dose
• Superficial anesthesia of cutaneous
structures
• Addition of dilute sodium bicarbonate
(10:1— lidocaine: 8.4% sodium
bicarbonate,anesthesia
~0.75 mg/mL
sodium
• Superficial
of cutaneous
bicarbonate) can lessen pain on injection
structures
• 0.5%–1.0% solution
• Maximal healthy adult dose, ~4 mg/kg
• Addition of epinephrine (5 μg/mL) increases duration of action and
maximal safe lidocaine dose
Topical Anesthesia
CHAPTER 22
Infiltration Anesthesia
Lidocaine
Bupivacaine
• 0.125%–0.25% solution
• Maximal healthy adult dose, ~2 mg/kg
• Addition of epinephrine (5 μg/mL) increases duration of action and
maximal safe bupivacaine dose
Nerve Block Anesthesia • Use with epinephrine-containing test dose • Risk of intravenous injection
Articaine
• 1 h duration
• For dental and periodontal procedures
• 4% solution, typically with epinephrine
• Contains both an amide and ester, so degraded in both plasma and liver
Lidocaine, mepivacaine
• 1–2 h duration
• Addition of epinephrine prolongs duration
and increases maximal safe level of drug
• Identification of blocked nerves (nerve
stimulation or ultrasound) may increase safety
and success of block
• 6-8 h duration
• Longer duration of sensory block with
bupivacaine than with ropivacaine
• Addition of epinephrine prolongs duration
and increases maximal safe level of drug
Safe doses depend on vascularity of tissue, generally:
• Lidocaine: 1%–1.5%, maximal healthy adult dose, ~4 mg/kg
• Mepivacaine: 1%–2%, maximal healthy adult dose, ~7
mg/kg (maximum 400 mg)
Bupivacaine, ropivacaine
Safe doses depend on vascularity of tissue, generally:
• Bupivacaine: 0.25%–0.375%, maximal healthy adult dose, ~2–3
mg/kg (maximum 400 mg)
• Ropivacaine: 0.5%–0.75%, maximal healthy adult dose, ~3–4
mg/kg (maximum 200 mg)
• Infusions through a catheter placed adjacent to the nerve can provide
sustained analgesia
• Identification of blocked nerves (nerve stimulation or ultrasound) may
increase safety and success of block
Epidural Anesthesia • Use with epinephrine-containing test dose • Risk of intravenous injection • Spread of block dependent on dose and
volume injected • Epidural catheter allows repeated dosing • Consider coagulation status of patient
Chloroprocaine
Bupivacaine
•
•
•
•
•
Ropivacaine
• Long duration
Lidocaine
Short duration
Epinephrine prolongs action
Intermediate duration
Epinephrine prolongs action
Long duration
•
•
•
•
•
•
2%–3% solution
Possible increased incidence of postprocedure back pain
2% solution
Maximal healthy adult dose, ~4 mg/kg
0.5% solution
Maximal healthy adult dose, ~2–3 mg/kg
• 0.5%–1.0% solution
• Maximal healthy adult dose, ~2–3 mg/kg
• May have less toxicity than equiefficacious dose of bupivacaine
Spinal Anesthesia • Dose and baricity of anesthetic strongly influence spread • Addition of opioids can prolong analgesia • Consider
coagulation status of patient
Lidocaine
• Short duration (60–90 min)
• ~25–50 mg for perineal and lower extremity surgery
• Association of spinal lidocaine with transient neurological symptoms
Tetracaine
• Long duration (210–240 min)
• Duration increased by epinephrine
• ~5 mg for perineal surgery
• ~10 mg for lower extremity surgery
Bupivacaine
• Long duration (210–240 min)
• ~10 mg for perineal and lower extremity surgery
• 15–20 mg for abdominal surgery
Drug Facts for Your Personal Formulary: Drugs Used to Treat Alcohol
Use Disorder
Drugs
Therapeutic Uses
Clinical Pharmacology and Tips
Disulfiram
• AUD
ALDH inhibitor.
Causes adverse effects from increased acetaldehyde when taken with
alcohol. Poor patient compliance.
Naltrexone
• AUD
• Opioid dependence after opioid
detoxification
Acamprosate
• AUD
Benzodiazepines
•
•
•
•
Fomepizole
• Methanol poisoning
Management of alcohol withdrawal
Anxiety/panic/seizure disorders
Insomnia
Anesthetic premedication
μ-opioid receptor antagonist.
Nausea, liver damage at high
doses.
Available in oral and long-acting injectable formulations.
Contraindicated
in patients
with liver
disease or takingstate.
opioids concurrently.
Unknown mechanism,
may block
hyperglutamatergic
May work best in abstinent alcoholics.
↑ GABA binding at GABAA receptors.
Chlordiazepoxide, lorazepam, diazepam, oxazepam, midazolam, and
clorazepate
are used in the U.S. to manage alcohol withdrawal symptoms.
ADH inhibitor.
Drugs Not FDA Approved for Treatment of AUD But Approved Elsewhere or Found Clinically Useful
Gabapentin
• AUD
• Epileptic seizures and neuropathic pain
Blocks neuronal voltage-gated Ca2+
channels. Reduced alcohol cravings in a
clinical trial.
Partial or full agonist at some central nAChR subtypes.
Varenicline
• ↓ alcohol consumption in clinical trials
• Smoking cessation
Nalmefene
• AUD
• Opioid overdose/dependence
μ- and κ-opioid receptor antagonist.
Approved in Europe for as-needed use to decrease drinking. Advantages
over naltrexone: no liver toxicity, longer duration of action, higher affinity.
Approved for opioid overdose but was discontinued in the U.S.
Baclofen
• AUD
• Spasticity
GABAB receptor agonist, skeletal muscle relaxant, and antispasmodic agent.
Drug Facts for Your Personal Formulary: Diuretics and Agents Regulating
Renal Excretion
Drug
Major Therapeutic Uses
Clinical Pharmacology and Tips
Carbonic Anhydrase Inhibitors
Acetazolamide
Dichlorphenamide
•
•
•
•
•
•
Glaucoma
Epilepsy
Altitude sickness
Diuretic resistance
Metabolic alkalosis
Familial periodic paralysis
• Ineffective as diuretic monotherapy because effects on renal excretion are
self-limiting
• Dichlorphenamide drug of choice for familial periodic paralysis
•
•
•
•
•
•
Elevated intraocular pressure
Elevated intracranial pressure
Dialysis disequilibrium syndrome
Diagnosis of bronchial hyperreactivity
Urologic irrigation
Management of some overdoses
• Frequently used to treat or prevent acute kidney injuries, efficacy unclear
• Expansion of extracellular fluid volume may cause pulmonary edema
Osmotic Diuretics
Mannitol
Inhibitors of Na+-K+-2Cl– Symport (Loop Diuretics; High-Ceiling Diuretics)
Bumetanide
Ethacrynic acid
Furosemide
Torsemide
• Acute pulmonary edema
• Edema associated with congestive heart
failure, liver cirrhosis, chronic kidney
disease, and nephrotic syndrome
• Hyponatremia
• Hypercalcemia
• Hypertension
• Higher doses needed with impaired renal function
• Torsemide may be superior to furosemide in heart failure
• Increased risk of ototoxicity with ethacrynic acid compared to other loop
diuretics
• Risk for hypokalemia and arrhythmia when combined with QT-prolonging drugs
Inhibitors of Na+-Cl– Symport (Thiazide Diuretics)
Thiazide type
Chlorothiazide
Hydrochlorothiazide
Methyclothiazide
Thiazide-like
Chlorthalidone
Indapamide
Metolazone
• Hypertension
• Edema associated with congestive heart
failure, liver cirrhosis, chronic kidney
disease, and nephrotic syndrome
• Nephrogenic diabetes insipidus
• Kidney stones caused by Ca2+ crystals
• Among first choice for treating hypertension
• Thiazide-like have longer half-lives than thiazide-type and thus may be superior
for hypertension
• Higher doses needed for treating edema in patients with impaired renal
function
• Frequently combined with a loop diuretic to effect “sequential blockade” of
tubular transport
• Risk for hypokalemia and arrhythmia when combined with QT-prolonging drugs
• Cause metabolic disturbances (e.g., elevate plasma glucose and LDL)
• May cause severe hyponatremia in some patients
Inhibitors of Renal Epithelial Na+ Channels (K+-Sparing Diuretics)
Amiloride
Triamterene
• Hypertension
• Edema associated with congestive heart
failure, liver cirrhosis, and chronic
kidney disease
• Liddle syndrome
• Lithium-induced nephrogenic diabetes
insipidus
• Low efficacy as monotherapy for edema
• Frequently combined with loop or thiazide diuretics to prevent hypokalemia
and increase diuresis
• Risk of hyperkalemia in renal insufficiency or when combined with
angiotensin- converting enzyme inhibitors or angiotensin-receptor
antagonists
Mineralocorticoid Receptor Antagonists (Aldosterone Antagonists; K+-Sparing Diuretics)
Eplerenone
Spironolactone
• Hypertension
• Edema associated with congestive heart
failure, liver cirrhosis, chronic kidney
disease
• Primary hyperaldosteronism
• Acute myocardial infarction (eplerenone)
• Heart failure (in combination with standard
therapy)
• Polycystic ovary disease
• Endogenous aldosterone levels determine therapeutic efficacy
• Sometimes combined with loop or thiazide diuretics to prevent hypokalemia
and increase diuresis
• Diuretics of choice for treating resistant hypertension due to primary
hyperaldosteronism and for refractory edema due to secondary
aldosteronism (e.g., heart failure, hepatic cirrhosis).
• High risk for hyperkalemia in chronic renal insufficiency
• Eplerenone contraindicated with potent inhibitors of CYP3A4 (e.g.,
ketoconazole, itraconazole)
• Spironolactone active metabolite has long half-life requiring slow
dose adjustments (over days)
Inhibitors of the Nonspecific Cation Channel (Naturietic Peptide Analogues)
Nesiritide
• Hospitalized patients with acutely
decompensated congestive heart failure
(New York Heart Association class IV)
• Intravenous only
• Clinical benefit remains questionable
• High risk of serious hypotension
Vasopressin Receptor Agonist
V1 receptor-agonist
Vasopressin
•
•
•
•
•
Postoperative abdominal distention
Abdominal roentgenography
Bleeding
Cardiac arrest
Hypovolemic shock
V2 receptor-agonist
Desmopressin
(DDAVP)
• Central diabetes insipidus
• Primary nocturnal enuresis
• Prevention of blood loss in patients with
specific bleeding disorders
• Contraindicated in nephrogenic diabetes insipidus
• Not for long-term therapy of central diabetes insipidus
• Use with extreme caution in patients with vascular disease
•
•
•
•
Contraindicated in nephrogenic diabetes insipidus
Drug of choice for central diabetes insipidus
Can be administered orally at high doses
Major adverse effect is water intoxication
Vasopressin Receptor Antagonists
Conivaptan
Tolvaptan
• Treatment of hypervolemic and euvolemic
hyponatremia
• Risk of too rapid correction with serious consequences (osmotic demyelination
syndrome)
• Close monitoring of serum Na+ required
Drug Facts for Your Personal Formulary: Inhibitors of the RAS
Drugs
Therapeutic Uses
Clinical Pharmacology and Tips
Angiotensin-Converting Enzyme Inhibitors • Inhibit the conversion of AngI to AngII
Captopril
Lisinopril
Enalapril
Benazepril
Quinapril
Ramipril
Moexipril
• Inhibit AngII production, thus
lowering arteriolar resistance
• Hypertension
• Acute myocardial infarction
• Congestive heart failure
• Diabetic nephropathy
• Scleroderma renal crisis
Enalaprilat (IV)
Fosinopril
Trandolapril
Perindopril
• Antihypertensive effects potentiated by inhibition of ACE-catalyzed breakdown of
bradykinin
• Antihypertensive effects potentiated by increase in Ang(1–7) levels and activation of
Ang(1–7)/Mas receptor pathway
• Increase PRC and PRA
• Adverse effects include cough in 5%–20% of patients, angioedema, hypotension,
hyperkalemia, skin rash, neutropenia, anemia, fetopathic syndrome
• Contraindicated in patients with renal artery stenosis and should be used with caution in
patients with impaired renal function or hypovolemia
• Should be stopped during pregnancy
• Intravenous administration
• Undergo both hepatic and renal elimination and should be used with caution in
patients with renal or hepatic impairment
Angiotensin Receptor Blockers • Block AT1 receptors
Losartan
Valsartan
Eprosartan
Irbesartan
Candesartan
Olmesartan
Telmisartan
Azilsartan
• Block the vasoconstrictor and
profibrotic effects of AngII by
inhibiting AT1 receptors while
permitting vasodilation through
activation of AT2 receptors
• Hypertension
• Congestive heart failure
• Diabetic nephropathy
• Antihypertensive effects potentiated by activation of the AT2 receptors
• Antihypertensive effects potentiated by ACE2-dependent conversion of AngII to
Ang(1–7) and activation of vasodilation via Ang(1–7)/Mas receptor pathway
• Increase PRC and PRA
• Adverse effects include hyperkalemia and hypotension
• Contraindicated in patients with renal insufficiency
• Should be stopped during pregnancy
Direct Renin Inhibitors • Inhibit renin and thus the conversion of angiotensinogen to AngI
Aliskiren
• Decrease AngI and AngII levels
• Hypertension
• Therapeutic value unclear; no evidence for superiority over ACEIs or ARBs
• Increase PRC but decrease PRA
• Contraindicated in diabetic nephropathy, pregnancy or renal insufficiency
Drug Facts for Your Personal Formulary: Coronary Artery Disease
Drug
Therapeutic Uses
Major Toxicity and Clinical Pearls
Organic Nitrates
Glyceryl trinitrate
(GTN, nitroglycerin)
Isosorbide dinitrate
(ISDN)
Isosorbide mononitrate
(ISMN)
• Angina (sublingual)
• Acute pulmonary edema (IV)
• Acute hypertension (IV)
• NO-mediated vasodilation of large (venous, arterial) > small (resistance) vessels ⇒
preferential preload reduction without steal effect
• Short-acting formulations of GTN or ISDN are standby drugs for all patients with CAD
• First choice for vasospastic angina, along with Ca2+ channel blockers
• Second choice for the prevention of exertional angina (longer-acting formulations)
• Adverse effects: headache, dizziness, postural hypotension, syncope
• Tolerance after > 16 h (leave nitrate-free interval of > 8 h)
• Do not use concurrently with PDE5 inhibitor
Molsidomine
• Angina
•
•
•
•
Inhaled NO
• Pulmonary hypertension in
neonates
• Relatively selective effect on pulmonary vascular bed
• Angina
• Hypertension
• Rate control in atrial
fibrillation
(verapamil, diltiazem)
•
•
•
•
• Angina
• Heart failure
• Hypertension
• Widely used for other
indications
(prevention of arrhythmias,
rate control in atrial fibrillation,
migraine, etc.)
• First choice for prevention of exertional angina
• Only antianginal drug class with proven prognostic benefits in CAD
• Adverse effects: bradycardia, AV block, bronchospasm, peripheral vasoconstriction,
worsening of acute heart failure, depression, worsening of psoriasis
• Polymorphic CYP2D6 metabolism (metoprolol)
• Additional vasodilation (carvedilol, nebivolol)
Ranolazine
• Angina
•
•
•
•
Ivabradine
• Angina
• Heart failure
• Selectively ↓ heart rate by inhibiting HCN currents in SA node
• Second choice in the prevention of exertional angina; approved in patients not
tolerating β blockers or having heart rate > 75 under β blockers
• Unwanted effects: bradycardia, QT prolongation, atrial fibrillation, phosphenes
• Contraindication: combination with diltiazem or verapamil
Nicorandil
• Angina
•
•
•
•
•
Direct NO donor
Second choice for the prevention of angina
Adverse effects same as above
No documented advantage over GTN/ISDN/ISMN
Ca2+ Channel Blockers
Dihydropyridines
Amlodipine
Felodipine
Lercanidipine
Nifedipine
Nitrendipine
Others
Diltiazem
Verapamil
Preferential arterial vasodilation ⇒ afterload reduction
First choice for vasospastic angina (dihydropyridines)
Second choice for preventing exertional angina
Immediate-release nifedipine and short-acting dihydropyridines can cause tachycardia and
hypotension and trigger angina
• Diltiazem and verapamil can ↓ heart rate and AV conduction; should not be used
with β blockers
• CYP3A4-mediated drug interactions with verapamil and diltiazem
• Other unwanted effects: peripheral edema (dihydropyridines), obstipation (verapamil)
β Blockers
Atenolol
Bisoprolol
Carvedilol
Metoprolol
Nadolol
Nebivolol
Many others
Inhibits late Na+ and other cardiac ion currents
Has weak β blocking and metabolic effects
Second choice in the prevention of exertional angina
CYP3A4-dependent metabolism
Dual nitrate-like and IKATP-stimulatory action
Hemodynamic profile between nitrates and dihydropyridines; ↓ afterload more than nitrates
Second choice in the prevention of exertional angina
Adverse effects: hypotension, headache, buccal and GI ulcers
Do not combine with PDE5 inhibitor
Drug Facts for Your Personal Formulary: Coronary Artery Disease (continued)
Drug
Therapeutic Uses
Major Toxicity and Clinical Pearls
• Angina
• Metabolic shift from fatty acid to glycolytic metabolism in the heart
• Second choice in the prevention of exertional angina
• May increase the incidence of Parkinson disease
Trimetazidine
Antiplatelet, Anti-integrin, and Antithrombotic Drugs
Aspirin
P2Y12 receptor
antagonists
(clopidogrel,
prasugrel, ticagrelor
cangrelor [IV])
• Prevention of thrombotic
events
(MI, stroke)
• Acute coronary syndromes
• Prevention of stent
thrombosis
• ↓ Platelet aggregation by inhibiting COX-1–mediated TxA2 production (aspirin) or ADP
receptors (P2Y12 receptor antagonists)
• Oral use only: clopidogrel, prasugrel, ticagrelor
• Irreversible action: aspirin, clopidogrel, prasugrel
• Prodrugs: clopidogrel, prasugrel
• Variable, CYP2C9-dependent metabolism (clopidogrel)
• Withdraw 5–7 days before surgery
• First choice in NSTEMI and STEMI
• Dual platelet inhibition after stenting
Abciximab
Eptifibatide
Tirofiban
• Percutaneous
coronary
interventions
•
•
•
•
Heparin
Low-molecular-weight
heparins (e.g.,
enoxaparine)
• Acute coronary syndromes
• Percutaneous
coronary
interventions
• Endogenous polysaccharide, inhibits thrombin (factor IIa) and factor Xa in an antithrombin
III–dependent manner
• Parenteral use only
• Heparin: short t1/2, complex pharmacokinetics, low bioavailability after subcutaneous.
injection
• Low-molecular-weight heparin: longer half-life, renal excretion; accumulation in renal
insufficiency
• Heparin-induced thrombocytopenia
Fondaparinux
• Acute coronary syndromes
• Percutaneous
coronary
interventions
• Synthetic pentasaccharide, antithrombin III-dependent, factor Xa inhibitor
• Most favorable efficacy-safety ratio
Bivalirudin
Lepirudin
• Percutaneous coronary
interventions (bivalirudin)
• Heparin-induced
thrombocytopenia
(HIT II)
recombinant
lepirudin
• Direct thrombin (factor IIa) inhibitors
• Parenteral use only
• Advantage of bivalirudin over heparin unclear
Antibody (abciximab) or small molecule antagonists at platelet GpIIb/IIIa receptor
Parenteral use only
Highly efficient platelet inhibition
Therapeutic value in the era of highly effective dual platelet inhibition unclear
Resistant Hypertension
Drug Facts for Your Personal Formulary: Antihypertensives
Antihypertensive Drug
Therapeutic Uses
Major Toxicity and Clinical Pearls
Thiazide type
Chlorothiazide
Hydrochlorothiazide
Thiazide-like
Chlorthalidone
Indapamide
Metolazone
• Hypertension
• Edema associated with HF, liver cirrhosis,
chronic kidney disease, nephrotic
syndrome
• Nephrogenic diabetes insipidus
• Kidney stones caused by Ca2+ crystals
• First choice for treating HTN
• Chlorthalidone may be superior to hydrochlorothiazide in HTN
• Lose efficacy at GFR < 30–40 mL/min (exceptions: indapamide,
metolazone)
• Potentiate effect of loop diuretics in HF (sequential tubular
blockade)
• Risk of hypokalemia and arrhythmia when combined with
QT-prolonging drugs
• Combine with ACEI/ARB or K+-sparing diuretic/MRA to prevent
hypokalemia
Loop diuretics
Bumetanide
Furosemide
Torsemide
• Acute pulmonary edema
• Edema associated with HF, liver cirrhosis,
chronic kidney disease, nephrotic
syndrome
• Hyponatremia
• Hypercalcemia
• Hypertension
• Not first choice for treating HTN with normal renal function:
action too short and followed by rebound
• Indicated acutely in malignant HTN and GFR < 30–40 mL/min
• Torsemide may be superior to furosemide in HF
• Risk of hypokalemia and arrhythmia when combined with
QT-prolonging drugs
β1 Blockers
Atenolol
Bisoprolol
Metoprolol
Nebivolol
Many others
• Hypertension
• Heart failure (bisoprolol, metoprolol,
nebivolol)
• Widely used for other indications
(angina, prevention of arrhythmias, rate
control in atrial fibrillation, migraine,
etc.)
• Role as first choice in the treatment of HTN debated; clear
indication for angina, HF, atrial fibrillation, etc.
• Bradycardia and AV block
• Bronchospasm, peripheral vasoconstriction
• Worsening of acute heart failure
• Depression
• Worsening of psoriasis
• Polymorphic CYP2D6 metabolism (metoprolol)
• Nebivolol NO-mediated vasodilation
Nonselective β blocker
Propranolol
•
•
•
•
•
•
•
•
•
•
Diuretics
Sympatholytic Drugs
α1 Blockers
Alfuzosin
Doxazosin
Prazosin
Tamsulosin
Silodosin
α1 and β blockers
Carvedilol
Labetalol
Hypertension
Migraine
Benign prostate hyperplasia
Hypertension
• Hypertension
• Heart failure (carvedilol)
Not first choice for treating HTN
Unwanted effects via blockade of β2 receptors
Not first choice for treating HTN
Higher rate of HF development (?)
Tachyphylaxis
Phenoxybenzamine (irreversible α1/α2 blockade)
used in pheochromocytoma
• β blocker of choice in patients with peripheral artery disease
• Among first choices for treating HF
• Labetalol first choice for HTN in pregnancy
Drug Facts for Your Personal Formulary: Antihypertensives (continued)
Antihypertensive
Drug
Therapeutic Uses
Major Toxicity and Clinical Pearls
Sympatholytic Drugs
Central sympatholytic drugs
Methyldopa
Clonidine/moxonidine
Reserpine
Guanfacine
• Hypertension
• Not first choice in treating HTN
• Fatigue, depression
• Nasal congestion
• Hypertension
• Angina
• Rate control in atrial fibrillation
(verapamil, diltiazem)
• Extended-release, long-acting dihydropyridines among first choice
in HTN
• Diltiazem and verapamil: only if effects on heart rate and AV
conduction are wanted, not in combination with β blockers; beware
CYP3A4-mediated drug interactions
Ca2+ Channel Blockers
CHAPTER 28
Dihydropyridines
Amlodipine, felodipine
Nifedipine
Clevidipine, isradipine
Lercanidipine,
nitrendipine
Others
Diltiazem, verapamil
Inhibitors of the Renin-Angiotensin System
ACE inhibitors
Benazepril
Captopril
Enalapril
Lisinopril
Quinapril
Ramipril
Moexipril
Fosinopril
Trandolapril
Perindopril
• Hypertension
• Heart failure
• Diabetic nephropathy
• Among first choice for treating HTN
• Short-acting captopril only for initiation of therapy; enalapril and
ramipril twice daily
• Cough in 5%–10% of patients, angioedema
• Hypotension, hyperkalemia, skin rash, neutropenia, anemia,
fetopathic syndrome
• Contraindications: pregnancy, renal artery stenosis; caution in
patients with impaired renal function or hypovolemia
• Fosinopril: hepatic and renal elimination, thus eliminated in patients
with HF and low renal perfusion
Angiotensin receptor blockers
Candesartan
Eprosartan
Irbesartan
Losartan
Olmesartan
Telmisartan
Valsartan
Azilsartan
• Hypertension
• Heart failure
• Diabetic nephropathy
•
•
•
•
Direct renin inhibitors
Aliskiren
• Hypertension
• Therapeutic value unclear; no evidence for superiority over ACEIs or
ARBs
• Combination with RAS inhibitors contraindicated
Hydralazine
• Hypertension
• Heart failure in African
Americans (fixed
combination with
ISDN)
• Not first choice in treating HTN
• Adverse effects: headache, nausea, flushing, hypotension,
palpitations, tachycardia, dizziness, and angina pectoris; generally
combined with β blocker to reduce baroreceptor reflex effects
• Use cautiously in patients with CAD
• Lupus syndrome at high doses
Minoxidil
• Hypertension
• Alopecia
•
•
•
•
Sodium nitroprusside
• Hypertensive emergencies
• Only short-term intravenously
• Adverse effect: hypotension
• Cyanide intoxication
Same as ACEI, less cough or angioedema
No evidence for superiority over ACEI
In combination with ACEI, more harm than benefit
Contraindicated in pregnancy
Vasodilators
Reserve antihypertensive in patients with renal insufficiency
Water retention, tachycardia, angina, pericardial effusion
Use in combination with diuretic, β blocker, and RAS inhibitor
Hypertrichosis
Drug Facts for Your Personal Formulary: Heart Failure Drugs
Drug
Therapeutic Uses
Major Toxicity and Clinical Pearls
Inhibitors of the Renin-Angiotensin System
ACE Inhibitors
Benazepril
Captopril
Enalapril
Lisinopril
Quinapril
Ramipril
• Heart failure
• Hypertension
• Diabetic nephropathy
Fosinopril
Trandolapril
Perindopril
Angiotensin Receptor
Blockers
Candesartan
Eprosartan
Irbesartan
Losartan
Olmesartan
Telmisartan
Valsartan
• First choice in treating heart failure
• Short-acting captopril only for initiation of therapy; enalapril requires twice-daily
dosing
• Cough in 5%–10% of patients, angioedema
• Hypotension, hyperkalemia, skin rash, neutropenia, anemia, fetopathic syndrome
• Contraindicated in patients with renal artery stenosis; caution in patients with impaired
renal function or hypovolemia
• Both hepatic and renal elimination, caution in patients with renal or hepatic
impairment
• Hypertension
• Heart failure
• Diabetic nephropathy
•
•
•
•
Only in cases of intolerance to ACEI
Unwanted effects as ACEI, but no cough or angioedema
No evidence for superiority over ACEI
In combination with ACEI more harm than benefit
• Heart failure
• Hypertension
• Widely used for angina,
prevention of arrhythmias,
rate control in atrial
fibrillation, migraine
• First choice in the treatment of heart failure
• Start low (1/10 target dose), go slow (2- to 4-weekly doubling)
• Adverse effects: bradycardia, AV block, bronchospasm, peripheral vasoconstriction,
worsening of acute heart failure, depression, worsening of psorias
• Polymorphic CYP2D6 metabolism (metoprolol)
β Blockers
Bisoprolol
Carvedilol
Metoprolol
Nebivolol
Mineralocorticoid Receptor Antagonists
Eplerenone
Spironolactone
• Heart failure
• Hypertension
• Hyperaldosteronism,
hypokalemia, ascites
•
•
•
•
First choice in treating symptomatic heart failure
Low doses (25–50 mg)
Most serious side effect is hyperkalemia
Spironolactone causes painful breast swelling and impotence in men, dysmenorrhea in
women due to nonselective binding to sex hormone receptors
• Heart failure
•
•
•
•
Superior to the ACEI enalapril
May become first choice in treating heart failure
↓ Degradation of natriuretic peptides, ↑ their beneficial actions
Hypotension
• Edema associated with
congestive heart failure, liver
cirrhosis, chronic kidney
disease, and nephrotic
syndrome
• Hypertension
• Nephrogenic diabetes insipidus
• Kidney stones caused by Ca2+
crystals
•
•
•
•
Symptomatic treatment of milder forms of heart failure
Loose efficacy at GFR < 30–40 mL/min (exception indapamide and metolazone)
Potentiate effect of loop diuretics in severe heart failure (sequential tubulus blockade)
Risk for hypokalemia and arrhythmia when combined with QT-prolonging drugs
Neprilysin Inhibitor/Angiotensin Receptor Blocker
Sacubitril/valsartan
Diuretics
Thiazide Type
Chlorothiazide
Hydrochlorothiazide
Thiazide-like
Chlorthalidone
Indapamide
Metolazone
Drug Facts for Your Personal Formulary: Heart Failure Drugs (continued)
Drug
Therapeutic Uses
Major Toxicity and Clinical Pearls
Loop Diuretics
Bumetanide
Furosemide
Torasemide
• Acute pulmonary edema
(intravenous)
• Edema associated with congestive
heart failure, liver cirrhosis, chronic
kidney disease, and nephrotic
syndrome
• Hyponatremia
• Hypercalcemia
• Hypertension with renal
insufficiency
•
•
•
•
• Heart failure in African Americans
• Approved only for African Americans
• Adverse effects: headache, nausea, flushing, hypotension, palpitations, tachycardia,
dizziness, angina pectoris; ⇒ use in combination with β blocker
• Compliance problems
• Lupus syndrome
• Heart failure
•
•
•
•
•
•
• Heart failure
• Not first choice in treating heart failure
• May exert benefits in patients not tolerating β blockers or having heart rate > 75 under
β blockers
• Unwanted effects: bradycardia, QT prolongation, atrial fibrillation, phosphenes
Symptomatic treatment of severe heart failure and acute decompensation
Often required in treating severe chronic heart failure, twice-daily dosing or more
Torasemide may be superior to furosemide in heart failure
Risk for hypokalemia and arrhythmia when combined with QT-prolonging drugs
Vasodilators
ISDN/hydralazine
CHAPTER 29
Positive Inotropes
Digoxin
Digitoxin
Not first choice in treating heart failure
May exert benefits in heart failure and atrial fibrillation
Low therapeutic index: proarrhythmic, nausea, diarrhea, visual disturbances
Digoxin kidney dependent, digitoxin not
Half-life 1.5 (digoxin) or 7 days (digitoxin)
Plasma concentration: 0.5–0.8 ng/mL (digoxin) or 10–25 ng/mL (digitoxin)
Heart Rate Reduction
Ivabradine
Intravenous Vasodilators: Acute decompensated heart failure
Nitroglycerin
Sodium nitroprusside
• Acute decompensated heart failure
• May ↑ cardiac output in acute congestion (↑ filling pressure and dilation) via ↓
preload and afterload
• NO releaser, stimulates soluble guanylyl cyclase
• Avoid if systolic blood pressure < 110 mmHg
• Prognostic benefit unclear
Neseritide
• Acute decompensated heart failure
•
•
•
•
Recombinant human BNP
Stimulates membrane-bound guanylyl cyclase
May ↑ cardiac output via ↓ preload and afterload
Therapeutic benefit unclear
Intravenous Positive Inotropes: Acutely decompensated heart failure
Dobutamine
Dopamine
Epinephrine
Norepinephrine
• Acute decompensated heart failure
• β1 receptor-mediated stimulation of cardiac output and, depending on drug, complex
vascular actions
• Last option in patients with systolic blood pressure <85 mmHg
• ↑ Cardiac energy consumption and risk of arrhythmia
• Use of catecholamines correlates with poor prognosis; use lowest possible doses for
shortest possible time
• Dobutamine causes less tachycardia than EPI and less afterload increase than NE
• Role of low-dose dopamine unclear
Enoximone
Milrinone
• Acute decompensated heart failure
• PDE3/4 inhibitors, ↑ cellular cAMP
• ↑ Cardiac output and dilate blood vessels (“inodilator”)
• May be used in patients on β blockers and with high peripheral and pulmonary arterial
resistance
• Blood pressure decrease is dose limiting
• Risks and prognostic effects: same as catecholamines (above)
Levosimendan
• Acute decompensated heart failure
• Combined Ca2+ sensitizer (troponin C binding) and PDE3 inhibitor
• ↑ Cardiac output and ↓ vascular resistance (“inodilator”)
• Advantages over catecholamines or simple PDE inhibitors unclear
Drug Facts for Your Personal Formulary: Antiarrhythmic Agents
Antiarrhythmic
Drug
Therapeutic Uses
Major Toxicity and Clinical Pearls
Class IA: Na+ Channel Blockers • Slow to intermediate off rate • Concomitant class III action (prolong QT)
Procainamide
• Acute treatment of AF, VT, and VF
• Chronic treatment to prevent
AF, VT, and VF
• 40% of patients discontinue within 6 months of therapy due to side effects: hypotension
(especially from intravenous use), nausea
• QT prolongation and torsades de pointes due to accumulation of active N-acetyl
metabolite
• Lupus-like syndrome (25%–50% with chronic use), especially in genetic slow acetylators
• Oral drug no longer widely available
Quinidine
• Chronic treatment to prevent
AF, VT, and VF
• Diarrhea (30%–50% of patients); diarrhea-induced hypokalemia may potentiate torsades
de pointes
• Marked QT prolongation and high risk (~1%–5%) of torsades de pointes at therapeutic or
subtherapeutic concentrations
• Immune thrombocytopenia (~1%)
• Cinchonism: tinnitus, flushing, blurred vision, dizziness, diarrhea
• Potent inhibitor of CYP2D6 and ABCB1: altered effects of digitalis, many antidepressants,
and others
Disopyramide
• Chronic treatment to prevent
AF, VT, and VF
• Anticholinergic effects (dry eyes, urinary retention, constipation)
• Long QT (torsades de pointes)
• Depression of contractility can precipitate or worsen heart failure; paradoxically, this can be
useful in hypertrophic cardiomyopathy to reduce outflow tract obstruction
Class IB: Na+ Channel Blockers • Fast off rate • Little effect on ECG
Lidocaine
• Acute treatment of VT and VF
• CNS: seizures and tinnitus
• CNS: tremor, hallucinations, drowsiness, coma
Mexiletine
• Chronic treatment to prevent
VT and VF
• Tremor and nausea
Class IC: Na+ Channel Blockers • Slow off rate • Prolong PR and broaden QRS intervals
Flecainide
• Chronic treatment to prevent
PSVT, AF, VT, and VF in the absence
of structural heart disease
• Available in some countries for
intravenous use in PSVT, AF
• Useful in CPVT uncontrolled by
β-blockers
• Much better tolerated than class IA or IB agents
• Risk of severe proarrhythmia in patients with structural heart disease; increased mortality
in patients with myocardial infarction (CAST)
• Blurred vision
• Can worsen heart failure
Class IC: Na+ Channel Blockers • Slow off rate • Prolong PR and broaden QRS intervals (continued)
Propafenone
• Chronic treatment to prevent
PSVT, AF, VT, and VF in the absence of
structural heart disease
• Available in some countries for
intravenous use in PSVT, AF
• Alternative to flecainide
for CPVT
• Also has β adrenergic blocking effects (worsening of heart failure and
bronchospasm), especially prominent in CYP2D6 poor metabolizers
• Risk of severe proarrhythmia in patients with structural heart disease
Nadolol
Propranolol
Metoprolol
Many others
• Chronic treatment to prevent
arrhythmias in congenital
LQTS and CPVT
• Rate control in AF
• Widely used for other indications
(angina, hypertension, migraine, etc.)
• β Adrenergic blocking effects (worsening of heart failure, bradycardia,
bronchospasm)
• Nadolol preferred by many for LQTS and CPVT
Esmolol
• Acute treatment to control rate in AF
• Ultrashort t1/2, intravenous use only
Class II: β Blockers
Class III: K+ Channel Blocker • Increase refractory period (prolong QT)
Amiodarone
• Drug of choice for acute treatment
of VT and VF and to slow
ventricular rate and convert AF
• Chronic treatment to prevent
AF, VT, and VF
• Hypotension, depressed ventricular function and torsades de pointes (rare) with
intravenous administration
• Pulmonary fibrosis with chronic therapy, which can be fatal (requires periodic
monitoring of lung function)
• Many other adverse effects: corneal microdeposits, hepatotoxicity,
neuropathies, photosensitivity, thyroid dysfunction
• Note: tissue half-life of several months
• Inhibitor of many drug-metabolizing and transport systems, with high potential
for drug interactions
Dronedarone
• Chronic treatment to
prevent AF
• Amiodarone analogue with lower efficacy than amiodarone
• GI disturbances, risk for fatal hepatotoxicity
• Increases mortality in patients with severe heart failure
Sotalol
• Chronic treatment to prevent
AF, VT, and VF
• Also has β adrenergic blocking effects
• High risk (~1%–5%) of torsades de pointes
Dofetilide
• Chronic treatment to
prevent AF
• Few adverse effects except high risk (~1%–5%) of torsades de pointes
Ibutilide
• Acute treatment to convert AF
• High risk (~1%–5%) of torsades de pointes
Class IV: Ca2+ Channel Blockers • Nondihydropyridine • Inhibit SA and AV nodes • Prolong PR
Diltiazem, Verapamil
• Acute intravenous use to convert
PSVT and for rate control in AF
• Chronic treatment to prevent
PSVT and control rate in AF
•
•
•
•
Hypotension (intravenous)
Sinus bradycardia or AV block especially in combination with β-blockers
Constipation
Worsening of heart failure
•
•
•
•
Short t1/2 (<5 sec)
Transient asystole
Transient dyspnea
Transient atrial fibrillation (rare)
Antiarrhythmic Drugs With Miscellaneous Mechanisms
Adenosine
(activates A receptors)
Drug of choice for acute treatment
PSVT
MgSO4
• Acute treatment of torsades
de pointes
Digoxin
(Na+-K+–ATPase inhibitor)
• Ventricular rate control in atrial
fibrillation
• Modest positive inotropic effect
Bibliography
• Adverse effects common and include GI symptoms, visual/cognitive
dysfunction, and arrhythmias, typically supraventricular arrhythmias with
heart block or atrial or ventricular extrasystoles
• Severe toxicities (e.g., with overdose) can be treated with antibody
• Probably mortality neutral
Drug Facts for Your Personal Formulary: Pulmonary Hypertension
Therapeutics
Drug
Indication
Clinical Pharmacology and Tips
cGMP Signaling Modulators: PDE5 Inhibitors
Sildenafil
Tadalafil
Vardenafil
• First-line therapy for moderate PAH
(functional class II-III)
• Oral administration
• Avoid nitrates and α adrenergic antagonists due to hypotension
• Major side effects: epistaxis, headache, dyspepsia, vision or hearing loss (not sildenafil),
flushing, insomnia, dyspnea, priapism
• Vardenafil, currently not recommended due to limited evidence for efficacy in PAH
cGMP Signaling Modulators: sGC Stimulator
Riociguat
• First-line therapy for moderate PAH
(functional class II-III)
• Oral administration
• Efficacy confirmed in PAH patients and CTEPH patients
• Side effects: headache, dyspepsia, edema, nausea, dizziness, syncope
IP Receptor Agonists: Prostacyclin and Prostacyclin Analogs
Epoprostenol
• First-line therapy for severe PAH
(functional class IV)
• Administration by continuous IV infusion
• Major side effects: jaw pain, hypotension, myalgia, flushing, nausea, vomiting,
dizziness
Short half-life requires immediate medical attention to pump failure
Treprostinil
• Same as epoprostenol
•
•
•
•
Available as IV, SC, inhaled and oral preps
Longer half-life than epoprostenol with similar side effects
Local adverse effects of SC dose may improve over time
Oral administration to be used as monotherapy only
IP Receptor Agonists: Prostacyclin and Prostacyclin Analogs (continued)
Iloprost
• Alternative for epoprostenol in
combination therapy for severe
PAH (function class IV)
• Inhaled administration, at least 2 h apart
• Side effects include flushing, hypotension, headache, nausea, throat irritation, cough,
insomnia
Selexipag
• Alternative for eprostenol in
combination therapy for severe
PAH (functional class IV)
• Oral administration
• Selective PGI2 receptor agonist
• Side effects include headache, jaw pain, nausea, diarrhea
Endothelin Receptor Antagonists: Oral administration, teratogenic
Bosentan
• First-line therapy for moderate PAH
(functional class II-III)
• Monitor liver function and hemoglobin levels
• Metabolized by CYP2C9 and CYP3A4
• Side effects: liver impairment, palpitations, itching, edema, anemia, respiratory
infections
Ambrisentan
• First-line therapy for moderate PAH
(functional class II-III)
• Side effects: edema, nasal congestion, constipation, flushing, palpitations,
abdominal pain
• Cyclosporin coadministration increases drug levels
• Low risk for liver toxicity
Macitentan
• First-line therapy for moderate PAH
(functional class II-III)
• Metabolized by CYP3A4
• Side effects include nasopharyngitis, headache, anemia
• Liver function and hemoglobin testing recommended prior to therapy
L-type Ca2+ Channel Blockers
Nifedipine
(long acting)
Amlodipine
Diltiazem
• Use only in PAH patients with positive
vasodilator testing
• Oral administration
• Side effects include edema, fatigue, hypotension
• Diltiazem: significant negative chronotropic and inotropic effects; avoid in bradycardia
.
Drug Facts for Your Personal Formulary: Agents That Modify Blood
Coagulation
Drugs
Therapeutic Uses
Clinical Pharmacology and Tips
Unfractionated Heparin
Heparin
•
•
•
•
•
Prophylaxis/treatment of venous thromboembolism
Acute coronary syndrome
Percutaneous coronary intervention
Cardiopulmonary bypass surgery
Disseminated intravascular coagulation
•
•
•
•
Administered SC 2–3 times daily for thromboprophylaxis
Administered IV for immediate onset of action with aPTT monitoring
Can be used in renal impairment
Can be used in pregnancy
• Prophylaxis against venous thrombosis
• Initial treatment of venous thromboembolism
• Maintenance treatment in patients with cancerassociated venous thromboembolism
• Acute coronary syndrome
•
•
•
•
Administered SC once or twice daily
Routine anti-factor Xa monitoring not required
Dosage adjustment required when CrCL < 30 mL/min
Can be used in pregnancy
•
•
•
•
• Once-daily SC injection
• Lower dose used for thromboprophylaxis and in acute coronary
syndrome
• Contraindicated if CrCL < 30 mL/min
• Use in pregnancy less established than for low-molecular-weight
heparin
• Routine anti-factor Xa monitoring not required
Low-Molecular-Weight Heparin
Enoxaparin
Dalteparin
Tinzaparin
(not in the
U.S.)
Fondaparinux
Fondaparinux
Prophylaxis against venous thromboembolism
Initial treatment of venous thromboembolism
Heparin-induced thrombocytopenia
Acute coronary syndrome in some countries
Other Anticoagulants
Desirudin
• Thromboprophylaxis after hip arthroplasty
• Twice-daily SC injection
• Dosage adjustment required with renal impairment
Bivalirudin
• Percutaneous coronary intervention
• Heparin-induced thrombocytopenia
• Administered IV
• ACT or aPTT monitoring
• Requires dose reduction with renal impairment
Argatroban
• Heparin-induced thrombocytopenia
• Hepatic metabolism
• Can be used in renal impairment
• Increases INR, which can complicate transition to warfarin
Vitamin K Antagonist
Warfarin
• Treatment of venous thromboembolism in tandem with
parenteral anticoagulation
• Secondary prevention of venous thromboembolism
• Prevention of stroke in atrial fibrillation
• Prevention of stroke in patient with mechanical heart
valves or ventricular assist devices
•
•
•
•
•
•
•
Oral vitamin K antagonist
Narrow therapeutic index
Requires regular INR monitoring
Multiple drug interactions
Dietary vitamin K interactions
Can be used in renal failure
Contraindicated in pregnancy
•
•
•
•
•
Fixed twice-daily oral dosing (once daily if used for thromboprophylaxis)
Reduce the dose with CrCL 15–30 mL/min
Contraindicated if CrCL < 15 mL/min
Use with caution in patients with recent bleeding, especially GI bleeding
Can be reversed with idarucizumab
Direct Oral Thrombin Inhibitor
Dabigatran etexilate
• Treatment of acute venous thromboembolism after at
least 5 days of parenteral anticoagulation
• Secondary prevention of venous thromboembolism
• Prevention of stroke in atrial fibrillation
• Thromboprophylaxis after hip or knee arthroplasty
Direct Oral Factor Xa Inhibitors
Rivaroxaban
•
•
•
•
•
Treatment of acute venous thromboembolism
Secondary prevention of venous thromboembolism
Prevention of stroke in atrial fibrillation
Thromboprophylaxis after hip or knee arthroplasty
Prevention of recurrent ischemia in stabilized acute
coronary syndrome patients (not in North America)
• Fixed oral dosing (once daily with the exception of initial treatment of
venous thromboembolism, which starts with twice-daily dosing for 21
days and once daily thereafter, or secondary prevention after acute
coronary syndrome where the drug is given twice daily)
• Avoid in patients with renal/hepatic dysfunction
• Use with caution in patients with recent bleeding, especially GI bleeding
Apixaban
•
•
•
•
Treatment of acute venous thromboembolism
Secondary prevention of venous thromboembolism
Prevention of stroke in atrial fibrillation
Thromboprophylaxis after hip or knee arthroplasty
• Fixed oral dosing (twice daily, higher dose for the first 7 days for acute
venous thromboembolism)
• Reduce dose for stroke prophylaxis if any two of age > 80 years, body
weight < 60 kg, or serum creatinine ≥ 1.5 mg/dL
• Use with caution in patients with recent bleeding, especially GI bleeding
Edoxaban
• Treatment of acute venous thromboembolism after at
least 5 days of parenteral anticoagulation
• Secondary prevention of venous thromboembolism
• Prevention of stroke in atrial fibrillation
• Fixed once-daily dosing
• Reduce the dose if any of CrCL 15–50 mL/min, body weight < 60 kg, or
concomitant potent P-glycoprotein inhibitor
• Not recommended for patients with CrCL < 15 mL/min
• Contraindicated if CrCL > 95 mL/min
• Use with caution in patients with recent bleeding, especially GI bleeding
Reversal Agents for Direct Oral Anticoagulants
Idarucizumab
• Reversal of dabigatran
• Humanized Fab fragment against dabigatran
• Bolus IV administration
• Rapid and complete reversal
Andexanet alfa
• Reversal of rivaroxaban, apixaban, or edoxaban
•
•
•
•
Ciraparantag
• Reversal of dabigatran, rivaroxaban, apixaban, or
edoxaban
• Synthetic small molecule
• Binds target drugs
• In phase 2 evaluation
Recombinant analogue of factor Xa
Acts as a decoy for oral factor Xa inhibitors
Given as IV bolus followed by 2-h IV infusion
In phase 3 evaluation
Fibrinolytic Drugs
Alteplase
• Thrombolysis in acute ischemic stroke, massive
pulmonary embolism, or myocardial infarction
• IV bolus followed by an infusion
• Risk of major bleeding, including intracranial bleeding
Reteplase
• Thrombolysis in myocardial infarction
• Two IV boluses
• Risk of major bleeding, including intracranial bleeding
Tenecteplase
• Thrombolysis in pulmonary embolism and myocardial
infarction
• Single IV bolus
• Risk of major bleeding, including intracranial bleeding
Inhibitors of Fibrinolysis
ε-Aminocaproic acid
• Reduce intraoperative bleeding
• Inhibits plasmin-mediated degradation of fibrin
• IV infusion
Tranexamic acid
•
•
•
•
•
• Inhibits plasmin-mediated degradation of fibrin
• Available in oral or IV form
• Given orally in patients undergoing dental procedures or in women with
menorrhagia and IV in patients with major trauma or undergoing major
orthopedic surgery
Major head injury
Major trauma resuscitation
Reduce intraoperative bleeding
Topical application for dental bleeding and epistaxis
Menorrhagia
Drug Facts for Your Personal Formulary: Agents That Modify Blood
Coagulation (continued)
Drugs
Therapeutic Uses
Clinical Pharmacology and Tips
Aspirin
• Acute myocardial infarction or acute ischemic stroke
• Secondary prevention in patients with stroke, coronary
artery disease, or peripheral artery disease
• COX-1 inhibitor (selectivity > 100x over COX-2)
• Antithrombotic effect achieved with low doses (<100 mg daily)
• Reduced toxicity with lower doses
Dipyridamole
• Secondary prevention of stroke when combined with
aspirin
• Available as a fixed-dose combined tablet with aspirin
Clopidogrel
• Acute coronary syndrome
• Secondary prevention in patients with myocardial
infarction, stroke, or peripheral artery disease
• Irreversible inhibitor of P2Y12
• Given once daily
• Variable response because common genetic polymorphisms attenuate
metabolic activation
• Proton pump inhibitors reduce conversion to active metabolite
Prasugrel
• After coronary intervention for acute coronary
syndrome
• Irreversible inhibitor of P2Y12
• Given once daily
• More predictable inhibition of ADP-induced platelet activation than
clopidogrel because of more efficient metabolic activation
• Contraindicated in patients with cerebrovascular disease, prior intracranial
bleed, or > 75 years of age
• Reduce dose in patients weighing < 60 kg
• Higher bleeding risk than clopidogrel
Ticagrelor
• Acute coronary syndrome with or without coronary
intervention
•
•
•
•
•
Cangrelor
• Percutaneous coronary intervention
• P2Y12 inhibitor
• Rapid onset and offset IV agent
• Higher bleeding risk than clopidogrel
• Coadministration of clopidogrel or prasugrel with cangrelor will have no
antiplatelet effect
Vorapaxar
• Secondary prevention in patients with a history of
myocardial infarction or peripheral artery disease
• PAR-1 antagonist
• Contraindicated in patients with cerebrovascular disease or prior intracranial
bleed
Abciximab
• Coronary intervention for acute coronary syndrome
• Glycoprotein IIb/IIIa antagonist
• Up to 10% bleeding risk
• Can cause thrombocytopenia
Eptifibatide
• Coronary intervention for acute coronary syndrome
•
•
•
•
Tirofiban
• Coronary intervention for acute coronary syndrome
• Glycoprotein IIb/IIIa antagonist
• Up to 10% bleeding risk
• Reduce dose if CrCL ≤ 60 mL/min
Antiplatelet Drugs
Reversible inhibitor of P2Y12
Given twice daily
Does not require metabolic activation
Higher bleeding risk than clopidogrel
Contraindicated in patients with a history of intracranial bleeding
Glycoprotein IIb/IIIa antagonist
Up to 10% bleeding risk
Can cause thrombocytopenia
Contraindicated in renal failure
Vitamin Supplementation
Vitamin K
•
•
•
•
Reversal of warfarin
Hypoproteinemia of the newborn
Biliary obstruction
Malnutrition
• Oral or SC administration preferred
• Can be given by slow IV infusion but high risk of adverse events
Drug Facts for Your Personal Formulary: Therapy for Dyslipidemias
Drugs
Therapeutic Uses
Clinical Pharmacology and Tips
HMG-CoA Reductase Inhibitors (Statins)
Atorvastatin
Simvastatin
Rosuvastatin
Lovastatin
Pravastatin
Fluvastatin
Pitavastatin
• The most effective and
best- tolerated agents
to treat dyslipidemias,
especially elevated
LDL-C
• Safety of statins during pregnancy has not been established. Women wishing to conceive
and nursing mothers should not take statins. During their childbearing years, women taking
statins should use highly effective contraception.
• Hepatotoxicity (one case per million person-years of use); measure liver enzymes (ALT) at
baseline and thereafter only when clinically indicated.
• Myopathy and rhabdomyolysis (one death per million prescriptions (30-day supply); risk ↑
with dose and concomitant administration of drugs that interfere with statin catabolism or
hepatic uptake.
Bile Acid–Binding Resins (Bile Acid Sequestrants)
Cholestyramine
Colestipol
Colesevelam
• Probably safest lipid-lowering
drugs (not absorbed
systemically)
• Recommended for patients
11–20 years of age
• Common GI side effects: bloating, dyspepsia, constipation.
• Cholestyramine and colestipol bind and interfere with absorption of many drugs; administer
all other drugs either 1 h before or 3–4 h after dose of a bile acid resin.
• Severe hypertriglyceridemia is a contraindication to the use of cholestyramine and colestipol;
they ↑ triglyceride levels.
• Favorably affects all lipid
parameters; most effective
agent for increasing HDL-C;
also lowers triglycerides
and reduces LDL-C
•
•
•
•
•
• Usual drugs of choice for
treating chylomicronemia,
hyperlipidemia with type III
hyperlipoproteinemia,
severe hypertriglyceridemia
(triglycerides > 1000 mg/dL)
•
•
•
•
•
Nicotinic Acid
Niacin
Should not be taken by pregnant women.
Flushing, pruritus, and dyspepsia limit patient compliance.
Rarer episodes of nausea, vomiting, and diarrhea.
Hepatotoxicity, manifested as ↑ serum transaminases.
Hyperglycemia and niacin-induced insulin resistance; in patients with known or suspected
diabetes, blood glucose levels should be monitored at least weekly until stable.
• Concurrent use of niacin and a statin can cause myopathy and is contraindicated.
• Contraindicated if any history of peptic ulcer disease.
• Gout is a relative contraindication.
Fibric Acid (Fibrates)
Gemfibrozil
Fenofibrate
Not in the U.S.:
Ciprofibrate
Bezafibrate
GI side effects occur in up to 5% of patients.
Fibrates should not be used by children or pregnant women.
A myopathy syndrome may occur in subjects taking clofibrate, gemfibrozil, or fenofibrate.
The FDA has withdrawn approval for coadministration of fibrates with statins.
Renal failure and hepatic dysfunction are relative contraindications to the use of fibrates.
618
Drug Facts for Your Personal Formulary: Therapy for Dyslipidemias (continued)
Drugs
Therapeutic Uses
Clinical Pharmacology and Tips
Cholesterol Absorption Inhibitor
Ezetimibe
• Monotherapy in patients with ↑
LDL-C who are statin intolerant
• Combination with statin ⇒
additive reductions in LDL-C
• Bile-acid sequestrants inhibit absorption of ezetimibe; avoid concurrent use.
• Combination products containing ezetimibe and a statin should not be used by
women in childbearing years in the absence of contraception.
• Generally well tolerated agent.
PCSK9 Inhibitors (Monoclonal Antibodies)
Alirocumab
Evolocumab
• Adjunct to diet and maximally
tolerated statin therapy for adults with
hoFH, heFH or clinical ASCVD who
require additional lowering of LDL-C
• Hypersensitivity or injection site reactions are possible.
• Most effective agents at reducing LDL-C.
• Like other monoclonal antibodies, influenza-like symptoms, nasopharyngitis, upper
respiratory infections may occur.
• Used in addition to maximally tolerated statin doses (complementary mechanism;
see Figure 33–4).
Omega-3 Fatty Acid Ethyl Esters
Omega-3 fatty acids
(EPA
and DHA)
• Adjunct for treating severe
hypertriglyceridemia (triglycerides
> 1000 mg/dL)
• Adverse effects may include arthralgia, nausea, fishy burps, dyspepsia, and increased
LDL.
• Since omega-3-fatty acids may prolong bleeding time, patients taking
anticoagulants should be monitored.
Inhibitor of Apo B-100 Synthesis (Antisense Oligonucleotide)
Mipomersen
• Used as an adjunct to lipidlowering agents and diet in
patients with hoFH
• Common adverse effects include injection site reactions, flu-like symptoms,
headache, and
elevation of liver enzymes.
• The agent is used under an FDA risk evaluation and mitigation strategy.
Inhibitor of Liver Microsomal Triglyceride Transfer Protein
Lomitapide
• Used as an adjunct to diet for
lowering LDL-C, total cholesterol, apo
B, and non–HDL-C in patients with
hoFH
• In patients with hoFH, treatment can reduce LDL-C by 40%–50%.
• Adverse effects include GI symptoms, elevation of serum liver enzymes, and
increased liver fat in most patients.
• The agent is used under an FDA risk evaluation and mitigation strategy.
Drug Facts for Your Personal Formulary: Immunosuppressants and Tolerogens
Drugs
Therapeutic Uses
Clinical Pharmacology and Tips
• Prednisone
The liver converts
prednisone to
prednisolone.
Prevent and treat transplant rejection, treat
GVHD in bone marrow transplant, autoimmune
disease, rheumatoid arthritis, ulcerative colitis,
multiple sclerosis, systemic lupus
erythematosus
• Broad effects on cellular immunity
• Affects transcription of many genes; ↓ NF-κB activation, ↓ pro-inflammatory
cytokines IL-1 and IL-6
• ↓ T-cell proliferation, cytotoxic T-lymphocyte activation and neutrophil and
monocyte function
• Can cause ↑ blood glucose, hypertension, Cushingoid habitus, ↑ weight, ↑ risk of
infection, osteoporosis, glaucoma, cataracts, depression, anxiety, psychosis
• Long-term treatment ⇒ adrenal suppression; withdraw slowly on alternate days
• Prednisolone
Rheumatoid arthritis, uveitis, ulcerative colitis,
multiple sclerosis, vasculitis, sarcoidosis,
systemic lupus erythematosus
• As above
• Methylprednisolone
Systemic lupus erythematosus, multiple sclerosis
• As above
• Dexamethasone
Rheumatoid arthritis, idiopathic
thrombocytopenic purpura
• As above
• Cyclosporine
Transplant rejection prophylaxis, transplant
rejection rescue therapy, rheumatoid
arthritis, psoriasis and other skin diseases,
xerophthalmia
• Use algorithms to delay dosing until renal function OK in kidney transplant
patients
• Monitor Cp to avoid side effects
• Side effects: tremor, hallucinations, drowsiness, coma, nephrotoxicity,
hypertension, hirsutism, hyperlipidemia, gum hyperplasia
• Metabolized by CYP3A ⇒ drug interactions
• Severe interactions with antiarrhythmics
• Tacrolimus
Transplant rejection prophylaxis,
transplant rejection rescue therapy
•
•
•
•
Glucocorticoids
Calcineurin Inhibitors
GI absorption is incomplete and variable
Side effects include nephrotoxicity, neurotoxicity, GI complaints, and hypertension
Glucose intolerance and diabetes mellitus
Monitor blood levels to avoid nephrotoxicity
Antiproliferative and Antimetabolic Agents
• Azathioprine
Purine metabolism inhibitor, adjunct for
prevention of organ transplant rejection,
rheumatoid arthritis
• Renal clearance has little effect on efficacy or toxicity
• Side effects include bone marrow suppression (leukopenia > thrombocytopenia >
anemia)
• Susceptibility to infections, hepatotoxicity, alopecia, GI toxicity
• Avoid allopurinol
• Mycophenolate
mofetil
Purine metabolism inhibitor, prophylaxis of
transplant rejection, used off label for systemic
lupus erythematosus, multiple sclerosis,
sarcoidosis
• Side effects include GI (diarrhea and vomiting) and hematologic (leukopenia,
pure red cell aplasia) problems
• Contraindicated in pregnancy
• Sirolimus
mTOR inhibitor, prophylaxis of organ
transplant rejection, incorporated into stents
to inhibit occlusion
•
•
•
•
•
•
• Everolimus
mTOR inhibitor, astrocytoma, breast cancer,
kidney and liver transplant reception
prophylaxis, pancreatic neuroendocrine tumor,
renal angiomyolipoma, renal cell cancer
• Pharmacokinetics distinct from sirolimus
• Toxicity similar to sirolimus
• Temsirolimus
mTOR inhibitor
Monitor blood levels
Hyperlipidemia
Anemia, leukopenia, thrombocytopenia
GI effects, mouth ulcers, hyperkalemia
Anticancer effects
Metabolized by CYP3A; requires close attention to drug interactions
T-cell costimulatory blocker
• Belatacept
Prevention of renal transplant rejection
• Due to an increased risk of post-transplant lymphoproliferative disorder
predominantly involving the CNS, progressive multifocal leukoencephalopathy,
and serious CNS infections, administration of higher than the recommended
doses or more frequent dosing is NOT recommended.
CHAPTER 35
Drug Facts for Your Personal Formulary: Immunosuppressants and
Tolerogens
Drugs
Therapeutic Uses
Clinical Pharmacology and Tips
(continued)
Antibodies
Antilymphocyte
globulin
• ATGAM
• Thymoglobulin
Prevention and treatment of organ
transplant rejection, aplastic
anemia
• Contains antibodies against numerous T-cell surface molecules
• Can elicit fever, chills, and potentially hypotension; use premedication:
steroid/acetaminophen/antihistamine
• Serum sickness, glomerulonephritis, anaphylaxis: rare
• Watch for leukopenia, thrombocytopenia
Muromonab-CD3
In trials for autoimmune diseases
• Depletes CD3-positive cells
Anti-CD25
(anti–IL-2 receptor
antibodies)
• Basailixmab
• Daclizumab
Prophylaxis of acute organ transplant
rejection,
multiple sclerosis (in clinical trial)
•
•
•
•
• Abetacept
• Belatacept
Prophylaxis of organ transplant
rejection, autoimmunity trials
• CTLA4-Ig fusion protein
• Risk for posttransplant lymphoproliferative disorder
Anti-CD52
• Alemtuzumab
Chronic lymphocytic leukemia, multiple
sclerosis, prevention and treatment of
transplant rejection
• Prolonged lymphocyte depletion (neutropenia, thrombocytopenia as side
effects)
• Secondary autoimmunity
Anti-CD154
(CD40 ligand)
Renal transplantation, autoimmune
diseases
• Blockade of B7 protein expression
• On hold due to thromboembolic events
Anti-CD20
• Rituximab
• Ocrelizumab
Rheumatoid arthritis, multiple sclerosis
• Deplete circulating mature B lymphocytes
Anti-TNF
• Infliximab
• Etanercept
• Adalimumab
• Golimumab
• Certolizumab
Rheumatoid arthritis, Crohn disease,
ankylosing
spondylitis,
plaque
psoriasis, psoriatic arthritis, ulcerative
colitis
• Infusion reaction with fever, urticaria, hypotension, and dyspnea can occur
• Risk of serious infections, lymphoma, other malignancies
Anti–IL-1
• Anakinra
• Canakininumab
• Rilonacept
Rheumatoid arthritis, cryopyrinassociated syndromes, evaluated
in gout
Anti–LFA-1
• Efalizumab
Psoriasis
Anti-CD2
• Alefacept
Psoriasis
• Belimumab (antiBLYS)
Systemic lupus erythematosus
Anti-VLA-4
• Natalizumab
Multiple sclerosis, Crohn disease
β Adrenergic blocking effects (worsening of heart failure and bronchospasm)
Block T-cell activation
Do not deplete
Good safety profile
• Withdrawn: excessive progressive multifocal leukoencephalopathy
• Targets α-4 integrin blocking T-cell traffic to organ
• Progressive multifocal leukoencephalopathy
Therapy for MS (Table 35–2 Summarizes More Detailed Therapies for MS.)
• Ocrelizumab
• Natalizumab
• Alemtuzumab
Multiple sclerosis
• β cell depleting. First line drug. Highly efficacious.
• Anti-VLA-4, blocks T cell traffic. Very efficacious.
• Anti-CD52. Highly efficacious. Second line drug due to side effects.
• IFN-β
Multiple sclerosis
• Modest efficacy but safe
• No longer first-line drug
• Fingolomod
Multiple sclerosis
• S1P-R agonist
• Potential cardiac complications
• Tecfidera
Multiple sclerosis
• Monitor WBCs; slight risk of progressive multifocal leukoencephalopathy
• Glatiramer acetate
Multiple sclerosis
• Potentially safe in pregnancy but less efficacious
• Teriflunomide
Multiple sclerosis
• Pyrimidine-synthesis inhibitor; pregnancy risk
Drug Facts for Your Personal Formulary: Eicosanoids
Drug
Therapeutic Uses
Clinical Pharmacology and Tips
Prostanoids and Prostanoid Analogues: PGE1/PGE2
Alprostadil (PGE1)
• Erectile dysfunction
• Temporary maintenance of
patent ductus arteriosus in
neonates
• Rapidly metabolized
• Prolonged erection (4–6 h) in 4% of patients
• Apnea in 10%–12% of neonates with congenital heart defects; ventilator assistance
should be available during treatment
Misoprostol
(PGE1 analogue)
• Protection from NSAID-induced
gastric toxicity
• Contraindicated for use in pregnant women; women who may become pregnant must use
birth control when taking misoprostol
• Combined with mifepristone to terminate early pregnancy
Dinoprostone (PGE2)
• Labor induction
• Rapidly metabolized
Prostanoids and Prostanoid Analogues: PGI2 (Prostacyclin)
Epoprostenol (PGI2)
• Pulmonary arterial hypertension
• Rapidly metabolized
• Administered by intravenous infusion
• Most common dose-limiting adverse effects are nausea, vomiting, headache,
hypotension, and flushing
Iloprost (PGI2 analogue)
• Pulmonary arterial hypertension
• Administered by inhalation
• Synthetic PGI2 analogue with longer t1/2
• May increase risk of bleeding when used with anticoagulants or platelet inhibitors
Treprostinil
(PGI2 analogue)
• Pulmonary arterial hypertension
• May be administered by subcutaneous/intravenous infusion or by inhalation
• Adverse events similar to Iloprost
Prostanoids and Prostanoid Analogues: PGF2
α
Carboprost
tromethamine
• Abortifacient (second trimester)
• Postpartum hemorrhage
• Common adverse effects are vomiting, diarrhea, nausea, fever, flushing
Bimatoprost
• Ocular hypertension
• Open-angle glaucoma
• Hypotrichosis of the eyelashes
• Upper respiratory tract infections in about 10% of patients
• May cause changes in pigmentation and hair growth
Latanoprost
• Ocular hypertension
• Open-angle glaucoma
• Increased iris pigmentation with time
Tafluprost
• Ocular hypertension
• Open-angle glaucoma
• Metabolized to active drug in the eye
• May cause increased iris pigmentation
Travoprost
• Ocular hypertension
• Open-angle glaucoma
• May cause increased iris pigmentation
Nonsteroidal Anti-Inflammatory Drugs
Listed in Chapter 38
Cysteinyl Leukotriene Receptor Antagonists/5-Lipoxygenase Inhibitors
Listed in Chapter 40
Bibliography
Drug Facts For Your Personal Formulary: NSAIDs
Drugs
Therapeutic Uses
Clinical Pharmacology and Tips
Salicylates • Used to treat pain, fever, inflammation • Adverse Effects: Primarily GI and CV, salicylate intoxication
Aspirin
• Vascular indications
• Pain/fever
• Rheumatoid disease / Rheumatic fever
• Irreversible COX inhibitor ⇒ long-acting inhibition of platelet function at
low doses
• At higher concentrations, small increments in dose disproportionately ↑ CP
and toxicity
• Use in children: limited due to Reye’s syndrome association
• Reduces the risk of recurrent adenomas in persons with a history of
colorectal cancer or adenomas
• Prolongs bleeding time for ~ 36 h after a dose
Salsalate
• Arthritis
• Rheumatic disorders
• Prodrug of salicylic acid
• Not approved in the US
Diflunisal
• Mild to moderate pain
• Osteoarthritis/Rheumatoid arthritis
• Salicylic acid derivative
• Largely devoid of antipyretic effects
• t1/2 prolonged with renal impairment
Mesalamine
(5-aminosalicylic acid)
• Inflammatory bowel disease
• Oral formulation delivers 5-aminosalicylic acid to lower GI tract; relative
bowel specificity reduces side effects
• May cause an acute intolerance syndrome (difficult to discern from an
exacerbation)
Sulfasalazine
• Rheumatoid arthritis
• Inflammatory bowel disease
• Active metabolite 5-aminosalicylic acid (see mesalamine) released by colonic
bacteria
• With G6PD deficiency: susceptibility to hemolytic anemia
Olsalazine
• Inflammatory bowel disease
• Active metabolite 5-aminosalicylic acid (see mesalamine) is released by
colonic bacteria.
Balsalazide
• Inflammatory bowel disease
• Active metabolite, 5-aminosalicylic acid (see mesalamine), is released by
colonic bacteria.
Para-Aminophenol Derivative • Only acetaminophen remains on the market
Acetaminophen
• Pain
• Fever
•
•
•
•
•
Weak nonspecific COX inhibitor at common doses
Low anti-inflammatory activity
Little effect on platelets
Overdose results in formation of hepatotoxic metabolite (NAPQI)
Toxicity risk ↑ with liver impairment, ethanol consumption ≥3 drinks/day, or
malnutrition
Acetic Acid Derivatives
Indomethacin
• Acute pain
• Arthritis, inflammatory conditions
• Patent ductus arteriosus
• Potent anti-inflammatory with frequent adverse events (20% discontinue)
• High-risk medication in patients ≥ 65 years
Sulindac
• Inflammatory diseases including
osteoarthritis, rheumatoid arthritis, acute
gouty arthritis, ankylosing spondylitis,
acute painful shoulder
• Sulfoxide prodrug
Etodolac
• Pain, osteoarthritis, rheumatoid arthritis, juvenile
arthritis
• Some COX-2 selectivity
Tolmetin
• Osteoarthritis, rheumatoid arthritis, juvenile
arthritis
• ~33% of patients experience side effects
Ketorolac
• Moderate-to-severe acute pain
• Off label: pericarditis, migraine
• Ocular pain, seasonal allergic conjunctivitis
• Potent analgesic, poor anti-inflammatory
• Max total systemic therapy: 5 days
• Oral, IM, IV, nasal, and ophthalmic administration
Diclofenac
•
•
•
•
•
•
•
•
•
Nabumetone
• Osteoarthritis, rheumatoid arthritis
Pain
Dysmenorrhea
Migraine (oral solution)
Osteoarthritis, rheumatoid arthritis
Ankylosing spondylitis
Some COX-2 selectivity
Short t1/2 requires relatively high doses to extend dosing interval
Rate of CV toxicity similar to that of COX-2 inhibitors
Liver toxicity (4%); severe liver injury in ~8 per 100,000 regular users
annually
• Some COX-2 selectivity
• 6-methoxy-2-napthylacetic acid prodrug
Fenamates • Anthranilic acids; Nonselective COX inhibitors with effects similar to other NSAIDs
Mefenamic acid
• Pain
• Dysmenorrhea
• For patients ≥ 14 years and ≤ 7 days of treatment
• ↑ hepatic enzymes in 5%
Meclofenamate
• Pain/fever, dysmenorrhea
• Osteoarthritis, rheumatoid arthritis, juvenile
arthritis
• Ankylosing spondylitis, acute gouty arthritis, acute
painful shoulder
• For patients ≥ 14 years
• ↑ hepatic enzymes in 5%
Propionic Acid Derivatives • Nonselective COX inhibitors with the effects and side effects common to other NSAIDs
Ibuprofen
•
•
•
•
Pain/fever, dysmenorrhea
Osteoarthritis, rheumatoid arthritis
Inflammatory diseases
Patent ductus arteriosus
•
•
•
•
Over-the-counter NSAID
Injectable solution available
t1/2: 2–4 h (adults); 23–75 h (premature infants); 0.9–2.3 h (children)
Interacts with aspirin’s antiplatelet effect
Naproxen
• Pain, dysmenorrhea
• Osteoarthritis, rheumatoid arthritis,
ankylosing spondylitis; gout; juvenile
arthritis, inflammatory diseases
• Patent ductus arteriosus
Fenoprofen
• Pain
• Osteoarthritis, rheumatoid arthritis
Ketoprofen
• Pain, dysmenorrhea
• Osteoarthritis, rheumatoid arthritis
• 30% develop side effects (usually GI, usually mild)
• ↑ hepatic enzymes ~1%
Flurbiprofen
• Osteoarthritis, rheumatoid arthritis
• ↑ hepatic enzymes > 1%
Oxaprozin
• Osteoarthritis, rheumatoid arthritis, juvenile
arthritis
• t1/2: 41-55 h
• Slow onset, not indicated for fever or acute pain
• Over-the-counter NSAID
• t1/2 variable (9–25 h), age-related
• FDA warning: naproxen may not have a lower risk of CV side effects
compared to other NSAIDs
• Interacts with aspirin’s antiplatelet effect
Enolic Acid Derivatives
Piroxicam
• Osteoarthritis, rheumatoid arthritis
• nonselective COX inhibitor with the longest t1/2 ~50 h
• Slow onset, not indicated for fever or acute pain
• Adverse effects, 20%, 5% of patients discontinue; more GI and serious skin
reactions than other NSAIDs
Meloxicam
• Osteoarthritis, rheumatoid arthritis, juvenile
arthritis
• Some COX-2 selectivity
• t1/2: 15-20 h
Diaryl Heterocyclic NSAIDs
Celecoxib
• Pain
• Dysmenorrhea
• Osteoarthritis, rheumatoid arthritis, juvenile
arthritis
• ankylosing spondylitis
• Off label use: gout
• COX-2 selective
• Sulfonamide
• Risk of myocardial infarction observed in randomized placebo controlled
trials.
Drug Facts For Your Personal Formulary: Gout
Drugs
Therapeutic Uses
Clinical Pharmacology and Tips
Drugs that relieve inflammation and pain
NSAIDs
• See NSAIDs, above
• See NSAIDs, above
Glucocorticoids
• See Chapter 46
• See Chapter 46
Colchicine
• Prophylaxis and the treatment of
acute gout flares
•
•
•
•
•
•
•
Depolymerizes microtubules ⇒ ↓ neutrophil migration into inflamed area
Narrow therapeutic index; toxic effects related to antimitotic activity
t1/2: 31 h (21–50 h)
Individualize dose on the basis of age, hepatic and renal function
Contraindicated in patients with GI, renal, hepatic or cardiac disorders
Adverse effects: primarily GI
Drug interactions with P-gp and CYP3A4 inhibitors
Xanthine oxidase (XO) inhibitors • Inhibit urate synthesis
Allopurinol
• Hyperuricemia in patients with gout
gout
• Calcium oxalate calculi
• Hyperuricemia associated with cancer
treatment
•
•
•
•
•
active metabolite: oxypurinol
t1/2: allopurinol 1–2 h, oxypurinol 18–30h; adjust dose in renal impairment
Rash, diarrhea, nausea frequent
Risk of gout attacks during the early months of therapy (tissue urate mobilization)
Serum [urate] usually ↓ in 24–48 h, normal 1–3 weeks
Febuxostat
• Hyperuricemia
•
•
•
•
non-purine
more selective for XO than allopurinol
t1/2: 5 to 8 h
Liver function abnormalities (5–7%)
Uricase • Oxidizes uric acid to allantoin (more soluble and inactive metabolite)
Pegloticase
• Chronic gout refractory to
conventional therapy
•
•
•
•
Rasburicase
•
• t1/2: 16 to 23 h
• ↓ Uric acid levels within hours of initial administration
• Not suitable for chronic gout; activity-limiting antibodies form against the drug.
Hyperuricemia associated
with malignancy (pediatric
and adult patients)
t1/2, 14 days
↓ Blood urate within hours of initial administration
Antibody development against drug may limit efficacy, cause hypersensitivity reactions
Adverse effects: bruising (11%), urticaria (11%), nausea (11%), gout flare during early
therapy (74%), chest pain (6%)
Uricosuric drugs–Inhibit of reabsorption of uric acid by organic anion transporters, thereby increasing excretion of uric acid
Probenecid
• Hyperuricemia associated with gout
(but not for acute attacks)
• Prolongation and elevation of betalactam plasma levels
•
•
•
•
Lesinurad
•
• t1/2: 5 h
• CYP2C9 substrate, so caution is recommended in patients who are CYP2C9 poor
metabolizers
• Must be used together with XO inhibitor due to renal failure risk
Bibliography
Gout in patients who have not
achieved the target serum uric acid
levels with XO inhibitor alone
Interferes with renal tubular handling of organic acids
t1/2: 6-12 h (dose–dependent)
Risk of gout attacks during the early months of therapy (tissue urate mobilization)
ineffective in patients with renal insufficiency
Drug Facts for Your Personal Formulary: H1 Antagonists
Drugs
Therapeutic Uses
Clinical Pharmacology and Tips
CHAPTER 39
First-Generation Antihistamines: H1 receptor inverse agonists • Most have central and anticholinergic effects
• Use with caution in children and in adults > 65 years of age
Doxepin
• Tricyclic antidepressant
• Insomnia
• Pruritis (topical cream)
• Pruritis (atopic dermatitis, eczema, lichen
simplex) (cream)
• Causes significant sedation/drowsiness
• Anticholinergic effects
• Increased risk of suicidal thoughts (children, adolescents, and young adults)
Carbinoxamine
Clemastine
Diphenhydramine
Dimenhydrinate
•
•
•
•
•
•
•
•
Pyrilamine (only available as an
ingredient in OTC combination
preparations)
• Symptoms of allergic response
Chlorpheniramine
Dexchlorpheniramine
Brompheniramine
Dexbrompheniramine
(component of cold medicine)
• Allergic conjunctivitis
• Allergic rhinitis
• Anaphylaxis (adjunct), histaminemediated angioedema,
dermatographism, pruritus, sneezing,
urticaria (brompheniramine)
• Symptoms of allergic response
Hydroxyzine
•
•
•
•
•
•
Cyclizine (discontinued in the
U.S.)
Meclizine (not for use in children)
• Motion sickness
• Nausea/vomiting
• Vertigo
• Antinausea properties due to prominent anticholinergic effects
• Less likely to cause drowsiness than other first-generation drugs
• Meclizine, most used, long effect (≥8 h)
Promethazine
•
•
•
•
•
Antiemetic
Motion sickness
Pruritus
Sedation
Symptoms of allergic response
(off-label use)
•
•
•
•
Cyproheptadine
•
•
•
•
•
•
•
•
Allergic conjunctivitis
Allergic rhinitis
Anaphylaxis
Histamine-mediated angioedema
Pruritus, allergy
Vasomotor rhinitis
Urticaria
Dermatographism
• May increase appetite, cause weight gain
• Has significant anticholinergic activity
• Also blocks serotonin effects by antagonizing the 5HT2A receptor
Symptoms of allergic response
Mild urticaria
Insomnia (diphenhydramine)
Motion sickness (dimenhydrinate,
diphenhdramine)
Pronounced tendency to cause sedation
Significant anticholinergic effects
GI side effects are low
Carbinoxamine and diphenhydramine: adjunct to epinephrine for anaphylaxis
• Anticholinergic effects
• Central effects < other first-generation drugs
• GI side effects are quite common
Less drowsiness than other first-generation drugs; CNS stimulation side effects
more common
Pruritis
Sedation
Antianxiety
Atopic dermatitis
Antiemetic
Urticaria
• CNS depressant action may contribute to antipruritic effects
Risk of fatal respiratory depression in children, especially < 2 years
May lower seizure threshold
Has local anesthetic activity
Most potent antihistamine antiemetic
Second-Generation Antihistamines: H1 receptor inverse agonists • Lack significant central and anticholinergic effects
Olopatadine (nasal and
ophthalmic only)
•
•
•
•
•
Allergic conjunctivitis
Allergic rhinitis
Ocular pruritus
Rhinorrhea
Sneezing
•
•
•
•
•
Approved for once-daily dosing
Eye drops may cause headaches in some
Nasal spray can cause epistaxis and nasal ulceration or septal perforation
Some increase in risk of somnolence with nasal spray
Nasal spray minor side effects include bitter taste and headache
Acrivastine (only marketed in
combination with
pseudoephedrine)
• Allergic rhinitis
• Nasal congestion
• Allergic symptoms
• ~40% metabolized by CYPs, reducing potential for drug interactions
• Somewhat higher risk of mild sedation than other second-generation drugs
Cetirizine
Levocetirizine
• Allergic rhinitis
• Atopic dermatitis (cetirizine)
• Urticaria (chronic idiopathic)
• Somewhat higher risk of mild sedation than other second-generation drugs;
more potent levocetirizine can be used at lower dose with less risk of sedation
• Only ~30% (cetirizine) or ~1% (levocetirizine) metabolized by CYPs, reducing
potential for drug interactions
Second-Generation Antihistamines: H1 receptor inverse agonists • Lack significant central and anticholinergic effects
(continued)
Loratadine
• Allergic rhinitis
• Desloratadine is the active metabolite of loratadine
Desloratadine
• Chronic idiopathic urticaria
• Exercise-induced bronchospasm
prophylaxis (loratadine)
• Pruritus (desloratadine)
• 24-h duration of activity so only once-a-day dosing is required
Fexofenadine
• Allergic rhinitis
• Chronic idiopathic urticaria
• Is the active metabolite of terfenadine (withdrawn from the market due
to risk of torsades de pointes)
• Only ~8% metabolized by CYPs, reducing potential for drug interactions
Alcaftadine (ophthalmic only)
• Allergic conjunctivitis
• Ocular pruritus
Bepotastine (ophthalmic only)
• Allergic conjunctivitis
• Ocular pruritus
• In addition to mast cell–stabilizing and anti-inflammatory properties, its H4
antagonist activity may give superior relief from ocular itching
• Approved for once-daily dosing
• Most common adverse reactions (<4%) are eye irritation, redness, and
pruritis
• Has mast cell–stabilizing and anti-inflammatory properties
• Most common (~25%) adverse reaction is mild taste
• Other minor (2%–5%) reactions are eye irritation, headache, and
nasopharyngitis
Ketotifen (ophthalmic only)
• Allergic conjunctivitis
• Ocular pruritus
Azelastine (nasal and
ophthalmic
only)
• Allergic conjunctivitis
• Allergic rhinitis (alone and combined
With fluticasone)
• Ocular pruritus
• Vasomotor rhinitis
Emedastine (ophthalmic only)
• Allergic conjunctivitis
• Ocular pruritus
• Lacks mast cell–stabilizing and anti-inflammatory properties
• Common side effect: headache (~11%)
• Minor reactions (<5%): abnormal dreams, bad taste, eye irritation
Epinastine (ophthalmic only)
• Allergic conjunctivitis
• Ocular pruritus
• In addition to mast cell–stabilizing and anti-inflammatory properties, its H2
antagonist activity may reduce eyelid edema
• Common side effect (~10%): symptoms of upper respiratory infection
• Minor ocular reactions: burning sensation, folliculosis, hyperemia, and
pruritis
• Has mast cell–stabilizing and anti-inflammatory properties
• Most common (~10%–25%) adverse reactions are red eyes and mild
headache
or rhinitis
• Has mast cell–stabilizing and anti-inflammatory properties
• Eye drops may cause transient eye burning/stinging
• Some increase in risk of somnolence with nasal spray
• Minor side effects with eye drops and nasal spray include bitter taste and
headache
Drug Facts for Your Personal Formulary: Asthma and COPD Therapeutics
Drug
Therapeutic Uses
Clinical Tips
Short-Acting β2 Agonists: Inhaled bronchodilators for symptom relief and acute bronchodilation
Albuterol (salbutamol)
• Asthma, COPD, and exercise-induced bronchospasm
• Inhaled: 180 μg (2 puffs) every 4 to 6 h as needed
• Nebulized: 2.5 mg via oral inhalation every 6–8 h as
needed over 5 to 15 min
• Oral: 2–4 mg by mouth every 6–8 h
• Also available nebulized and inhaled as levalbuterol (active isomer, so half the
dose)
• May need to be nebulized with oxygen in severe exacerbation
• Adverse effects: tachycardia, palpitations, muscle tremors, and hyperkalemia
Levalbuterol
(L-albuterol)
• Bronchodilator
• Inhaled (MDI nebulizer)
• Half of doses of racemic albuterol
• No advantage over racemic albuterol
• Adverse effects: tachycardia, palpitations, muscle tremors, and hyperkalemia
Pirbuterol
• 400 μg (2 puffs) every 4–6 h as needed
• Inhaled (MDI nebulizer)
• Similar to albuterol
• Adverse effects: tachycardia, palpitations, muscle tremors, and hyperkalemia
Long-Acting β2 Agonists: Add-on therapy to ICSs in asthma; can be used alone in COPD
Formoterol
•
•
•
•
Asthma as add-on to ICS
Maintenance and treatment of severe COPD
Inhaled: 12 μg (contents of 1 capsule) every 12 h
Nebulized 20 μg in 2 mL, twice per day
• Used as maintenance, usually in a combination with an ICS
• Can also be used as a reliever of bronchospasm
• Adverse effects: tachycardia, palpitations, muscle tremors, and hyperkalemia
Arformoterol
Salmeterol
Indacaterol
Olodaterol
• Arformoterol for severe COPD
• Maintenance treatment for COPD
• Arformoterol, inhaled (nebulized), 15 μg in 2 mL
twice daily
• Salmeterol, inhaled 50 μg twice daily
• Indacaterol, inhaled (DPI) 75 cetazolamide OD
• Olodaterol, inhaled 2.5 cetazolamide once daily
• Cannot be used as a reliever, only for maintenance treatment for COPD
• Adverse effects: tachycardia, palpitations, muscle tremors, and hyperkalemia
Anticholinergics: Muscarinic receptor antagonists inhaled as bronchodilators
Ipratropium bromide
Albuterol/ipratropium
combination
• Inhaled, 2 puffs (17 μg/puff ) 3–4 times/d
• Combination albuterol 103 μg/ipratropium
18 μg/puff; 2 puffs 4 times daily
•
•
•
•
Largely replaced by LAMAs
Avoid spraying in eyes
Adverse effects include dry mouth, tachycardia, urinary retention, glaucoma
Combination with albuterol may be used as a reliever
Tiotropium Bromide
• 2.5 μg via oral inhalation (2 puffs of 1.25 μg/
actuation) once daily
• Caution in patients with urinary retention or glaucoma history
Umeclidinium bromide
• Inhaled (DPI) 62.5 μg (1 puff ) once daily
Aclidinium bromide
• Inhaled (DPI) 400 μg (1 puff) twice daily
Glycopyrrolate
• Inhaled (DPI) 1 capsule (15.6 μg) inhaled twice daily
LAMA-LABA Combination Inhalers: Maintenance treatment for COPD
Glycopyrrolate/
indacaterol
• Inhaled (DPI) 1 inhalation (glycopyrrolate 15.6 μg/
indacaterol 27.5 μg) twice daily
Umeclidinium/
vilanterol
• Inhaled (DPI) 1 inhalation (umeclidinium 62.5 μg/
25 μg vilanterol) once daily
Tiotropium/olodaterol
• Inhaled (mist inhaler), 2 inhalations (containing
2.5 μg tiotropium/2.5 μg of olodaterol per
inhalation) once daily
• Side effects of anticholinergics and β2 agonists as above
• Maintenance treatment for COPD
Inhaled Corticosteroids: Maintenance treatment for asthma
Beclomethasone
dipropionate (BDP)
• Inhaled (MDI, DPI); 88 μg (1 spray = 44 μg) twice
daily
• Not to exceed 440 μg twice daily
• More systemic effects than other ICSs: orally bioavailable BDP is converted to an
active metabolite, beclomethasone monopropionate, following absorption
• Local effects: hoarse voice, candidiasis
• Systemic effects: growth suppression, bruising, adrenal suppression
Fluticasone propionate
• Inhaled (MDI, DPI); 50, 100, 250 μg 2 puffs, twice
daily
• Do not exceed 1000 μg daily
• Fewer systemic effects than BDP
• Local: hoarse voice, candidiasis
Budesonide
• Inhaled via jet nebulizer either once daily or divided
into 2 doses (maximum daily dose 0.5 mg/d)
• Fewer systemic effects than BDP
• Used in children less than 8 who cannot use PDI
• Local: hoarse voice, candidiasis
Ciclesonide
• Inhaled (MDI) 80 μg twice daily
• Least-systemic effects of all ICSs; may be effective once daily
• Local: hoarse voice, candidiasis
Drug Facts for Your Personal Formulary: Asthma and COPD Therapeutics
(continued)
CHAPTER 40
Drug
Therapeutic Uses
Clinical Tips
ICS/LABA Combination Inhalers: Maintenance treatment in asthma and COPD
Fluticasone propionate/
salmeterol
• Inhaled (DPI)
• Starting dosage based on asthma severity
Budesonide/formoterol
• Inhaled (MDI) (80 μg budesonide and 4.5 μg
formoterol per inhalation) twice daily
Fluticasone furoate/
vilanterol
• Inhaled (DPI) 1 inhalation (fluticasone furoate
100 μg/vilanterol 25 μg) once daily
• Use lowest dose that maintains asthma control
• Use only in severe COPD or asthma-COPD overlap
• Adverse effects as for ICSs and LABAs
Systemic Corticosteroids: Short course or oral maintenance for asthma (and COPD)
Prednisone
Prednisolone
• Oral: 40–80 mg once daily or divided dose for
3–10 days for acute exacerbation
• Minimal dose for maintenance
• Prednisone converted to prednisolone in the liver
• Bruising, weight gain, edema, osteoporosis, diabetes, cataracts, adrenal
suppression (see Chapter 46)
Hydrocortisone
succinate
• IM/IV: 100–500 mg every 12 h for acute severe
asthma
• Only if patient not able to take oral steroids
Methylprednisolone
• IV: 100–1000 mg for acute severe asthma
• Rarely indicated because of steroid side effects
Antileukotrienes (Leukotriene Modifiers) for Asthma Maintenance
Montelukast
Zafirlukast
Zileuton
• Oral: montelukast (10 mg once/d); zafirlukast
(20 mg twice/d); zileuton (600 mg four times/d
or
1200 mg twice/d)
• Less effective than ICS in asthma
• Headache, Churg-Strauss syndrome
• Zileuton may cause hepatic dysfunction (do not use if ALT increased)
Methylxanthines: Add-on maintenance treatment of severe asthma and COPD
Theophylline (oral)
Aminophylline (IV)
• Aminophylline (IV) is indicated for severe
exacerbation that does not respond to
nebulized β agonists; shorter action than
theophylline
• Interaction with drugs that affect CYP450
• Nausea, headaches, diuresis, arrhythmias, seizures
Phosphodiesterase 4 Inhibitor: Maintenance for severe COPD
Roflumilast
• Severe COPD
• Oral administration 500 μg once daily
• Add to maximal inhaled therapy if severe disease with acute exacerbations
and chronic bronchitis
Anti-IgE: Maintenance Treatment for severe asthma
Omalizumab
• Severe asthma
• Subcutaneous administration
• Dose depends on total IgE; given every 2–4
weeks
• Expensive, so mainly indicated in severe asthma that is difficult to control
• Well tolerated; occasional headache
• Occasional anaphylaxis
.
.
Drug Facts for Your Personal Formulary: Pituitary-Related Drugs
Drugs
Therapeutic Uses
Clinical Pharmacology and Tips
Pituitary Hormones (Recombinant)
Growth hormone
(somatropin)
• Stimulating growth in childhood
• In GH-deficient adults, replacing GH
• Given by daily SC injection to stimulate body growth, primarily through
stimulation of IGF-1. As growth ceases, test for GH deficiency to determine
if GH should be continued into adulthood.
• Given only to adults with GH deficiency proven by GH stimulation tests or known
organic childhood GH deficiency and low IGF-1 levels on testing off GH treatment.
• Treatment in adults decreases fat mass, increases muscle mass, increases bone
mass, and improves quality of life.
Oxytocin
• Augmentation of labor
• Management of postpartum
hemorrhage
• Administered by intravenous infusion.
• Hyperstimulating the uterus should be avoided during augmentation of labor.
• May provoke hypotension and reflex tachycardia.
Human chorionic
gonadotropin
• Testing of Leydig cell function
• Male infertility
• Cryptorchidism in children
• Stimulates LH receptor, causing increased testicular testosterone production.
• Induces testicular descent in children with cryptorchidism.
Tesamorelin
• Treatment of HIV-associated
lipodystrophy
• N-Terminally modified version of human GHRH with primary effect of reducing
visceral and other body fat in patients with HIV lipodystrophy.
Insulinlike growth factor
1 (mecasermin)
• Treatment of children with mutations
in the GH receptor or transduction
mechanisms mediating GH action or
IGF-1 gene defects
• Adverse effects include hypoglycemia and lipohypertrophy.
Other Peptide Hormones
Other Peptide Hormones (continued)
Gonadotropin-releasing
hormone agonist
analogues
• Goserelin
• Histrelin
• Leuprolide
• Nafarelin
• Triptorelin
• Endometriosis
• Diagnosis and treatment of
precocious puberty
• Palliative treatment of hormoneresponsive tumors (prostate and
breast cancer)
• Prolonged stimulation of the GnRH receptor by analogues results in
downregulation of those receptors with decreased gonadotropin secretion.
Gonadotropinreleasing
hormone
antagonist
analogues
• Ganirelix
• Cetrorelix
• Degarelix
• Suppression of gonadotropin
secretion and used in conjunction
with exogenous gonadotropins
for assisted reproduction
• Palliative treatment of advanced
prostate cancer (degarelix)
• Antagonism at the GnRH receptor results in decreased gonadotropin secretion
without initial LH surge as seen with agonist analogues.
Somatostatin Analogues: Act on somatostatin receptors to reduce hormone secretion
Octreotide
• Acromegaly
Long-acting release form is the standard type; given monthly.
Lanreotide
• Acromegaly
• Long-acting release form is the only available standard type; given monthly.
Pasireotide
• Acromegaly
• Cushing disease
• Short-acting subcutaneous form is the only version FDA-approved for Cushing
disease.
• LAR form given monthly is the only version FDA-approved for acromegaly.
• Additional adverse effects include significant hyperglycemia in many patients.
Dopamine Agonists: Act on dopamine receptors (D2) to decrease prolactin secretion and prolactinoma size
Bromocriptine
• Treatment of hyperprolactinemia
• Reduction in size of prolactinomas
• Treatment of Parkinson disease
• An ergot derivative that has to be given one or more times daily.
• Common adverse effects include nausea, vomiting, headache, and postural
hypotension.
Cabergoline
•
•
•
•
• A long-acting ergot derivative given once or twice weekly.
• Has greater efficacy and tolerability than bromocriptine and may be active in
patients who do not respond to bromocriptine.
• At high doses used in patients with Parkinson disease; it cross reacts at the
5HT2B receptor, causing cardiac valve abnormalities (not seen when used for
patients with prolactinomas).
Quinagolide
• Treatment of hyperprolactinemia
• Reduction in size of prolactinomas
Treatment of hyperprolactinemia
Reduction in size of prolactinomas
Parkinson disease
Acromegaly
• Not available in the U.S.
Hormone Receptor Blockers
Pegvisomant
• Treatment of acromegaly
• Blocks GH receptor and thus the activity of high GH levels and the generation
of IGF-1 in acromegaly. Given by subcutaneous injections daily alone or
weekly in combination with somatostatin analogues.
Drug Facts for Your Personal Formulary: Thyroid and Antithyroid Drugs
Drugs
Therapeutic Uses
Clinical Pharmacology and Tips
Thyroid Hormone Preparations: Replace T4 or T3 normally produced by the thyroid
CHAPTER 43
Levothyroxine (T4)
• Hypothyroidism
• TSH suppression in thyroid cancer
•
•
•
•
Liothyronine (T3)
• When rapid onset of action is desired
(sometimes for myxedema coma)
• When rapid termination of action is desired
(preparing patients with thyroid cancer for
radioiodine therapy)
• Plasma t1/2 ~ 18-24 h
• Multiple daily doses needed to achieve needed CPss
• Levothyroxine (T4) generally preferred over liothyronine (T3) for the longterm therapy of hypothyroidism
Desiccated thyroid and
T4-T3 mixtures
• Generally not a preferred therapy, although
occasional hypothyroid patients say they feel
better than when taking levothyroxine
• Mixture of levothyroxine and liothyronine (2–5:1 by weight)
• Supplies a relative excess of T3 compared to normal thyroidal
secretion, which is ~ 11:1 T4 to T3 by weight
• No convincing evidence of greater efficacy than levothyroxine (T4 alone)
Plasma t1/2 ~ 1 week
Deiodinases convert circulating T4 to the bioactive hormone T3
Dosage generally needs to increase during pregnancy
Congenital hypothyroidism requires rapid diagnosis and correction to allow
normal physical and mental development
• Overtreatment can lead to osteoporosis and atrial fibrillation
Antithyroid Drugs: Thionamides: Interfere with incorporation of iodine into tyrosyl residues and inhibit iodotyrosyl-coupling reactions
Methimazole
• Reduce thyroid hormone production
• Carbimazole (available in Europe) converted to methimazole after
absorption
• Long intrathyroidal t1/2 allows once-daily dosing for most patients
• Preferred antithyroid drug
• Do not use in first trimester of pregnancy due to embryopathy
Propylthiouracil
• Reduce thyroid hormone production
• May also reduce T4 to T3 conversion
• Major concern is liver toxicity; rare but more commonly seen in children and
pregnancy
• Only indications are for thyroid storm due to action on reducing T4 to T3
conversion and in the first trimester of pregnancy
Antithyroid Drugs: Ionic Inhibitors: Iodine uptake by antagonizing the sodium-iodide symporter
Perchlorate
• Primarily used to enhance the response to
thioamides in refractory Graves disease (e.g.,
that associated with amiodarone)
• Not available commercially; must be specialty compounded
Antithyroid Drugs: Iodide: Acute reduction in thyroid hormone
Lugol solution
KISS: potassium iodide
saturated solution
(or SSKI)
• Acutely reduce the secretion and synthesis of
thyroid hormone
• “Escape”from thyroid inhibition after 7–10 days
• Strictly contraindicated in pregnancy
• Acutely reduce the secretion and synthesis of
thyroid hormone
• “Escape”from thyroid inhibition after 7–10 days
• Strictly contraindicated in pregnancy
Antithyroid Drugs: Radioactive Iodine: Used to destroy hyperfunctioning thyroid tissue
131
I
• Effective for permanent treatment of Graves
disease and toxic nodule or toxic goiter
• Destruction of iodide-avid thyroid cancer
• Highly effective for permanent cure to hyperthyroidism
• Effective treatment of hyperthyroidism usually results in permanent
hypothyroidism and lifelong requirement for levothyroxine replacement
• Absolutely contraindicated in pregnancy
• Treatment of thyroid cancer requires TSH stimulation (endogenous or
exogenous)
Recombinant Human TSH Agonist for the TSH Receptor
Thyrotropin alpha
• Stimulate radioiodine uptake and thyroglobulin
release in patients with thyroid cancer after
thyroidectomy
• Prepare patients for radioiodine ablation of
thyroid remnants after thyroidectomy for thyroid
cancer
• Allows assessment of residual or recurrent thyroid cancer without stopping
levothyroxine and becoming clinically hypothyroid
• Allows radioiodine therapy of thyroid remnants without stopping
levothyroxine and becoming clinically hypothyroid
Thyroid Cancer Chemotherapeutics: Tyrosine kinase inhibitors
Sorafenib
Lenvatinib
• Radioiodine-resistant, progressive papillary, or
follicular thyroid cancer
• Response not predicted by presence or absence of specific oncogene
mutations
• Lack of response to one kinase inhibitor does not necessarily predict lack of
response to others
Vandetanib
• Progressive medullary thyroid cancer
• Can be used in hereditary or sporadic medullary thyroid cancer
• Responses may be seen in patients with or without RET gene mutations
Cabozantinib
Drug Facts for Your Personal Formulary: Estrogens, Progestins,
GnRH, Gonadotropins
Drug
Therapeutic Uses
Major Toxicity and Clinical Pearls
• Menopause hormone therapy
• Components of oral contraceptives
• Treatment of transgender individuals
• Depending on the preparation, may be available for
oral, parenteral, transdermal, or topical administration
• Act via ERα and ERβ
• Precaution: prescribe the lowest effective dose for the
shortest duration consistent with treatment goals and risks
for each individual patient
• Increased risk of thromboembolism
• Potencies of various oral preparations differ due to
differences in first-pass metabolism
Estrogens
Steroidal Estrogen and
Derivatives
Estradiol
Estradiol valerate
Estradiol cypionate
Ethinyl estradiol
Mestranol,
equilin
Estrone sulfate
Nonsteroidal Compounds
Diethylstilbestrol
Bisphenol A, genistein
Selective Estrogen Receptor Modulators
Tamoxifen
• Treatment of breast cancer
• Antiestrogenic, estrogenic, or mixed activity depending
on tissue
Raloxifene
• Treatment of osteoporosis (estrogen agonist in bone)
• Reduces total cholesterol and LDL but does not increase
HDL
• To reduce risk of breast cancer in high-risk
postmenopausal women
Toremifene
• Treatment of breast cancer
• Tissue-selective actions on ERs
• Beneficial estrogenic actions in bone, brain, and liver
during postmenopausal hormone therapy
• Antagonist activity in breast and endometrium
• Increased risk of thromboembolism
Antiestrogens
Clomiphene
• Treatment of infertility in anovulatory women
• Primarily a receptor antagonist but also has weak agonist
activity
Fulvestrant
• Treatment of breast cancer in women with disease
progression after tamoxifen
• Used in women with resistance to aromatase inhibitors
• Receptor antagonist in all tissues
Estrogen Synthesis Inhibitors
• Treatment of breast cancer (exemestane, letrozole, and
anastrozole approved in the U.S.)
• Steroidal inhibitors: substrate analogues that
irreversibly inactivate aromatase
• Nonsteroidal inhibitors: interact reversibly with the
heme groups of CYPs
• Risk of osteoporosis with long-term use
Pregnanes Progesterone
Medroxyprogesterone acetate
Megestrol acetate
•
•
•
•
• Formulations: oral, injection, vaginal gel, slow-release
intrauterine device, vaginal insert
• Progesterone: rapid first-pass metabolism
• MPA and high-dose micronized progesterone are
available for oral use
Estranes
Norethindrone
19-Norethindrone
• Used in oral and injectable contraceptives
• 19-Nortestosterone derivatives
• Progestational activity but also some androgenic and
other activities
Gonanes
Norgestrel
Norgestimate
• Used in oral and injectable contraceptives
• 19-Nortestosterone derivatives, ethyl rather than
methyl group at position 13
• Progestational components of contraceptives
Aromatase Inhibitors
Steroidal inhibitors
Formestane
Exemestane
Nonsteroidal inhibitors
Anastrozole
Letrozole, vorozole
Progestins
Menopause hormone therapy
Contraception
Assisted reproductive technology
Depot MPA used as a long-acting injectable contraceptive
Antiprogestins and Progesterone Receptor Modulators
Mifepristone (RU 38486)
• Termination of early pregnancy
• Competitive receptor antagonist of both progesterone
receptors
• May have some agonist activity
Ulipristal acetate
• Emergency contraception
• Partial progesterone receptor agonist
GnRH Agonist and Antagonists
GnRH agonist
Leuprolide
•
•
•
•
•
Controlled ovarian hyperstimulation
Endometriosis
Uterine leiomyomas
Precocious puberty
Menstrual suppression in special circumstance
(e.g., thrombocytopenia)
• Initial agonist action (“flare effect”) results in increase in
FSH and LH
• After 1–3 weeks, desensitization and
pituitary downregulation result in a
hypogonadotropic, hypogonadal state
• Risk of osteoporosis with long-term use
GnRH antagonist
Cetrorelix, ganirelix
Goserelin, buserelin
Triptorelin, nafarelin
• Controlled ovarian hyperstimulation
• Competitive GnRH receptor antagonist
• Immediate decline in LH and FSH levels
• Risk of osteoporosis with long-term use
• Ovulation induction
• Controlled ovarian hyperstimulation
• hMG may contain FSH, LH, and hCG and purification
results in standardization of the FSH and LH activity
• Injectable or intravenous
LH
Recombinant LH
• Controlled ovarian hyperstimulation in women with LH
deficiency due to hypogonadotropic hypogonadism
• Injectable or intravenous
hCG
Recombinant hCG
Urinary hCG
Highly purified urinary hCG
• Promotes meiotic maturation from prophase I to metaphase II in
oocytes
• Injectable or intravenous
• Also used to stimulate testosterone and sperm
production in men
Gonadotropins
FSH
Recombinant FSH
Follitropin-alpha
Follitropin-beta
Human menopausal
menotropins
Menotropins
Urofollitropins
Highly purified urinary FSH
Drug Facts for Your Personal Formulary: Androgens; PDE5 Inhibitors
Drugs
Therapeutic Uses
Clinical Pharmacology and Tips
Testosterone Esters • Effective for weeks to months. Wide fluctuations in serum concentrations
Testosterone enanthate
testosterone cypionate
• Treatment of male hypogonadism
•
•
•
•
Formulated as oils for injection
Administer as a deep I.M. injection every 1-2 weeks.
Generally effective in causing and maintaining virilization.
Fluctuations in serum concentrations result in fluctuations in
energy, mood, and libido.
• Available as gels, implants, buccal tabs
Testosterone undecanoate
• Treatment of male hypogonadism
• Formulated as oil for injection
• Administer as a deep I.M. gluteal injection. Observe for 30 min after
injection for anaphylaxis or pulmonary microembolism.
• Administer every 10 weeks.
Testosterone undecanoate for oral
administration (not available in
the U.S.)
• Treatment of male hypogonadism
• Taken 2-3 times a day with food
• Absorbed into lymphatics
Testosterone Transdermal Patch
Several FDA-approved products
• Treatment of male hypogonadism
• Worn without interruption and changed once a day
• High rate of skin rash
• Treatment of male hypogonadism
• Applied once a day
• Relatively steady serum testosterone concentration
Transdermal Testosterone Gels
Several FDA-approved products
842
Drug Facts for Your Personal Formulary: Androgens; PDE5 Inhibitors (continued)
Drugs
Therapeutic Uses
Clinical Pharmacology and Tips
•
•
•
•
•
• Risk of hepatoxicity
17α- alkylated Androgens
Danazol
Stanozolol (not marketed in the
U.S.)
Treatment of angioedema
Treatment of hemolytic anemia
Angioedema prophylaxis
Endometriosis
Fibrocystic breast disease
GnRH Analogs
Leuprolide
Goserelin
Triptorelin
Histrelin
Buserelin (not available in the
U.S.)
• Treatment of metastatic prostate cancer
• Leuprolide also approved for
endometriosis, precocious puberty,
prostate cancer and uterine leiomyomata
• Goserelin also approved for breast cancer,
dysfunctional uterine bleeding, and
endometriosis
• Histrelin also approved for precocious
puberty and prostate cancer
• Parenteral administration
• Suppresses LH secretion and thereby causes profound
hypogonadism
Androgen Receptor Antagonists
Flutamide
Bicalutamide
Nilutamide
Enzalutamide
• Adjuvant treatment of metastatic prostate
cancer
• Used in conjunction with GnRH agonists
• Treatment of lower urinary tract symptoms
due to benign prostatic hyperplasia
• Finasteride also approved for alopecia
• Shrinks the size of the prostate by decreasing the production of
dihydrotestosterone in the prostate
• Dutasteride also marketed as fixed-dose combination with
tamsulosin
• Male erectile dysfunction
• Pulmonary arterial hypertension
(sildenafil, tadalafil)
• Contraindicated in patients using nitrate vasodilators (can cause
dangerously low blood pressure)
• Side effects: headache, flushing, blue-green tinted vision
• Erection lasting > 4h requires medical attention
5α-reductase inhibitors
Finasteride
Dutasteride
PDE5 Inhibitors
Sildenafil, vardenafil,
tadalafil, avanafil
Drug Facts for Your Personal Formulary: Adrenal Related
Drugs
Therapeutic Uses
Clinical Pharmacology and Tips
Replacement Therapy
Hydrocortisone/cortisone
Primary and secondary chronic adrenal
insufficiency
• Hydrocortisone is the synthetic equivalent of cortisol.
• Daily oral dose of hydrocortisone is 20–30 mg, preferably as divided doses.
• Although nonphysiologic glucocorticoids are sometimes used, hydrocortisone or
cortisone is preferred for replacement therapy.
• Tip: Two-thirds of dose in the morning, one-third of dose in the evening.
Hydrocortisone,
other
glucocorticoids
Acute adrenal insufficiency
Critical illness-related cortisol
insufficiency (CIRCI)
• CIRCI reflects inadequate cortisol production or may occur with abrupt cessation of
administered glucocorticoids.
• High-dose intravenous hydrocortisone (50–100 mg/6 h) or a constant infusion
of 10 mg/h is needed.
• An alternative is prednisone at 1 mg/kg/d.
Fludrocortisone
(9α-fluorocortisol)
Mineralocorticoid replacement
• Doses of 0.05–0.2 mg/d.
• Lower dose is used initially and is titrated upward as required by blood pressure,
plasma renin levels, and response to upright posture.
• Fludrocortisone has a t1/2 ≥ 24 h so divided doses are not necessary.
Anti-inflammatory Agents: Systemic
Prednisolone,
methylprednisolone
Dexamethasone,
budesonide Others
Across the spectrum of inflammatory
Disease
Preterm (24–34 weeks) delivery
• Initial high-dose tapering to low dose in short-course therapy.
• In early therapy—insomnia, weight gain, emotional lability
• With high-dose/long-term therapy: psychosis, increased susceptibility to infection,
osteoporosis, osteonecrosis, myopathy, HPA axis suppression.
• On cessation of therapy: acute hypocortisolism.
• Tip: Constant vigilance.
Anti-inflammatory Agents: Topical
Betamethasone
Hydrocortisone
Beclomethasone
Dexamethasone
Triamcinolone
acetonide
Dermatitis, pemphigus, atopic
dermatitis, vitiligo, psoriasis, etc.
•
•
•
•
Fluorinated steroids have better skin penetration than hydrocortisone.
Effects are magnified by occlusive dressings.
Local adverse events: atrophy, striae, and exacerbation of skin infection.
Tip: Skin-lightening cosmetics include corticosteroids and may produce serious
systemic adverse events.
Drug Facts for Your Personal Formulary: Adrenal Related (continued)
Drugs
Therapeutic Uses
Clinical Pharmacology and Tips
Anti-inflammatory Agents: Ophthalmic
Dexamethasone
Triamcinolone acetonide
Fluocinolone acetate (implant)
Macular disease (degeneration, edema,
retinal vein occlusion)
Postoperative inflammation
Corneal injury, Uveitis
• Commonly repeated at 3-month intervals
• Adverse effects: glaucoma, cataract formation
• Contraindications: glaucoma, eye infections
Anti-inflammatory Agents: Inhaled
CHAPTER 46
Beclomethasone, budesonide,
ciclesonide, flunisolide,
fluticasone, mometasone,
triamcinolone acetonide
Asthma, chronic obstructive
pulmonary disease
• Rapid metabolism postabsorption into blood is the key for lung selectivity and lower
incidence of adverse events.
• Chronic use in children may slow growth velocity without compromising final height.
• Tip: Ciclesonide, a pro-drug converted to active des-ciclesonide in the lung, has low
oral bioavailability and less HPA suppression.
Anti-inflammatory Agents: Intranasal
Mometasone furoate
Fluticasone furoate
Fluticasone
propionate
Allergic rhinitis, rhinosinusitis,
rhinoconjunctivitis, nasal polyposis,
postoperatively for sinus ostia stenosis
surgery
• Potent localized activity, minimal systemic risk.
• Tip: Avoid frequent use.
Anti-inflammatory Steroids: Intra-articular
Hydrocortisone
Relief of joint pain
• Local and systemic adverse events rare.
• Success varies with difficulty (e.g., vertebral facet joints versus knees).
Acute lymphatic leukemia
Chronic lymphatic leukemia
Thymoma
Non-Hodgkin lymphoma
Multiple myeloma, breast cancer
• Used in combination with a variety of chemotherapeutic agents.
• Used for primary cytotoxic effects, plus relief of pain and nausea and appetite
stimulation.
• Tip: No place in acute or chronic myelogenous leukemia.
Dexamethasone
Cushing disease
• ↓ ACTH secretion from pituitary corticotrophs but not from ectopic sources.
Metyrapone
Integrity of entire HPA axis
• Inhibits CYP11B1, thereby reducing cortisol and ↑ levels of precursor steroids.
• Failure to adequately ↑ precursor levels indicates impaired HPA function.
Cosyntropin
(synthetic ACTH)
Ectopic ACTH secretion
Adrenal insufficiency
Lateralization of aldosterone
overproduction
• Cosyntropin is a truncated synthetic form of ACTH used to test adrenal reserve.
• Tip: Cosyntropin is commonly used as either a bolus before or a continuous
infusion during adrenal venous sampling to distinguish between unilateral and
bilateral aldosterone oversecretion in primary aldosteronism.
Peritumoral brain edema postsurgery
(off-label use); diagnostic testing
• A synthetic CRH, preferred to high-dose dexamethasone in relieving peritumoral
brain edema.
• Used diagnostically to distinguish Cushing disease from ectopic ACTH syndrome.
Pasireotide
ACTH oversecretion (Cushing disease)
• Targets SSTR5 (abundant on corticotrophs), ↓ ACTH secretion; used for recurrent or
non-resectable ACTH-secreting adenomas
Cabergoline
ACTH oversecretion and
hyperprolactinemia
• D2 receptor agonist; ↓ ACTH secretion, ↓ prolactin secretion; useful but not FDAapproved for Cushing disease
Chemotherapy
Dexamethasone
Prednisolone
Methylprednisolone
Prednisone
Diagnostics
Stimulant of ACTH Secretion
Corticorelin
Inhibitors of ACTH Secretion
Inhibitors of Corticosteroid Production
Ketoconazole
Hypercortisolism (off-label use)
(Used at lower doses as antifungal
agent; see Chapter 61)
• ↓ CYP17 (17α-hydroxylase) and CYP11A1 (cholesterol side chain cleavage), ↓ adrenal
and gonadal steroidogenesis
• Adverse effects: hepatic toxicity; drug interactions due to inhibition of CYP3A4 and Pglycoprotein
Metyrapone
Hypercortisolism; adjunctive therapy
after pituitary irradiation
• Inhibits CYP11B1 (11-deoxy cortisol → cortisol),
• ↓ cortisol; 4 g/d to maximally ↓ steroidogenesis
• chronic use may cause hirsutism & hypertension
Etomidate
Rapid control of hypercorticolism (off
label use)
(Also a short-acting anesthetic; see
Chapter 21)
• Inhibits CYP11B1 (11-deoxy cortisol → cortisol),
• ↓ cortisol production at sub-anesthetic doses
• Administer as IV bolus, 0.03 mg/kg
Inhibitors of Corticosteroid Production (continued)
Mitotane
Treating inoperabl adrenocortical carcinoma
(See also Chapter 66)
• Activated by adrenal cortical CYPs to an acyl chloride with cytolytic effects
• Inhibits CYP11A1 (cholesterol side chain cleavage), ↓ steroidogenesis
Hypercortisolism
(Used at lower doses as anti- progesterone for
termination of early pregnancy; see Chapter 44)
• GR antagonist, IC50~2.2 nM (IC50 for anti-progesterone effect, ~0.025 nM)
• Used at 300-1200 mg/d to treat inoperable hypercortisolism that is
resistant to other agents
Glucocorticoid Antagonist
Mifepristone
(RU486)
884
Drug Facts for Your Personal Formulary: Agents for Diabetes and Hypoglycemia
Drugs
Therapeutic Uses
Clinical Pharmacology and Tips
Insulin—short acting (regular)
•
•
•
•
Type 1 and type 2 diabetes
Control prandial rise in blood glucose
Acute correction of hyperglycemia
Intravenous infusion for DKA and
hyperglycemia in hospitalized setting
•
•
•
•
Injected SC, IM, or IV
Onset of action 30–45 min after subcutaneous injection
Duration of action of 4–6 h after subcutaneous injection
Major adverse event: hypoglycemia
Insulin analogues—short acting
(lispro, aspart, glulisine)
• Type 1 and type 2 diabetes
• Control prandial rise in blood glucose
• Used in insulin pump for treatment of
diabetes
•
•
•
•
•
Genetically modified to accelerate insulin absorption profile
Injected SC or IM
Onset of action 5–15 min after SC injection
Duration of action of 3–4 h after SC injection
Major adverse event: hypoglycemia
Insulin—long acting (NPH)
• Provide basal insulin in type 1 and
type 2 diabetes
• Reduce fasting hyperglycemia in
type 2 diabetes
• Formulated to prolong insulin absorption
• Usually requires twice-daily subcutaneous injection to provide 24-h
basal insulin coverage
• Combined with short-acting insulin in basal/bolus regimen
• Given at bedtime in type 2 diabetes to reduce hepatic glucose
production
• Duration of action of 8–12 h
• Major adverse event: hypoglycemia
Insulin analogues—long acting
(glargine, detemir, degludec)
• Provide basal insulin in type 1 and
type 2 diabetes
•
•
•
•
•
Genetically modified to prolong absorption
Once-a-day subcutaneous injection ⇒ 24-h basal insulin coverage
Combined with shorting action insulin in basal/bolus regimen
Duration of action of 18–42 h
Major adverse event: hypoglycemia
•
•
•
•
•
•
•
Reduce hepatic glucose production
Weight neutral
Do not cause hypoglycemia
Adverse events include diarrhea, nausea, lactic acidosis
(black-box warning)
Use cautiously in renal insufficiency, hospitalized patients; temporarily
discontinue therapy prior to potential renal insults (e.g., radiocontrast media)
Avoid use in patients with hepatic dysfunction
Can be combined with other agents
Inexpensive
Reduce carbohydrate breakdown in GI tract
Adverse effects: GI flatulence, elevated liver function tests
Can be combined with other agents
Relatively modest glucose lowering
Insulin Formulations
CHAPTER 47
Oral Glucose-Lowering Agents
Biguanides (metformin)
• Therapy of type 2 diabetes
• Usually initial agent in type 2 diabetes
•
α-Glucosidase inhibitors
Acarbose, miglitol, voglibose
• Therapy of type 2 diabetes
•
•
•
•
Dipeptidyl peptidase 4
inhibitors Sitagliptin,
saxagliptin, linagliptin,
alogliptin, vildagliptin
• Therapy of type 2 diabetes
• Prolong action of GLP-1; promotes insulin secretion
• Can be combined with other agents
• Relatively modest glucose lowering
Insulin
secretagogues—
sulfonylureas Second
generation: glyburide,
glibenclamide, glipizide,
and others
• Therapy of type 2 diabetes
•
•
•
•
Insulin secretagogues—
nonsulfonylureas
Repaglinide, nateglinide
• Therapy of type 2 diabetes
•
•
•
•
SLGT2 inhibitors
Canagliflozin, dapagliflozin,
empagliflozin
• Therapy of type 2 diabetes
•
•
•
•
Stimulate insulin secretion
Major adverse event is hypoglycemia
Adjustments needed in renal/liver disease
Newer agents more potent, may have better safety profile than firstgeneration agents.
• Can be combined with other agents
• Modest weight gain
• Inexpensive
↑ Insulin secretion; quicker onset and shorter duration than sulfonylureas
Major adverse event: hypoglycemia
Adjustments needed in renal/liver disease
Can be combined with other agents
Prevent glucose reabsorption and promote renal glucose excretion
Mild weight loss and BP reduction
Do not cause hypoglycemia
May ↑ rate of lower urinary tract and genital mycotic infections,
hypotension, and DKA
• Can be combined with other agents
Other Glucose-Lowering Agents (continued)
• Therapy of type 2 diabetes
• Increase insulin sensitivity
• Adverse effects: peripheral edema, CHF, weight gain, fractures,
macular edema
• Use with caution in CHF, liver disease
• Can be combined with other agents
GLP-1 agonists
Albiglutide, dulaglutide, exenatide,
liraglutide
• Therapy of type 2 diabetes
•
•
•
•
•
•
↑ Insulin secretion, ↓ gastric emptying, ↓ glucagon
Injected subcutaneously
Often associated with weight loss
Adverse events include nausea
Do not use with agents that ↓ GI motility
Risk of hypoglycemia with insulin
Amylin analogue
Pramlintide
• Adjunctive therapy with insulin in type 1
and type 2 diabetes
•
•
•
•
•
•
•
Slows gastric emptying, decreases glucagon
Injected subcutaneously
↓ Postprandial glycemia
Often associated with weight loss
Adverse events include nausea
Do not use with agents that ↓ GI motility
Risk of hypoglycemia with insulin
• Emergency treatment of severe
hypoglycemia
• Diagnostic aid for GI radiographic
examination
•
•
•
•
Injected SC, IM, or IV
Quickly raises blood glucose
Relaxes smooth muscles of the GI tract
+ Inotropism and chronotropism on heart
Thiazolidinediones
Rosiglitazone, pioglitazone
Other Glucose-Lowering Agents
Drugs to Reverse Hypoglycemia
Glucagon
Other Pancreatic Islet-Related Hormones or Drugs
Diazoxide
• Treatment of hypertensive crisis
• Treatment of pathologic
hyperinsulinemia
• Inhibits insulin secretion
• Adverse events include nausea, vomiting, fluid retention,
hyperuricemia, hypertrichosis, thrombocytopenia, and
leukopenia
Somatostatin analogues
Octreotide, lanreotide
• Treatment of carcinoid tumors,
glucagonomas, VIPomas, acromegaly,
and Cushing disease
• Injected intramuscularly
• Inhibits hormone release
• Adverse events include gallbladder abnormalities
Drug Facts for Your Personal Formulary: Agents Affecting Mineral Ion
Homeostasis and Bone Turnover
Drugs
Therapeutic Uses
Clinical Pharmacology and Tips
•
•
•
•
•
•
• Vitamin D2
• May cause hypercalcemia
Vitamin D Analogues
Ergocalciferol
Vitamin D deficiency
Nutritional rickets
Vitamin D–resistant rickets
Familial hypophosphatemia
Hypoparathyroidism
Osteomalacia/osteoporosis
Cholecalciferol
• Vitamin D3
• May cause hypercalcemia
Doxercalciferol
• Secondary hyperparathyroidism in patients
with CKD
• 1-Hydroxylated ergocalciferol (1-OH-D2)
• “Activated” in the liver by 25-hydroxylation
• May cause hypercalcemia, hypercalciuria, or hyperphosphatemia
Alfacalcidol
• Secondary hyperparathyroidism in patients
with CKD
• 1-Hydroxylated cholecalciferol (1-OH-D3)
• “Activated” in the liver by 25-hydroxylation
• May cause hypercalcemia, hypercalciuria, or hyperphosphatemia
Dihydrotachysterol
•
•
•
•
Familial hypophosphatemia
Hypoparathyroidism
Osteoporosis
Secondary hyperparathyroidism in patients
With CKD
• Hypocalcemia
• Secondary hyperparathyroidism in patients
with CKD
•
•
•
•
Calcitriol
• Hypocalcemia
• Secondary hyperparathyroidism in patients
with CKD
• Hypoparathyroidism
• 1,25-Dihydroxylated form of cholecalciferol
• Activated form of vitamin D
• May cause hypercalcemia, hypercalciuria, or hyperphosphatemia
Paricalcitol
• Secondary hyperparathyroidism in patients
with CKD
• 1,25-Dihydroxy-19-norvitamin D2
• Minimal effects on serum calcium and phosphorus
Maxacalcitol
• Secondary hyperparathyroidism in patients
with CKD
•
•
•
•
Calcipotriol
• Psoriasis
• Negligible effects on serum calcium
• For topical application only
Calcifediol
Reduced form of ergocalciferol
“Activated” in the liver by 25-hydroxylation
May cause hypercalcemia, hypercalciuria, or hyperphosphatemia
Not available in the U.S.
• 25-Hydroxylated form of cholecalciferol
• “Activated” in the kidney by 1-hydroxylation
• Not available in the U.S.
1,25-Dihydroxy-22-oxavitamin D3
Shorter t1/2 than calcitriol
Potent suppressor of PTH gene expression
Not marketed in the U.S.
Phosphate-Binding Agents • Taken with meals to reduce the amount of dietary phosphate absorbed
Calcium carbonate
• Treatment and prevention of CKD-MBD
• Inexpensive, well tolerated, commonly used
• 40% elemental calcium
Calcium acetate
• Treatment and prevention of CKD-MBD
• Well tolerated, commonly used
• 25% elemental calcium
Sevelamer hydrochloride
• Treatment and prevention of CKD-MBD
• Nonabsorbable polymer that acts as a nonselective anion exchanger
• Risk of metabolic acidosis
Sevelamer carbonate
• Treatment and prevention of CKD-MBD
• Same polymeric structure as sevelamer hydrochloride, with chloride
replaced by carbonate
• Decreased risk of metabolic acidosis
Lanthanum carbonate
• Treatment and prevention of CKD-MBD
• Risk of gastrointestinal obstruction and ileus
• Contraindicated in bowel obstruction
Sucroferric oxyhydroxide
(oral formulation)
• Treatment and prevention of CKD-MBD
• Polynuclear iron(III)–oxyhydroxide compound that binds phosphate by
ligand exchange
• Negligible absorption of iron
• Injectable formulation is used for iron replacement therapy
Ferric citrate
• Treatment and prevention of CKD-MBD
• Iron absorption may lead to increased systemic iron parameters and
toxicity
Drug Facts for Your Personal Formulary: Agents Affecting Mineral Ion
Homeostasis and Bone Turnover (continued)
Drugs
Therapeutic Uses
Clinical Pharmacology and Tips
CHAPTER 48 AGENTS AFFECTING MINERAL ION HOMEOSTASIS AND BONE TURNOVER
Bisphosphonates • Inhibit osteoclast-mediated bone resorption
Etidronate
• Paget disease
• Heterotopic ossification
• Hypercalcemia
•
•
•
•
Clodronate
• Paget disease
• Treatment and prevention of osteoporosis
• Hypercalcemia of malignancy
• Prevention of bone loss in breast cancer and
ultiple myeloma
• Risk of nephrotoxicity
• Osteonecrosis of the jaw reported
• Not commercially available in the U.S.
Tiludronate
• Paget disease
• Esophagitis, esophageal ulcers or erosions reported with oral administration
• Caution in creatinine clearance < 35 mL/min
• Osteonecrosis of the jaw reported
Pamidronate
• Paget disease
• Hypercalcemia of malignancy
• Prevention of bone loss in breast cancer and
multiple myeloma
•
•
•
•
•
10–100 times more potent than etidronate
Risk of nephrotoxicity
Osteonecrosis of the jaw reported
Fractures of the femoral shaft reported
Available in the U.S. only for parenteral administration
Alendronate
• Paget disease
• Treatment and prevention of osteoporosis
•
•
•
•
10–100 times more potent than etidronate
Esophagitis, esophageal ulcers or erosions reported with oral administration
Contraindicated in those with abnormalities that delay esophageal emptying
Osteonecrosis of jaw, fractures of femoral shaft reported
Ibandronate
• Treatment and prevention of osteoporosis
•
•
•
•
Esophagitis, esophageal ulcers or erosions reported with oral administration
Contraindicated in those with abnormalities that delay esophageal emptying
Risk of nephrotoxicity
Osteonecrosis of jaw, fractures of the femoral shaft, anaphylaxis reported
Risedronate
• Paget disease
• Treatment and prevention of osteoporosis
•
•
•
•
•
•
Third-generation agent
10,000 times more potent than etidronate
Esophagitis, esophageal ulcers or erosions reported with oral administration
Contraindicated in those with abnormalities that delay esophageal emptying
Osteonecrosis of jaw, fractures of the femoral shaft reported
Many dosing regimens (daily to 2 months)
Zoledronate
•
•
•
•
•
•
•
•
•
•
•
Third-generation agent
10,000 times more potent than etidronate
Contraindicated in hypocalcemia and creatinine clearance < 35 mL/min
May cause severe hypocalcemia
Risk of nephrotoxicity
Osteonecrosis of jaw, fractures of femoral shaft, anaphylaxis reported
Annual dosing for postmenopausal use
• Treatment of osteoporosis
•
•
•
•
Anabolic agents
Increase new bone formation
Use should be limited to ≤ 2 years
Should not be used in patients who are at increased baseline risk for osteosarcoma
rhPTH
• Adjunctive treatment of hypocalcemia in
patients with hypoparathyroidism
• Recombinant human parathyroid hormone [rhPTH(1-84)]
• Severe hypercalcemia reported
• Should not be used in patients who are at increased baseline risk for
osteosarcoma
• Only available under an REMS program
Long acting PTH
• Treatment of osteoporosis
• Increases serum calcium concentrations in rodents for almost 24 h
• Investigational use only
Paget disease
Treatment and prevention of osteoporosis
Hypercalcemia of malignancy
Adjunctive treatment of bone metastases
from solid tumors and osteolytic lesions of
multiple myeloma
Esophagitis, esophageal ulcers or erosions reported with oral administration
Contraindicated in those with abnormalities that delay esophageal emptying
Risk of nephrotoxicity
Osteonecrosis of the jaw reported
Parathyroid Hormone Analogues
Teriparatide
[hPTH(1-34)]
Abaloparatide
[hPTHrP(1-34)]
Calcium-Sensing Receptor Mimetics • Cinacalcet
Cinacalcet
• Secondary hyperparathyroidism in adults with
CKD on dialysis
• Hypercalcemia in adults with parathyroid
carcinoma
• Hypercalcemia in adults with primary
hyperparathyroidism who are not candidates
for surgical parathyroidectomy
• May cause severe hypocalcemia
• Concomitant use of strong inhibitors of CYP3A4 should be avoided
• Dose adjustment may be required for concomitant medications that are CYP2D6
substrates
Miscellaneous Antiresorptive Agents
Calcitonin
• Paget disease
• Hypercalcemia
• Postmenopausal osteoporosis
• Direct inhibitor of osteoclastic bone resorption
• Anaphylaxis/hypersensitivity reported
Denosumab
• Treatment and prevention of osteoporosis
• Treatment to increase bone mass in adults at
high risk for fracture receiving cancer therapy
•
•
•
•
Raloxifene
• Treatment and prevention of osteoporosis
• Selective estrogen receptor modulator
• Contraindicated in adults with history of venous thromboembolism; increased
risk of deep vein thrombosis and pulmonary embolism
Hydrochlorothiazide
• Osteoporosis
• Hypercalciuria
• Reduce urinary calcium excretion
• Constrain bone loss in patients with hypercalciuria
• Prophylaxis of dental caries
• Childhood consumption of fluoridated drinking water reduces incidence of
caries in permanent teeth
• Topical application can reduce the incidence of caries by 30%–40%
Human monoclonal antibody that binds with high affinity to RANKL
Contraindicated in setting of preexisting hypocalcemia
Osteonecrosis of the jaw reported
Fractures of the femoral shaft reported
Fluoride
Sodium fluoride
Drug Facts for Your Personal Formulary: Antisecretory Agents and
Gastroprotectives
Drugs
Therapeutic Uses
Clinical Pharmacology and Tips
Proton Pump Inhibitors
CHAPTER 49
Dexlansoprazole
• Gastroesophageal reflux disease
• Erosive esophagitis
•
•
•
•
•
•
Generally well tolerated
Possible interaction with clopidogrel (controversial)
Increased incidence of osteoporosis-related fractures of hip, wrist, or spine
Diarrhea
Interstitial nephritis
May cause cyanocobalamin (vitamin B12) deficiency with daily long-term use (>3 years)
Esomeprazole
Lansoprazole
Omeprazole
Pantoprazole
•
•
•
•
•
•
Gastric ulcers
Duodenal ulcers
Erosive esophagitis
Gastroesophageal reflux disease
Helicobacter pylori eradication
Zollinger-Ellison syndrome
•
•
•
•
•
•
•
•
OTC forms for acid reflux
Generally well tolerated
Possible interaction with clopidogrel (controversial)
Increased incidence of osteoporosis-associated fractures of hip, wrist, or spine
Diarrhea
Interstitial nephritis
May cause cyanocobalamin (vitamin B12) deficiency with daily long-term use (>3 years)
Interactions with diagnostic investigations for neuroendocrine tumors
Rabeprazole
• Gastroesophageal reflux disease
• Helicobacter pylori eradication
• Zollinger-Ellison syndrome
•
•
•
•
•
Generally well tolerated
Possible interaction with clopidogrel (controversial)
Increased incidence of osteoporosis-associated bone fractures of hip, wrist, or spine
Diarrhea
Interstitial nephritis
Histamine 2 Receptor Antagonists
Cimetidine
Famotidine
Nizatidine
Ranitidine
• Gastric ulcer (to promote healing)
• Duodenal ulcer (to promote healing)
• Gastroesophageal reflux disease
• No longer recommend for treating active ulcers
• Generally well tolerated
Mucosal Defensive Agents
Misoprostol
• Ulcer prophylaxis
•
•
•
•
Sucralfate
• Ulcer prophylaxis
• Generally well tolerated
• Constipation
Antacids
• Acid reflux
• Esophagitis
• OTC; generally well tolerated
• Na+ and AL+3 loads: potential problems in CV and renal disease
.
Rarely used because of side effects
Cannot be used in women of childbearing potential
Diarrhea
Marketed in combination with diclofenac
.
Drug Facts for Your Personal Formulary: Antisecretory Agents and Gastroprotectives
Drugs
Therapeutic Uses
Clinical Pharmacology and Tips
Prokinetic Agents (agents acting through specific receptors to regulate GI motility)
CHAPTER 50
MOR antagonist
Alvimopan
• Postoperative ileus
• Myocardial infarction
• Hypokalemia
• Dyspepsia
5HT4 receptor
agonists Cisapride
Prucalopride
•
•
•
•
•
• Serious cardiac risks
• Headache
• Diarrhea
D2 receptor antagonist
Domperidone
Metoclopramide (also 5HT3 receptor
antagonist, 5HT4 receptor agonist)
• Gastroparesis
• Prevention of nausea and vomiting
•
•
•
•
•
Serious cardiac risks, especially in older persons
Limited pediatric use
Tardive dyskinesia
Limited pediatric use
Short-term use only
Motilin receptors
Erythromycin (stimulate motilin
receptors on GI smooth muscle
cells)
• Gastroparesis
•
•
•
•
Short-term use only
Ototoxicity
Pseudomembranous colitis
Cardiac risks
CCK peptide analogue
Sincalide
(C-terminal octapeptide of CCK)
• Intravenous injection
• Gallbladder contraction
• Pancreatic secretion
• Intestinal motility
• Accelerates barium transit through
small bowel for diagnostic testing
•
•
•
•
•
Nausea, vomiting, diarrhea
Sweating
Light-headed
Headache
May cause serious allergic reactions
• Increase fecal bulk
• Bloating
Docusate
• Constipation
• Marginal efficacy
Mineral oil
• Constipation
• Side effects preclude regular use
• Interferes with absorption of fat-soluble vitamins
• Oil leakage
Polyethylene glycol–electrolyte solutions
• Colonic cleansing prior to examination
• Constipation (powder form)
• Nausea
• Cramping and bloating
Saline laxatives–Mg2+
• Constipation
•
•
•
•
•
Nondigestible sugars and alcohols
Lactulose
Sorbitol
• Constipation caused by opioids
• Idiopathic chronic constipation
• Lactulose also used to treat hepatic
encephalopathy
• Abdominal discomfort
• Flatulence
Diphenylmethane derivatives
Bisacodyl
Sodium picosulfate
• Constipation
• Bowel cleansing prior to colonoscopy
•
•
•
•
Can damage mucosa
Inflammatory response
May cause hypermagnesemia
May decrease glomerular filtration rate
Anthraquinone laxatives
Senna
• Constipation
•
•
•
•
Plant derivatives
Melanosis coli
Nausea and vomiting
Cramping
Gastroesophageal reflux disease
Gastroparesis
Intestinal pseudoobstruction
Severe constipation
Neonatal feeding intolerance
Laxatives
Dietary Fiber
Psyllium Methylcellulose
Stool-Softening Agents
Osmotically Active Agents
Urgency
Watery stools
Renal insufficiency
Heart disease
Diuretic therapy
Stimulant Laxatives
941
Laxatives (continued)
Ricinoleic acid
Castor oil
• Act on small intestine
• Stimulate secretion
• Increase intestinal transit
• Potential toxic effect from ricin
• Not clinically recommended
Enemas and suppositories
Glycerin
• Bowel distension
• Glycerin for rectal use
• Discomfort
Guanylate cyclase-C agonist
Linaclotide
Plecanatide
• Opioid-induced constipation
• Contraindicated in children up to 6 years
• Diarrhea
Cl- channel activator
Lubiprostone
• Chronic idiopathic constipation
• Opioid-induced constipation
• IBS with constipation
• Nausea
• Diarrhea
Pro-Secretory Agents
Drugs for Opioid-Induced Constipation
MOR antagonists
Methylnaltrexone
Naloxegol
Naldemedine
• Opioid-induced constipation
•
•
•
•
•
Peripheral MOR antagonist
Diarrhea
Abdominal pain
Nausea and vomiting
Flatulence
• Opioid-induced constipation
•
•
•
•
•
Respiratory depression
Addiction
Nausea and vomiting
Constipation
Diarrhea
5HT3 receptor antagonist
Alosetron
• Diarrhea-predominant IBS in women
• Ischemic colitis
• Constipation
Antibiotics—empiric therapy
Fluoroquinolone
Ciprofloxacin
Levofloxacin
Norfloxacin
Ofloxacin
Alternative antibiotics
Azithromycin
Rifaxamin
• Acute diarrhea
• Traveler’s diarrhea
• Azithromycin: preferred
treatment for children with
traveler’s diarrhea
• Rifaxamin: preferred for diarrheapredomi
nant IBS
•
•
•
•
•
•
Avoid if Escherichia coli suspected
Avoid if Clostridium difficile suspected
Controversial in children (azithromycin is preferred for children)
Nausea
Peripheral edema
Dizziness
Bile acid sequestrants
Cholestyramine
Colesevelam
Colestipiol
• Bile salt–induced diarrhea
•
•
•
•
Bloating
Flatulence
Abdominal discomfort
Constipation
Bismuth subsalicylate
• Acute diarrhea
• Nausea and abdominal cramping
• Dark stools
α2 adrenergic receptor agonist
Clonidine
• Diabetic diarrhea
•
•
•
•
Crofelemer (plant derived)
• HIV/AIDS diarrhea
• Infectious diarrhea must not be suspected
• Inhibits CFTR and reduces Cl-secretion
MOR agonists
Diphenoxylate
Difenoxin
Loperamide
• Acute diarrhea
• Chronic diarrhea
• Traveler’s diarrhea
•
•
•
•
•
•
MOR/KOR agonist DOR antagonist
Eluxadoline
• Diarrhea-predominant IBS
• Pancreatitis
• Sphincter of Oddi spasm
• Constipation
SST receptor agonist
Octreotide
• Severe secretory diarrhea due to GI
tumors
• Postgastrectomy dumping
syndrome
Opioid receptor agonist/antagonist
Oxycodone:naloxone (2:1 ratio)
Antidiarrheal Agents
Hypotension
Depression
Drowsiness
Fatigue
Limit use to 10 days
Use with caution in children
Constipation
Toxic megacolon
CNS depression in children
Paralytic ileus
• Sinus bradycardia
• Chest pain
• Headache
• Abdominal pain
• Nausea
• Diarrhea
942
Drug Facts for Your Personal Formulary: Antisecretory Agents and
Gastroprotectives (continued)
Drugs
Therapeutic Uses
Clinical Pharmacology and Tips
Enkephalinase inhibitor
Racecadotril
• Acute diarrhea
• Proven safety in children
Tryptophan hydroxylase inhibitor
Telotristat ethyl
• Severe diarrhea due to carcinoid
tumors
• Adverse Effects: Constipation, Nausea, Headache,
Depression
Antidiarrheal Agents (continued)
Antispasmodic Agents (Anticholinergics)
Dicyclomine
Glycopyrrolate
Hyoscyamine
Methscopolamine
• Abdominal and urgency in IBS
•
•
•
•
•
Contraindicated in colitis, reflux esophagitis, and bowel obstruction
Dizziness
Dry mouth
Nausea
Blurred vision
• Motion sickness
• Nausea and vomiting
• Sedation
• Dry mouth
• Promethazine is contraindicated in children < 2 years old
• Nausea and vomiting of pregnancy
•
•
•
•
NK1 antagonists
Aprepitant
Rolapitant
• Chemotherapy-induced nausea and
vomiting
• Postoperative nausea and vomiting
• Given with dexamethasone and a 5HT3 antagonist
• Contraindicated in patients on cisapride, pimozide, or thioridazine
• Fatigue, constipation, hiccups
5HT3 antagonists
Dolasetron
Granisetron
Ondansetron
Palonesetron
Tropisetron
• Chemotherapy-induced nausea and
vomiting
• Radiation-induced nausea and
vomiting
• Postoperative nausea and vomiting
•
•
•
•
•
•
ECG effects
Serotonin syndrome
Headache
Constipation
Fatigue
Malaise
NK1/5HT3 antagonists
Netupitant
Palonesetron
• Chemotherapy-induced nausea and
vomiting
•
•
•
•
Serotonin syndrome
Headache
Constipation
Fatigue
Cannabinoid receptor agonists
Dronabinol
Nabilone
• Chemotherapy-induced nausea and
vomiting
• Psychoactive
• Many CNS side effects
Dopamine receptor antagonists
Olanzapine (5HT2A and 5HT2C, D1-4, H1,
α1 adrenergic, and M receptor
antagonists)
Phenothiazines (D2, H1, 5HT2A, M, and
α1 receptor antagonists)
Chlorpromazine
Prochlorperazine
• Chemotherapy-induced nausea and
vomiting
• Refractory nausea and vomiting
•
•
•
•
Muscarinic receptor antagonist
Scopolamine
• Motion sickness
• Nausea and vomiting
• Cardiovascular actions
• Constipation, drowsiness, dry mouth, blurred vision
• Many other side effects
• Headache
• Abdominal pain
Simethicone
• Malabsorption (postpancreatectomy;
cystic
fibrosis)
• Pancreatitis pain
• Flatulence, bloating
Teduglutide (GLP-2 receptor analogue)
• Short-bowel syndrome
•
•
•
•
Ursodeoxycholic acid (bile acid)
• Dissolution of gallstones
• Nausea, headache
• GI disturbances
Antiemetic Agents
CHAPTER 50
Antihistamines
Cyclizine, diphenhydramine, meclizine,
promethazine
Doxylamine succinate and pyridoxine
(H1 receptor antagonist and vitamin B6)
Drowsiness
Dry mouth
Light-headedness
Constipation
D2 antagonism at CTZ
Somnolence
Hypotension
Increased mortality in elderly patients with dementia-related
psychosis
• Cardiac effects
• Extrapyramidal reactions
Miscellaneous Agents
Pancreatic enzymes
Colonic polyps/malignancy
Pancreatitis
Abdominal pain and distention
Nausea, headache
Drug Facts for Your Personal Formulary: Drugs for the Treatment of
Inflammatory Bowel Diseases
Drugs
Therapeutic Uses
Clinical Pharmacology and Tips
Mesalamine-Based Drugs
CHAPTER 51
Mesalamine (5-ASA)
• Induction and maintenance of remission in
mild-to-moderate ulcerative colitis
• Used in combination with glucocorticoids
for severe ulcerative colitis
• Effects are primarily topical with limited effects on deeper tissue inflammation
• Following oral administration, jejunum is primary site of absorption, so utility in
more distal disease is limited
• Can be delivered as a suppository for rectal disease
Sulfasalazine
• Induction and maintenance of remission in
mild-to-moderate ulcerative colitis
• Used in combination with glucocorticoids
for severe ulcerative colitis
• Prodrug, delivers 5-ASA to more distal GI regions following metabolism by colonic
bacteria
• Sulfapyridine is also released; may cause adverse effects in patients sensitive to
sulfa drugs
Olsalazine
• Induction and maintenance of remission in
mild-to-moderate ulcerative colitis
• Used in combination with glucocorticoids
for severe ulcerative colitis
• Prodrug with two azo-linked 5-ASA molecules
• Eliminates the side effects associated with the sulfapyridine moiety of
sulfasalazine
Balsalazide
• Induction and maintenance of remission in
mild-to-moderate ulcerative colitis
• Used in combination with glucocorticoids
for severe ulcerative colitis
• Prodrug with a 5-ASA molecule linked to an inert, unabsorbable second moiety
• Eliminates the side effects associated with the sulfapyridine moiety of
sulfasalazine
Glucocorticoids: Minimize duration of use. Taper dose prior to stopping to minimize disease relapse and avoid adrenal
insufficiency that follows rapid glucocorticoid withdrawal after prolonged therapy has suppressed the HPA axis.
Prednisone
• Induction of remission in moderate-tosevere Crohn disease and ulcerative colitis
• Hepatic metabolism to active moiety, prednisolone
• Not used for maintenance therapy due to serious adverse effects
Methylprednisolone
• Induction of remission in moderate-tosevere Crohn disease and ulcerative colitis
• Can be administered orally, intravenously, or intramuscularly to patients who
respond poorly to oral prednisone
• Preferred over hydrocortisone, which has higher incidence of Na+ retention and K+
wasting
Hydrocortisone
• Induction of remission in moderate-tosevere Crohn disease and ulcerative colitis
• Administered intravenously to patients who respond poorly to oral prednisone
Budesonide
• Induction of remission in mild-tomoderate Crohn disease and ulcerative
colitis, particularly in distal disease
• Not effective for long-term maintenance of
clinical remission
• Prominent first-pass metabolism reduces side effects that can result from
maintenance of higher systemic levels
Immunomodulatory Agents
6-Mercaptopurine
• Used as an adjunct to glucocorticoids
and biologics in the treatment of
moderate-to- severe Crohn disease and
ulcerative colitis
• Effective in maintenance of remission
• Slow-acting drug; maximum therapeutic benefit may take months to achieve
• Other metabolites also have anti-inflammatory activity
• Fourfold increased risk of lymphoma in patients with IBD treated with thiopurines
Azathioprine
• Used as an adjunct to glucocorticoids
and biologics in the treatment of
moderate-to- severe Crohn disease and
ulcerative colitis
• Effective in maintenance of remission
• Maintenance of remission in Crohn
disease, particularly steroid-resistant or
steroid- dependent disease
• Often used in combination with biologic
agents
• Prodrug metabolized nonenzymatically in blood to active form, 6-mercaptopurine
• Other metabolites also have anti-inflammatory activity
• Fourfold increased risk of lymphoma in patients with IBD treated with thiopurines
Cyclosporine
• Used to treat specific cases of severe
Crohn disease, including fistulizing
disease
• Not useful for maintenance of remission
• Erratic and incomplete absorption means blood levels must be monitored
• Significant adverse events profile
Tacrolimus (FK506)
• Useful for the treatment of refractory Crohn
disease
• Immunomodulator with similar mechanism as cyclosporine but with better oral
absorption
Methotrexate
• Folic acid analogue that has anti-inflammatory activity of unclear mechanism
• Administered parenterally
• Cleared unaltered by the kidney, so inhibition of renal excretion mechanisms may
lead to drug toxicity
Biologics: Anti–TNF-α
Infliximab
• Induction or maintenance of remission
in moderate-to-severe Crohn disease
or ulcerative colitis in patients who
have not responded well to other
therapies
• Partly humanized, chimeric anti–TNF-α monoclonal antibody
• Usually administered by intravenous infusion
• Patients may develop antibodies against the drug
Adalimumab
• Induction or maintenance of remission
in moderate-to-severe Crohn disease
or ulcerative colitis in patients who
have not responded well to other
therapies
• Fully humanized anti–TNF-α monoclonal antibody; reduced incidence of antidrug
antibodies
• Administered subcutaneously
• Useful for patients for whom infliximab has lost efficacy or has caused adverse
reactions
Certolizumab pegol
• Induction or maintenance of remission in
moderate-to-severe Crohn disease in
patients who have not responded well to
other therapies
• Humanized anti–TNF-α monoclonal antibody bound to PEG to increase plasma t1/2
• Administered subcutaneously
• Useful for patients for whom infliximab has lost efficacy or caused adverse
reactions
• May be a better option in pregnant women due to less drug crossing placental
barrier
Vedolizumab
• Induction or maintenance of remission
in moderate-to-severe Crohn disease
or ulcerative colitis in patients who
have not responded to other
therapies
• Humanized anti-α4β7 monoclonal antibody
• Given by intravenous infusion
• May cause hypersensitivity reactions
Ustekinumab
• Induction or maintenance of remission in
moderate-to-severe Crohn disease in
patients who have not responded to other
therapies
• Humanized monoclonal antibody against p40 subunit of IL-12 and IL-23
• Administered subcutaneously
• Long-term safety profile has not yet been established
Metronidazole
• Used as adjunctive therapy in
mild-to- moderate Crohn disease
• Sometimes used in conjunction
with ciprofloxacin
• Used in pediatric IBD
• Modest therapeutic benefit in Crohn disease
• Little to no benefit in ulcerative colitis
Ciprofloxacin
• Used as adjunctive therapy in
mild-to- moderate Crohn disease
• Sometimes used in conjunction with
metronidazole
• Used in pediatric IBD
• Modest therapeutic benefit in Crohn disease
• Little to no benefit in ulcerative colitis
Rifaximin
• Used as adjunctive therapy in
mild-to- moderate Crohn disease
• Used in pediatric Crohn disease
• Less experience with this drug compared to metronidazole or ciprofloxacin
• Some utility in ulcerative colitis and
pouchitis, but few clinical trials
• Effects are transient; long-term colonic colonization rarely occurs
• Watch for progress on fecal transplant therapy
Biologics: Other
Antibiotics
Probiotics
Various types
and
formulations
Bibliography
.
Drug Facts for Your Personal Formulary: Regimens for Malaria Treatment
Drug Indication
Adult Dosage
Pediatric Dosagea
Artemetherlumefantrine
P. falciparum from
chloroquine-resistant or
unknown areas
Tablet: 20 mg artemether,
lumefantrine. Dose: 4 tablets.
Day 1: 2 doses separated by
8 h; thereafter twice daily
× 2 days
Wgt (kg)
5–15
15–25
25–<35
>35
Tablets/dose
1
2
3
4
Use same 3-day schedule as adults
Comments
Adults; headache
anorexia, dizziness,
asthenia,
arthralgia myalgia
Take with food or whole milk. If
patient vomits within 30 min,
repeat dose. Contraindicated in
pregnancy.
Children: fever,
cough, vomiting,
loss of appetite,
headache
See Artemether
See Artemether CDC guidelines
Pediatric tablet = 62.5 mg
atovaquone/25 mg proguanil
5–8 kg: 2 ped tab orally/d × 3 d
>8–10 kg: 3 ped tab daily × 3 d
>10–20 kg: 1 adult tab daily × 3 d
>20–30 kg: 2 adult tab daily × 3 d
>30–40 kg: 3 adult tab daily × 3 d
>40 kg: 4 adult tab daily × 3 d
Abdominal pain,
nausea, vomiting,
diarrhea, headache,
rash, mild
reversible
elevations in liver
aminotransferase
levels
Not indicated for use in pregnant
women due to limited data.
Contraindicated if hypersensitivity
to atovaquone or proguanil; severe
renal impairment (creatinine
clearance
< 30 mL/min).
Should be taken with food to
increase absorption of atovaquone.
600 mg base (1000 mg salt)
orally immediately, followed
by 300 mg base (500 mg salt)
orally at 6, 24, and 48 h
Total dose: 1500 mg base
(2500 mg salt)
10 mg base/kg orally immediately,
followed by 5 mg base/kg orally at
6, 24, and 48 h
Total dose: 25 mg base/kg
Nausea, vomiting,
rash, headache,
dizziness, urticaria,
abdominal pain,
pruritus
Safe in children and pregnant
women. Give for chemoprophylaxis
(500 mg salt orally every week) in
pregnant women with
chloroquine-sensitive
P. vivax.
Contraindicated if retinal or
visual field change;
hypersensitivity to
4-aminoquinolines.
Use with caution in those with
impaired liver function since the
drug is concentrated in the liver.
Oral: 20 mg base/kg/d orally
divided 3 times daily × 7 d
IV: 10 mg base/kg loading
dose IV followed by 5 mg
base/kg IV every 8 h; switch to
oral clindamycin (as above) as
soon as patient can take oral
meds; duration = 7 d
Oral: 100 mg orally twice daily
× 7 d.
IV: 100 mg IV every 12 h and
then switch to oral doxycycline
(as above) as soon as patient
can take oral medication;
treatment course = 7 d.
Oral: 20 mg base/kg/d orally
divided 3 times daily × 7 d
IV: 10 mg base/kg loading dose IV
followed by 5 mg base/kg IV every
8 h; switch to oral clindamycin
(oral dose as above) as soon as
patient can take oral medication;
treatment course = 7 d
Oral: 2.2 mg/kg orally every 12 h
× 7 d.
IV: Only if patient is not able to
take oral medication; for children
< 45 kg, give 2.2 mg/kg IV every
12 h and then switch to oral
doxycycline (dose as above) as
soon as patient can take oral
medication; for children > 45 kg,
use same dosing as for adults;
duration = 7 d.
Diarrhea, nausea, rash
Always use in combination
with quinine-quinidine.
Safe in children and pregnant
women.
Nausea, vomiting,
diarrhea,
abdominal pain,
dizziness,
photosensitivity,
headache,
esophagitis,
odynophagia.
Rarely hepatotoxicity,
pancreatitis, and
benign intracranial
hypertension seen
with tetracycline
class of drugs.
Always use in combination
with quinine or quinidine.
Contraindicated in children <
8 y, pregnant women, and
persons with known
hypersensitivity to
tetracyclines.
Food, milk, and Ca2+ antacids
decrease absorption and decrease
GI disturbances.
To prevent esophagitis, take
tetracyclines with large
amounts of fluids (patients
should not lie
down for 1 h after taking the
drugs). Barbiturates,
carbamazepine, or
phenytoin may cause reduction inp C
of doxycycline.
Artesunate
(IV; available from CDC)
Severe malaria; see CDC
guidelines.
U.S. treatment IND (CDC): 4
equal doses of artesunate
(2.4 mg/kg each) over a
3-day period followed by oral
treatment with atovaquoneproguanil, doxycycline,
clindamycin, or mefloquine
(to avoid emergence of
resistance)
Atovaquone-proguanil
P. falciparum from
chloroquine-resistant areas P.
vivax
Adult tablet 250 mg
atovaquone/100 mg proguanil
4 Adult tablets orally per day
× 3 days
Chloroquine phosphate
P. falciparum from
chloroquine-sensitive areas P.
vivax from chloroquinesensitive areas
All P. ovale
All P malariae
All P. knowlesi
Clindamycin (oral or IV)
P. falciparum from
chloroquine-resistant areas
P. vivax from chloroquineresistant areas
Doxycycline (oral or IV)
P. falciparum and P. vivax
from chloroquine-resistant
areas
Potential
Adverse Effects
Drug Facts for Your Personal Formulary: Regimens for Malaria Treatment
(continued)
CHAPTER 53
Drug Indication
Adult Dosage
Pediatric Dosagea
Potential
Adverse Effects
Hydroxychloroquine
(oral)
Secondary alternative for
treatment of P. falciparum
and P. vivax from
chloroquine-sensitive areas
All P. ovale
All P. malariae
620 mg base (= 800 mg
salt) orally immediately,
followed by 310 mg base
(= 400 mg salt) orally at 6,
24, and 48 h Total dose:
1550 mg base
(= 2000 mg salt)
10 mg base/kg orally
immediately, followed by
5 mg base/kg orally at
6, 24, and 48 h
Total dose: 25 mg base/kg
Nausea, vomiting,
rash, headache,
dizziness, urticaria,
abdominal pain,
pruritusb
Safe in children and pregnant women.
Contraindicated if retinal or visual
field change; hypersensitivity to
4-aminoquinolines.
Use with caution in those with
impaired liver function.
Mefloquinec
P. falciparum from
chloroquine-resistant
areas, except ThailandBurmese and ThailandCambodian border regions
P. vivax from chloroquineresistant areas
684 mg base (= 750 mg
salt) orally as initial dose,
followed by 456 mg base
(= 500 mg salt) orally given
6–12 h after initial dose
13.7 mg
base/kg
(= 15 mg salt/kg) orally
as initial dose, followed
by 9.1 mg base/kg (= 10
mg salt/kg) orally given
6–12 h after
initial dose
Nausea, vomiting,
diarrhea, abdominal
pain; dizziness,
headache,
somnolence,
sleep disorders;
myalgia, mild skin
rash, and fatigue;
moderate-to-severe
neuropsychiatric
reactions; ECG
changes (sinus
arrhythmia, sinus
bradycardia, 1°
AV block, QTc
prolongation, and
abnormal T waves.
Contraindicated if hypersensitive to
the drug or to related compounds;
cardiac conduction abnormalities;
psychiatric disorders; and seizure
disorders.
Do not administer if patient has
received related drugs (chloroquine,
quinine, quinidine) less than 12 h ago
Total dose = 1250 mg salt
Total dose = 25
mg salt/kg
Comments
Primaquine phosphate
Radical cure of P. vivax
and P. ovale (to eliminate
hypnozoites)
30 mg base orally per day
× 14 d
0.5 mg base/kg orally per
day
× 14 d
GI disturbances,
methemoglobinemia
(self-limited),
hemolysis in persons
with G6PD deficiency
Quinine sulfate (oral) P.
falciparum from
chloroquine-resistant areas
P. vivax from chloroquineresistant areas
542 mg base (650 mg
salt)d orally 3 times
daily
× 3 d (infections acquired
outside Southeast Asia) to
7 d (infections acquired in
Southeast Asia)
8.3 mg base/kg (10 mg
salt/ kg) orally 3 times
daily × 3 d (infections
acquired outside
Southeast Asia) to 7 d
(infections acquired in
Southeast Asia)
Cinchonism,e sinus
arrhythmia,
junctional rhythms,
atrioventricular
block, prolonged QT
interval, ventricular
tachycardia,
ventricular fibrillation
(these are rare and
more commonly
seen with quinidine),
hypoglycemia
Must screen for G6PD deficiency
prior to use.
Contraindicated in persons with
G6PD
deficiency; pregnant women.
Should be taken with food to
minimize GI adverse effects.
Combine with tetracycline,
doxycycline, or clindamycin, except
for P. vivax infections in children < 8 y
or pregnant women.
Contraindicated in hypersensitivity,
including history of blackwater
fever, thrombocytopenic purpura,
or thrombocytopenia associated
with quinine or quinidine use; many
cardiac conduction defects and
arrhythmiasf; myasthenia gravis; optic
neuritis.
Quinidine gluconate
(intravenous) Severe
malaria (all species,
independently of
chloroquine resistance)
Patient unable to take oral
medication
Parasitemia > 10%
6.25 mg base/kg (= 10 mg
salt/kg) loading dose IV
over
1–2 h, then 0.0125 mg
base/ kg/min (0.02 mg
salt/kg/min) continuous
infusion for at least 24 h
Note alternative regimeng
Same as adult
Cinchonism,
tachycardia,
prolongation of QRS
and QTc intervals,
flattening of T wave
(effects are often
transient).
Ventricular
arrhythmias,
hypotension,
hypoglycemia
Combine with tetracycline,
doxycycline, or clindamycin.
Contraindicated in hypersensitivity;
history of blackwater fever
including history of blackwater
fever, thrombocytopenic purpura
or thrombocytopenia associated with
quinine or quinidine use; many
cardiac conduction defects and
arrhythmiash; myasthenia gravis; optic
neuritis.
Tetracycline (oral or IV) P.
falciparum and P. vivax from
chloroquine-resistant areas
(with quinine/ quinidine)
Oral: 250 mg 4 times daily
× 7d
IV: dosage same as for oral
25 mg/kg/d orally, divided,
4x daily × 7 d
IV: dosage same as for oral
See doxycycline
See doxycycline.
Drug Facts for Your Personal Formulary: Antiparasitic Agents: Protozoal
Infections Other Than Malaria
Drugs
Therapeutic Uses
Clinical Pharmacology and Tips
Metronidazole
• Amoebic colitis and liver abscess
•
•
•
•
Tinidazole
• Amoebic colitis and liver abscess
• Always administer with luminal agent
Paromomycin
• Luminal agent (eradicates E. histolytica from gut)
• Drug of choice due to side effects of 8-hydroxyquinolones
• Side effects of paromomycin: GI (nausea/vomiting/diarrhea)
Iodoquinol
• Luminal agent
• Use less than 2 g/d for less than 20 days to avoid neurotoxicity
Metronidazole
• Giardiasis
• 5-day course
• Not FDA-approved for indication, but years of experience
Tinidazole
• Giardiasis
• Single dose sufficient
Paromomycin
• Giardiasis
• Used in pregnancy
Nitazoxanide
• Giardiasis
• Orally bioavailable
• Can treat resistant infections
• Adverse events are rare
Metronidazole
• Trichomoniasis
• Drug of choice
• 2 g once
• If failure, give second dose in 4–6 weeks
Tinidazole
• Trichomoniasis
• 2 g once
• Can be used for resistant infection
Pyrimethamine
• Acute or congenital toxoplasmosis
• Combine with sulfadiazine or clindamycin
• Give with leucovorin
• Can cause bone marrow suppression
Sulfadiazine
• Acute or congenital toxoplasmosis
• Combine with pyrimethamine and folic acid
• Can cause bone marrow suppression
Clindamycin
• Acute toxoplasmosis
• Combine with pyrimethamine
• Use if cannot tolerate sulfonamide
Spiramycin
• Acute toxoplasmosis during early pregnancy
• Prevents fetal transmission
• Available via individual investigator IND
• Drug of choice for cryptosporidiosis
• Restore immune function in immunocompromised patients
Pentavalent antimony
compounds (sodium
stibogluconate)
• Cutaneous, mucocutaneous leishmaniasis
• Visceral leishmaniasis (not in India)
• 20 days IV/IM for cutaneous disease
• 28 days IV/IM for visceral disease
• Side effects: pancreatitis, elevated hepatic transaminases, bone
marrow suppression
• Can cause hemolytic anemia and renal failure
• Available only through CDC
Amphotericin B
• Visceral leishmaniasis
• Second-line agent for cutaneous disease
•
•
•
•
Miltefosine
• Cutaneous leishmaniasis
• Visceral leishmaniasis
• Only oral agent
• GI side effects (vomiting/diarrhea)
• Teratogenic: do not use in pregnancy
Amebiasis
Always administer with luminal agent
Orally administered: > 80% bioavailable
Common side effects: headache and metallic taste
Can have disulfiram-like effect
Giardiasis
Trichomoniasis
Toxoplasmosis
Cryptosporidiosis
Nitazoxanide
Leishmaniasis
Used for antimony-resistant cases
Used during pregnancy
Side effects: renal toxicity, low potassium
Liposomal formulation preferred
Trypanosomiasis: African sleeping sickness
CHAPTER 54
Pentamidine
• Early-stage T. brucei gambiense before CNS
involvement
• IV administration associated with hypotension, tachycardia, and
headache
• Hypoglycemia occurs; monitor blood glucose
• Nephrotoxic, can cause renal failure
Suramin
• Early-stage T. brucei rhodesiense
• Second-line agent for early-stage T.
brucei gambiense (only if pentamidine is
contraindicated)
• Immediate reactions: malaise, nausea, and fatigue
• Side effects of multiple doses: renal toxicity, delayed
neurological complications (headache, metallic taste,
paresthesias, peripheral neuropathy)
• Only available through CDC
Nifurtimox + eflornithine
combination therapy (NECT)
• Late-stage T. brucei gambiense
• Safer and more effective than melarsoprol or eflornithine alone
• First-line regimen for this indication
• Side effects: abdominal pain, headache, tissue infections,
pneumonia
• Only available through CDC
Melarsoprol
• Late-stage T. brucei rhodesiense
• Second-line agent for late-stage T.
brucei gambiense (only if NECT
contraindicated)
• Fatal encephalopathy: 2%–10% of patients
• Coadminister with prednisolone to reduce the prevalence of
encephalopathy
• Only available through CDC
Trypanosomiasis: Chagas disease
Benznidazole
• Drug of choice for Chagas
• Requires 60 days of treatment
• Urticarial dermatitis in 30% of patients; coadministration of
antihistamines or corticosteroids can help
• Better tolerated in children, less well tolerated in adults > 50
years
• Most effective if administered early in the course of infection
(acute stage)
• Efficacy in chronic Chagas is lower
• Give with food to minimize GI effects
• Monitor blood cell counts
• Available only through CDC
Nifurtimox
• Alternative treatment for Chagas
• Requires 60 days of treatment
• Less well tolerated than benznidazole
Clindamycin and quinine
• Severe babesiosis
• Quinine: monitor for cardiac effects (prolonged QT interval)
Azithromycin and atovaquone
• Mild-moderate babesiosis
Tetracycline
• Balatinidiasis
• Drug of choice
Trimethoprim-sulfamethoxazole
• Cyclosporiasis, isosporiasis
• Drug of choice
Other Protozoal Infections
SECTION VII
Bibliography
.
Drug Facts for Your Personal Formulary: Anthelmintics
Drugs
Therapeutic Uses
Clinical Pharmacology and Tips
CHAPTER 55
Benzimidazoles: β-Tubulin inhibitors
Albendazole
•
•
•
•
•
Intestinal nematode infections
Cysticercosis
Cutaneous larva migrans
Toxocariasis
Echinococcosis
• Monitor for liver and hemotologic toxicity in long-term
therapy
• Absorption improved with fatty food
Mebendazole
• Intestinal nematode infections
• Poorly absorbed; useful for intestinal luminal nematode
Triclabendazole
• Fascioliasis
• Available from the CDC under an investigational new drug
protocol
Macrocyclic Lactones: Glutamate gated chloride channel blockers
Ivermectin
•
•
•
•
Onchocerciasis
Lymphatic filariasis
Scabies and head lice
Strongyloidiasis
• Safety in pregnancy and children < 15 kg not certain
Moxidectin
• Investigational for onchocerciasis
• Licensed only for veterinary use in the U.S.
• Schistosomiasis
• Food-borne trematode infections (opisthorciasis and
paragonamiasis)
• Intestinal tapeworm infections
• Dizziness is a common adverse effect
• May impair mental alertness; avoid tasks such as driving
Praziquantel
Miscellaneous Anthelmintics
phy
Diethylcarbamazine
• Lymphatic filariasis
• Contraindicated in onchocerciasis
• Available from CDC under an investigational new drug
protocol
Metrifonate
• Second-line drug for Schistosoma haematobium
infection
• Not licensed for use in the U.S.
Oxamniquine
• Second-line drug for Schistosoma mansoni
infection
• Discontinued in the U.S.
Niclosamide
• Intestinal tapeworm infection
• Discontinued in the U.S.
Oxantel and pyrantel pamoate
• Second-line drug for intestinal nematode infection
• Oxantel pamoate is not licensed for use in the U.S.
• Pyrantel pamoate is sold OTC to treat pinworm infections
Doxycycline
• Filarial infection
• 6-Week course of therapy advised
Levamisole
• Excellent activity against Ascaris lumbricoides
• Low-to-moderate efficacy against Trichuris trichiura
and hookworm infections
• May cause agranulocytosis at high doses
Nitazoxanide
• Effective against intestinal helminths
• Antiprotozoal and antiviral activity
• Broad-spectrum antiparasitic agent
• Side effects are rare
Drug
Therapeutic Uses
Clinical Pharmacology and Tips
Sulfonamides: Competitive inhibitors of bacterial dihydropteroate synthase, thereby disrupting folate synthesis
General: Bacteriostatic; limited efficacy as monotherapy, renal elimination, hypersensitivity reactions
Sulfisoxazole (PO)
• Lower UTIs
• Otitis media (with erythromycin)
• Some activity vs. Streptococcus pyogenes, S. pneumoniae, Staphylococcus aureus,
Haemophilus influenzae, Escherichia coli, Nocardia
• Rapid renal excretion
Sulfadiazine (PO)
• Toxoplasmosis (with pyrimethamine)
• Similar to sulfisoxazole, with good activity against Toxoplasma gondii
• Reasonable CSF penetration
• Higher risk of crystalluria, requires hydration
Sulfadoxine (PO)
• Prophylaxis and treatment of
malaria (with pyrimethamine)
• Similar to sulfisoxazole, with some activity vs. Plasmodium falciparum
• Long t1/2
Sulfacetamide
(ophthalmic)
• Treatment of ocular infections
• Activity similar to sulfisoxazole
• High penetration into ocular fluids
Silver sulfadiazine
(topical)
Mafenide (topical)
• Prevention of infection in burn patients
• Activity similar to sulfisoxazole
• Burning and itching at application site
• Application over large surface may lead to systemic absorption and adverse effects
Sulfonamide and Dihydrofolate Reductase Inhibitor Combination: Sequential inhibition of folate synthesis
Trimethoprimsulfamethoxazole
(IV, PO)
•
•
•
•
•
•
UTI
Upper respiratory tract infections
Shigellosis
Pneumocystis jiroveci pneumonia
Skin/soft tissue infections due to S. aureus
Infections due to Nocardia,
Stenotrophomonas maltophila,
Cyclospora, Isospora
•
•
•
•
•
•
•
•
•
Excellent activity vs. S. aureus, Staphylococcus epidermidis, Streptococcus pyogenes
Good activity vs. Proteus, E. coli, Klebsiella, Enterobacter, Serratia, Nocardia, Brucella
Some activity vs. S. pneumoniae
Formulated in 5:1 (sulfa:TMP) ratio, giving 20:1 serum levels
Well absorbed on oral administration
Good penetration into CSF
Metabolized and renally eliminated
Hypersensitivity reactions (i.e., rash) common
Dose-related bone marrow suppression, hyperkalemia
Quinolones: Bactericidal inhibitors of bacterial gyrase and topoisomerase, prevent DNA unwinding
General: Drug interactions with cations, neurologic adverse effects, tendonitis/tendon rupture, photosensitivity; typically avoided in
children and pregnant women
Norfloxacin (PO)
• UTI, prostatitis
• Traveler’s diarrhea
• Good activity vs. E. coli, Klebsiella, Proteus, Serratia, Salmonella, Shigella
• Some activity vs. Pseudomonas
• Effective concentrations only achieved in GI and urinary tracts
Ciprofloxacin (IV, PO)
• UTI, prostatitis
• Traveler’s diarrhea
• Intra-abdominal infections
(with metronidazole)
• Pseudomonas infections
• Anthrax, tularemia
•
•
•
•
•
Levofloxacin (IV, PO)
•
•
•
•
•
• Excellent activity vs. E. coli, Klebsiella, Proteus, Serratia, Salmonella, Shigella,
streptococci, H. influenzae, Legionella, Chlamydia
• Good activity vs. Pseudomonas, S. aureus
• Good bioavailability and tissue distribution
• Renal elimination
• S-isomer of ofloxacin
Respiratory tract infections
UTI, prostatitis
Chlamydia
Traveler’s diarrhea
Intra-abdominal infections
(with metronidazole)
• Pseudomonas infections
Excellent activity vs. E. coli, Klebsiella, Proteus, Serratia, Salmonella, Shigella
Good activity vs. Pseudomonas
Some activity vs. S. aureus, streptococci
Good bioavailability and tissue distribution
Renal and nonrenal elimination
SECTION II
Drug Facts for Your Personal Formulary: Sulfonamides, TrimethoprimSulfamethoxazole, Quinolones, and Agents for Urinary Tract Infections
CHAPTER 56
Drug Facts for Your Personal Formulary: Sulfonamides, Trimethoprim- Sulfamethoxazole,
Quinolones, and Agents for Urinary Tract Infections (continued)
Drug
Therapeutic Uses
Clinical Pharmacology and Tips
Quinolones: Bactericidal inhibitors of bacterial gyrase and topoisomerase, prevent DNA unwinding
General: Drug interactions with cations, neurologic adverse effects, tendonitis/tendon rupture, photosensitivity; typically
avoided in children and pregnant women
Moxifloxacin (IV, PO)
• Respiratory tract infections
• Intra-abdominal infections
• Mycobacterial infections
• Excellent activity vs. E. coli, Klebsiella, Proteus, Serratia, streptococci,
H. influenzae, Legionella, Chlamydia
• Good activity vs. S. aureus, Bacteroides fragilis
• Good bioavailability and tissue distribution
• Renal and nonrenal elimination; not for UTI
• QT prolongation
Urinary Agents: Diverse mechanisms, effective concentrations reached only in urine
Methenamine (PO)
• Chronic suppression of cystitis
• Forms formaldehyde in urine
• Requires acidic urine for activity
• Excellent activity against most uropathogens except for Proteus and
Enterobacter
• GI distress at high doses
Nitrofurantoin (PO)
• Cystitis treatment
• Cystitis prophylaxis
•
•
•
•
•
•
DNA damage through reactive intermediates
Excellent activity vs. E. coli, Enterococcus
Some activity vs. Klebsiella, Enterobacter
Rapid absorption and elimination
Colors urine brown
Acute pneumonitis and chronic interstitial pulmonary fibrosis
Fosfomycin (PO)
• Cystitis treatment
•
•
•
•
Inhibits early cell wall synthesis
Excellent activity vs. E. coli, Proteus, Enterococcus
Some activity vs. Klebsiella, Enterobacter
Single-dose treatment of acute uncomplicated cystitis
Drug Facts for Your Personal Formulary: β-Lactam Antibiotics
Drugs
Therapeutic Uses
Clinical Pharmacology and Tips
Penicillins—Inhibitors of Bacterial Cell Wall Peptidoglycan Synthesis
General: Bactericidal, renal elimination, hypersensitivity reactions (rash, anaphylaxis)
Penicillin G (IV),
penicillin V (PO);
IM depot formulations
(benzathine, procaine)
•Penicillin-susceptible
Streptococcus
pneumoniae
infections:pneumonia,
meningitis
• Streptococcal pharyngitis,
endocarditis, skin and soft tissue
infection
• Neisseria meningitidis infections
• Syphilis
• Excellent activity vs. Treponema pallidum, βhemolytic streptococci, N. meningitidis, grampositive anaerobes
• Good activity vs. S. pneumoniae, viridans streptococci
• CSF penetration with inflammation
Penicillinase-resistant penicillins
Oxacillin (IV),
nafcillin (IV),
dicloxacillin (PO)
• Skin and soft tissue infections
• Serious infections due to MSSA
•
•
•
•
Aminopenicillins
Amoxicillin (PO),
ampicillin (PO/IV)
• Upper respiratory tract infections
(sinusitis, pharyngitis, otitis media)
• Enterococcus faecalis infections
• Listeria infections
• Excellent activity vs. β-hemolytic streptococci, E. faecalis
• Good activity vs. S. pneumoniae, viridans streptococci,
Haemophilus influenzae
• Some activity vs. Proteus, Escherichia coli
• CSF penetration with inflammation
• Rash more common than other penicillins
Aminopenicillin/β-lactamase inhibitors
Amoxicillin/clavulanate (PO),
ampicillin/sul actam (IV)
• Upper respiratory tract infections
(sinusitis, otitis media)
• Intra-abdominal infections
• Activity: amoxicillin and ampicillin plus
• Excellent activity vs. H. influenzae, Bacteroides fragilis,
Proteus
• Good activity vs. E. coli, Klebsiella, MSSA
Antipseudomonal penicillins
Piperacillin/tazobactam (IV)
• Nosocomial infections: pneumonia,
intra-abdominal infections, urinary tract
infections
•
•
•
•
Excellent activity vs. MSSA
Good activity vs. streptococci
Nafcillin nonrenal elimination
CSF penetration with inflammation
Activity: ampicillin/sulbactam plus
Excellent activity vs. E. coli, Klebsiella
Good activity vs. Pseudomonas, Citrobacter, Enterobacter
Poor CSF penetration
Cephalosporins—Inhibitors of Bacterial Cell Wall Peptidoglycan Synthesis
General: Bactericidal, renal elimination, hypersensitivity reactions (rash, anaphylaxis)
First-generation cephalosporins
Cefazolin (IV), cephalexin (PO), cefadroxil (PO)
• Skin and soft tissue infections
• Serious infections due to MSSA
• Perioperative surgical prophylaxis
• Excellent activity vs. MSSA, streptococci
• Some activity vs. Proteus, E. coli, Klebsiella
• Poor CSF penetration
Second-generation cephalosporins
Cefuroxime (IV/PO), cefoxitin (IV), cefotetan (IV),
cefaclor (PO), cefprozil (PO)
• Upper respiratory tract infections
(sinusitis, otitis media)
•
Cefoxitin/cefotetan: gynecologic
infections, perioperative surgical
prophylaxis
• Good activity vs. MSSA, streptococci, H. influenzae, Proteus,
E. coli, Klebsiella
• Cefoxitin/cefotetan: some activity vs. B. fragilis
Third-generation cephalosporins
Cefotaxime (IV), ceftriaxone (IV),
cefpodoxime (PO), cefixime (PO), cefdinir (PO),
cefditoren (PO), ceftibuten (PO)
• Community-acquired pneumonia,
meningitis, urinary tract infections
• Streptococcal endocarditis
• Gonorrhea
• Severe Lyme disease
• Excellent activity against streptococci, H. influenzae, Proteus,
E. coli, Klebsiella, Serratia, Neisseria
• Good activity vs. MSSA
• Some activity vs. Citrobacter, Enterobacter
• Ceftriaxone renal and nonrenal elimination
• Good CSF penetration
• Ceftriaxone: neonatal kernicterus (use cefotaxime), biliary
pseudolithiasis
Cephalosporins—Inhibitors of Bacterial Cell Wall Peptidoglycan Synthesis
General: Bactericidal, renal elimination, hypersensitivity reactions (rash, anaphylaxis) (continued)
• Nosocomial infections: pneumonia,
meningitis, urinary tract infections,
intra-abdominal infections (with
metronidazole)
• Excellent activity against H. influenzae, Proteus, E. coli, Klebsiella,
Serratia, Neisseria, streptococci,a MSSAa
• Good activity vs. Pseudomonas, Enterobacterb
• Some activity vs. Enterobacter (ceftazidime, ceftolozane/
tazobactam)
• Ceftazidime/avibactam active vs. ESBL and KPC-producing
Enterobacteriaceae
• Good CSF penetration
• Cefepime: encephalopathy at high doses
Anti-MRSA cephalosporins
Cefaroline (IV)
• Community-acquired pneumonia
• Skin and soft tissue infections
• Excellent activity against streptococci, MSSA, MRSA,c
H. influenzae, Proteus, E. coli, Klebsiella, Serratia
• Some activity vs. Citrobacter, Enterobacter
Carbapenems—Inhibitors of Bacterial Cell Wall Synthesis
General: Bactericidal, renal elimination, hypersensitivity reactions (rash, anaphylaxis), seizure risk
Imipenem/cilastatin (IV),
meropenem (IV),
doripenem (IV)
• Nosocomial infections: pneumonia,
intra-abdominal infections, urinary
tract infections
• Meningitis (meropenem)
• Excellent activity against streptococci, MSSA, H. influenzae,
Proteus, E. coli, Klebsiella, Serratia, Enterobacter, B. fragilis
• Good activity vs. Pseudomonas, Acinetobacter, Enterococcus
faecalisd
• Good CSF penetration
• Imipenem coformulated with renal dihydropeptidase inhibitor
cilastatin
• Seizures at high doses in patients with prior seizure history
(imipenem > meropenem, doripenem)
Ertapenem (IV)
• Community-acquired infections
and nosocomial infections without
Pseudomonas risk
• Excellent activity against streptococci, MSSA, H. influenzae,
Proteus, E. coli, Klebsiella, Serratia, Enterobacter, B. fragilis
• Lacks activity against Pseudomonas, Enterococcus
• Lower seizure risk than imipenem
Monobactam—Bactericidal Inhibitor of Bacterial Cell Wall Synthesis
Aztreonam (IV)
Bibliography
• Nosocomial infections: pneumonia,
urinary tract infections
• Excellent activity against H. influenzae, Proteus, E. coli, Klebsiella,
Serratia
• Good activity vs. Pseudomonas
• Lacks any gram-positive activity
• Lacks cross-allergenicity with other β-lactams (except ceftazidime)
• Good CSF penetration, renal elimination
SECTION VII
Antipseudomonal cephalosporins
Ceftazidime (IV),
ceftolozane/tazobactam (IV),
ceftazidime/avibactam (IV),
cefepime (IV)
.
Drug Facts for Your Personal Formulary: Aminoglycosides
Drug
Therapeutic Uses
Clinical Pharmacology and Tips
Aminoglycosides—Inhibitors of Bacterial Protein Synthesis
General: Bactericidal, no GI absorption (<1%), oral administration used only for bowel decontamination or intestinal parasites, poor
CSF penetration, renal elimination, nephrotoxicity, ototoxicity (cochlear and vestibular), neuromuscular blockade
Gentamicin (IV)
• UTI
• Peritonitis
• Endocarditis in combination with a cell-wall
active agent
• Plague
• Tularemia
• Good activity vs. Enterobacteriaceae, Pseudomonas
• Some activity vs. Neisseria, Haemophilus,
Moraxella
• Synergistic activity when combined with a cell-wall
agent against many organisms
• Vestibular > cochlear toxicity
• Toxicity primarily renal and reversible
Tobramycin (IV, inhalation)
• UTI
• Lung infections, including cystic fibrosis
exacerbations
• Nosocomial sepsis of unknown origin
• Similar to gentamicin, with better activity against
Pseudomonas aeruginosa
• Cochlear ≈ vestibular toxicity
Amikacin (IV)
• UTI
• Lung infections, including cystic fibrosis
exacerbations
• Nosocomial sepsis of unknown origin
• Mycobacterial infections
• Similar to tobramycin, with activity against
some gram-negative bacilli resistant to other
aminoglycosides
• Activity against a variety of mycobacteria
• Cochlear > vestibular toxicity
Streptomycin (IV)
• Endocarditis in combination with a cell-wall
Active agent
• Tuberculosis
• Plague
• Tularemia
• Similar to gentamicin, with activity against some
gentamicin-resistant enterococci
• Activity against Mycobacterium tuberculosis
• Vestibular > cochlear toxicity
• Vestibular toxicity is irreversible
Neomycin (PO, topical; urologic
irrigation)
• Minor skin infections
• Bowel preparation prior to intra-abdominal surgery
• Bladder irrigation
• Similar activity to gentamicin but only used topically,
not systemically
• Can cause skin rash
Paromomycin (PO, IM, topical)
• Cryptosporidia infection
• Intestinal amebiasis
• Leishmaniasis
• Diarrhea, nausea, vomiting
• IM use for visceral leishmaniasis
• Topical use for cutaneous leishmaniasis
Drug Facts for Your Personal Formulary: Protein Synthesis Inhibitors and
Miscellaneous Antibacterial Agents
Drugs
Therapeutic Uses
Clinical Pharmacology and Tips
Tetracyclines and Glycylcyclines—Inhibitors of Bacterial Protein Synthesis
General: Bacteriostatic; oral formulations interact with orally administered cations (calcium, iron, aluminum); avoid in pregnancy and
children < 8 years old due to permanent tooth discoloration, photosensitivity
Tetracycline (IV, PO)
• Inflammatory acne
• Use for other indications has largely been
replaced by doxycycline
• Good activity vs. rickettseae, Chlamydia, Mycoplasma, Legionella, Ureaplasma,
Borrelia, Francisella tularensis, Pasteurella multocida, Bacillus anthracis,
Helicobacter pylori
• Some activity vs. Streptococcus pneumoniae, Streptococcus pyogenes,
Staphylococcus aureus, Haemophilus influenzae
• Good CSF penetration
• Renal excretion
• Renal toxicity, hepatotoxicity at high doses
Doxycycline (IV, PO)
•
•
•
•
•
•
•
•
•
•
•
•
Minocycline (IV, PO)
• Skin/soft-tissue infections
• Mycobacterial infections
• Nocardiosis
• Similar to doxycycline, with improved activity vs. staphylococci, Acinetobacter,
and Stenotrophomonas maltophilia
• Renal elimination
• Vestibular toxicity
Tigecycline (IV)
•
•
•
•
• Similar to minocycline, with improved activity vs. Escherichia coli, Klebsiella,
enterococci, Bacteroides fragilis
• Wide distribution with low serum levels
• Hepatic elimination
Community-acquired pneumonia
Skin/soft-tissue infection
Urogenital chlamydia
Lymphogranuloma venereum
Syphilis (penicillin alternative)
Rocky Mountain spotted fever
Anthrax, tularemia
Lyme disease, leptospirosis
Intra-abdominal infection
Skin and soft-tissue infection
Pneumonia
Increased risk of death in pooled analysis;
reserve as alternative therapy
Similar to tetracycline, with improved activity vs. streptococci and staphylococci
Good CSF penetration
Dual renal/biliary elimination
Preferred tetracycline for most indications due to more favorable activity,
tolerability, and frequency of administration
Chloramphenicol—Inhibitor of Bacterial Protein Synthesis
General: Bacteriostatic; dose-dependent bone marrow suppression, idiosyncratic fatal aplastic anemia, fatal “gray baby syndrome” in
neonates receiving high doses
• Rickettsial infections
• Bacterial meningitis
• Because of risk of fatal toxicities, reserve as
alternative therapy
• Good activity vs. S. pneumoniae, H. influenzae, Neisseria meningitidis, rickettseae,
Vibrio, Enterococcus
• Variable serum levels due to clearance of prodrug before hydrolysis
• Excellent CSF penetration
• Hepatic clearance
Macrolides and Ketolides—Inhibitors of Bacterial Protein Synthesis
General: Bacteriostatic; widely distributed but with limited CSF penetration, gastrointestinal distress, QT prolongation, major
(erythromycin, clarithromycin, telithromycin) to minor (azithromycin) inhibitor of drug-metabolizing CYPs
Erythromycin
(IV, PO, topical)
•
•
•
•
Erysipelas and cellulitis
Ophthalmia neonatorum
Diphtheria
Pertussis
Clarithromycin (PO)
•
•
•
•
Erysipelas and cellulitis
Community-acquired pneumonia
Acute exacerbations of chronic bronchitis
Helicobacter pylori gastritis (in combination with
other agents)
• Mycobacterium avium treatment and prophylaxis
• Similar to erythromycin, with improved activity vs. streptococci and
staphylococci
• Good activity vs. Moraxella catarrhalis, H. pylori, and nontuberculous
mycobacteria
• Active metabolite
• Some drug accumulation in severe renal impairment
• Tinnitus at high doses
Azithromycin (IV, PO)
•
•
•
•
•
•
•
•
•
•
Telithromycin (PO)
• Community-acquired infection
• Due to risk of severe hepatotoxicity, reserve as
alternative therapy
Community-acquired pneumonia
Acute exacerbations of chronic bronchitis
Otitis media
Bacterial pharyngitis
Chlamydia
Mycobacterium avium treatment and prophylaxis
• Good activity against Mycoplasma, Chlamydia, Legionella,
Campylobacter, Bordetella pertussis, Corynebacterium diphtherieae
• Some activity against S. pneumoniae, S. pyogenes, H. influenzae
• Oral formulations have variable absorption
• Stimulates motilin receptors; gastrointestinal prokinetic properties
• Chlolestatic hepatitis with long-term use
Similar to clarithromycin, improved activity vs. H. influenzae
Extensive tissue distribution and concentration in tissues
Anti-inflammatory properties
Long t1/2, ~48 h
• Similar to azithromycin with activity against macrolide-resistant streptococci
and staphylococci
• Severe hepatotoxicity
Lincosamides—Bacteriostatic Protein Synthesis Inhibitor
Clindamycin
(IV, PO, topical)
•
•
•
•
•
•
•
Skin and soft-tissue infection
Inflammatory acne
Lung abscess
Streptococcal pharyngitis
Pneumocystis pneumonia
Toxoplasma encephalitis
Nonsevere malaria
• Good activity vs. S. pneumoniae, S. pyogenes, viridans streptococci,
Actinomyces, Nocardia
• Some activity versus S. aureus, Bacteroides spp., Toxoplasma,
Pneumocystis, Plasmodium
• Wide tissue distribution, especially into bone; modest CSF penetration
• Metabolized in liver, excreted in urine and bile
• Diarrhea, rarely Clostridium difficile colitis
Streptogramins—Bactericidal Protein Synthesis Inhibitor, Components Act Synergistically
Quinupristin/
dalfopristin (IV)
• Skin and soft-tissue infection
• Vancomycin-resistant Enterococcus faecium
infections
• Good activity against streptococci, staphylococci, E. faecium,
Mycoplasma, Legionella, Chlamydophila
• Hepatic metabolism with biliary excretion
• Infusion site phlebitis
• Arthralgias, myalgias
• CYP inhibitor
Oxazolidininones—Bacteriostatic Protein Synthesis Inhibitors
General: Excellent oral absorption; wide distribution, including to CNS; myelosuppression; peripheral neuropathy with long-term use;
risk of serotonin syndrome with concomitant antidepressant use
Linezolid (IV, PO)
•
•
•
•
•
Skin and soft-tissue infections
Pneumonia
Vancomycin-resistant enterococcal infections
Nocardiosis
Drug-resistant tuberculosis
Tedizolid (IV, PO)
• Skin and soft-tissue infections
• Good activity against streptococci, staphylococci, enterococci, Nocardia, Listeria
• Some activity against mycobacteria
• Nonenzymatic degradation with elimination in urine
• Similar activity to linezolid but lower risk of myelosuppression and drug
interactions
• Hepatic metabolism and fecal excretion
• Longer t1/2 than linezolid
SECTION VII
Chloramphenicol
(IV, PO – not in the
U.S.)
Drug Facts for Your Personal Formulary: Protein Synthesis Inhibitors and
Miscellaneous Antibacterial Agents (continued)
CHAPTER 59
Drugs
Therapeutic Uses
Clinical Pharmacology and Tips
Polymyxins—Bactericidal Cell Membrane-Disrupting Agents
Colistin (polymyxin E)
(IV, inhaled)
• Serious infections due to multidrug-resistant
gram-negative organisms
• Prevention of cystic fibrosis exacerbations
(inhaled)
• Good activity vs. Acinetobacter, E. coli, Klebsiella, Pseudomonas, including
multidrug-resistant strains
• Prodrug; complex pharmacokinetics with renal and nonrenal elimination
• Substantial nephrotoxicity and neurotoxicity
Polymyxin B (IV,
topical)
• Serious infections due to multidrug-resistant
gram-negative organisms
• Topical treatment/prevention of skin and
soft-tissue infections
• Similar activity and toxicity as colistin
• Nonrenally eliminated; does not achieve high urinary levels
Glycopeptides and Lipoglycopeptides—Bactericidal Inhibitors of Cell Wall Synthesis
Vancomycin (IV, PO)
• Skin and soft-tissue infections
• Bacteremia and endocarditis due to
gram-positive bacteria
• Pneumonia
• Meningitis
• Clostridium difficile colitis (oral formulation)
• Surgical prophylaxis for procedures with high risk
of MRSA
• Good activity vs. vast majority of gram-positive bacteria, Staphylococcus
(including MRSA), streptococci, E. faecalis
• Oral formulation not well absorbed and only used for treatment of C. difficile
colitis
• Modest CNS penetration in presence of inflammation
• Renal elimination
• Infusion-related reactions (red man syndrome) associated with rapid infusion
• Nephrotoxicity at high doses
Telavancin (IV)
• Skin and soft-tissue infections
• Pneumonia
• Similar activity to vancomycin with activity against some vancomycin-resistant
strains of Enterococcus
• Renal elimination
• Higher nephrotoxicity relative to vancomycin
• QT prolongation
• Avoid in pregnancy
Dalbavancin (IV)
• Skin and soft-tissue infections
• Similar activity to vancomycin
• Highly protein bound
• Extremely long t1/2; once-weekly dosing
Oritavancin (IV)
• Skin and soft-tissue infections
• Similar activity to telavancin
• Highly protein bound
• Extremely long half-life; single-dose therapy for skin infections
Daptomycin (IV)
• Skin and soft-tissue infections
• Staphylococcal and streptococcal bacteremia
• Vancomycin-resistant enterococcal infections
•
•
•
•
•
•
Lipopeptide, similar activity to vancomycin
Retains activity against some vancomycin-resistant strains of Enterococcus
Protein bound; limited CNS penetration
Inactivated by pulmonary surfactant; not effective for pneumonia
Renal elimination
Rare myositis and rhabdomyolysis
Nitroimidazoles—Disruptors of DNA Synthesis in Anaerobes
Metronidazole
(IV, PO, topical)
• Clostridium difficile colitis
• Empiric coverage of anaerobic organisms, as
in intra-abdominal and skin and soft-tissue
infections
• Helicobacter pylori gastritis (in combination with
other agents)
• Bacterial vaginosis
• Bacterial spectrum limited to anaerobic organisms, including B. fragilis and
Clostridium
• Excellent absorption
• Wide distribution, including CNS
• Hepatic elimination
• CYP inhibitor; drug interactions with warfarin
• Peripheral neuropathy with prolonged use
Topical Agents—Inhibitors of Bacterial Cell Wall Synthesis
Bacitracin (topical)
• Prevention and treatment of skin and soft-tissue
infections
• Ophthalmic infections
• Activity against broad array of gram-positive and gram-negative organisms
• Nephrotoxicity with parenteral use
Mupirocin (topical)
• Treatment of minor skin infections
• Eradication of nasal carriage of S. aureus
• Activity against broad array of gram-positive and gram-negative organisms
• May cause irritation at site of application
Drug Facts for Your Personal Formulary: Antimycobacterial Drugs
CHATER 60
Drug
Therapeutic Uses
Major Toxicity and Clinical Pearls
Rifampin
•
•
•
•
Tuberculosis
M. kansasii disease
Leprosy
M. marinum, M. uclerans, M. malmoense, and
M. haemophilum diseases
• Prophylaxis of meningococcal disease and
Haemophilus influenzae meningitis
• Brucellosis
•
Combination therapy in selected cases of
staphylococcal endocarditis or osteomyelitis,
especially those caused by staphylococci “tolerant”
of penicillin
• Peak concentration and AUC-driven efficacy
• Rifampin potently induces CYPs and thus increases metabolism of
many classes of drugs. Prior to putting a patient on rifampin, all the
patient’s medications and contraception should be examined for
potential interactions.
• Hypersensitivity reactions, especially with high-dose intermittent
therapy, including flu-like symptoms, eosinophilia, interstitial
nephritis, acute tubular necrosis, thrombocytopenia, hemolytic
anemia, and shock
• Hepatitis, especially in combination with other anti-TB agents, in
alcoholics, or preexistent liver disease
Rifapentine
• Treatment of tuberculosis
• Prophylaxis of tuberculosis
• 97% protein binding
• Long t1/2 of ~ 14–18 h, allowing more intermittent dosing
(1–2 times weekly)
• Moderate CYP3A induction
Rifabutin
• Used as rifampin replacement to avoid drug interactions of
rifampin with other medications, especially in HIV coinfection
• Treatment of disseminated MAC in patients with AIDS
•
•
•
•
•
• M. tuberculosis infection
• M. kansasii infection
• Prophylaxis of tuberculosis disease
• Patients divided into slow, intermediate, and fast acetylators,
which has consequence of efficacy and toxicity.
• Hepatotoxicity, increased above age of 42 years
• Peripheral neuritis: should be administered with pyridoxine
• Reversible vasculitis
• Overdose is associated with the clinical triad of (1) seizures
refractory to treatment with phenytoin and barbiturates, (2)
metabolic acidosis, and (3) coma
• Many drug interactions via inhibition and induction of several
CYP450 enzymes
Rifamycins
Weaker CYP3A induction than rifampin
Concentrations higher in tissue than plasma
t1/2 ~ 45 h
Neutropenia in 25% of patients with HIV
Primary reasons for therapy discontinuation include rash, GI
intolerance, and neutropenia.
• Uveitis and arthralgias in patients receiving rifabutin doses
> 450 mg daily
Isoniazid
Isoniazid
Pyrazinamide
Pyrazinamide
• No activity against M. bovis
• Activated under acidic conditions; synergizes with rifampin
• Pyrazinamide clearance reduced in renal failure; reduce
dosing frequency is reduced to 3 x/week at low GFR.
• Removed by hemodialysis; redose after each session
• Adverse effects: hepatotoxicity and hyperuricemia
•
•
•
•
• Incidence of optic neuritis leading to decreased visual acuity and
loss of red-green discrimination. Test visual acuity and red-green
discrimination prior to the start of therapy and periodically
thereafter.
• In renal failure, ethambutol should be dosed at 15–25 mg/kg
three times a week instead of daily, even in patients
receiving hemodialysis.
Ethambutol
Ethambutol
Tuberculosis
M. avium complex infections
M. kansasii infection
Activity against M. gordonae, M. marinum, M. scrofulaceum,
and M. szulgai
Bicyclic Nitroimidazoles
Pretomanid,
delaminid
• Treatment of MDR-TB; being tested for regimens used to treat
drug-susceptible TB
• Kills both replicating and nonreplicating M. tuberculosis
• Delaminid: QT segment prolongation
• Treatment of leprosy
• GI problems are encountered in 40%–50% of patients.
• Abdominal pain due to crystal deposition in cavities and tissues
• Body secretion, eye, and skin reddish-black discoloration occur in
most patients
• Treatment of MDR-TB; being tested for regimens used to treat
drug-susceptible TB
• Apparent volume of distribution > 10,000 L
• Controversy regarding side effects profile and increased number
of deaths compared to placebo
• QT interval prolongation
• Treatment of MDR-TB and XDR-TB
• Same mutations in ethionamide-resistant bacteria as for
isoniazid-resistant bacteria
• 50% of patients are unable to tolerate a single dose larger than
500 mg because of GI toxicity.
• Adverse effects: postural hypotension, mental
depression, drowsiness, asthenia; neurological toxicity
• Concomitant administration with pyridoxine is recommended.
• Hepatitis in ~ 5% of cases
Riminophenazines
Clofazimine
Diarylquinone
Bedaquiline
Ethionamide
Ethionamide
Para-aminobenzoic Acid Analogues
Dapsone
•
•
•
•
•
Treatment of leprosy
Combined with chlorproguanil for the treatment of malaria
Treatment of Pneumocystis jiroveci infection and prophylaxis
Prophylaxis of Toxoplasma gondii infection
Anti-inflammatory effects for treatment of pemphigoid,
dermatitis herpetiformis, linear IgA bullous disease,
relapsing chondritis, and brown recluse spider bite ulcers
• G6PD deficiency should be tested prior to use.
• NADH-dependent methemoglobin reductase deficiency–
associated methemoglobinemia
• Hemolysis at doses of 200–300 mg of dapsone per day
• Used topically for acne
Aminosalicylic acid
• Treatment of MDR-TB
•
•
•
•
•
• Treatment of MDR-TB
• Oral second-line drug
• “Psych-serine”: 50% of patients develop neuropsychiatric
symptoms; headache, somnolence, severe psychosis, seizures,
and suicidal ideas
• Must be redosed after dialysis
Should be administered with food
Dose must be reduced in renal dysfunction.
Adverse events incidence is ~ 10%–30%.
GI problems predominate
Hypersensitivity reactions in 5%–10% of patients
Cycloserine
Cycloserine
SECTION VII
• Tuberculosis
Drug Facts For Your Personal Formulary: Antifungal Agents
Drugs
Therapeutic Uses
Clinical Pharmacology and Tips
Polyenes: Interact with ergosterol in the fungal cell membrane
Amphotericin B deoxycholate
(C-AMB)
•
•
•
•
•
•
•
•
•
Invasive candidiasis
Invasive aspergillosis
Blastomycosis
Histoplasmosis
Coccidioidomycosis
Cryptococcosis
Mucormycosis
Sporotrichosis
Empirical therapy in the
immunocompromised host
Amphotericin B colloidal
dispersion (ABCD) (not
available in the U.S.)
• Associated with significant nephrotoxicity, including azotemia, renal tubular
acidosis, and hypochromic, normocytic anemia
• Associated with acute reactions, including infusion-related fever and chills
• C-AMB is better tolerated by premature neonates than by older children and adults
• All three amphotericin B lipid formulations are less nephrotoxic than C-AMB.
• Infusion-related reactions are highest with ABCD and lowest with L-AMB.
Liposomal amphotericin
B (L-AMB)
Amphotericin B lipid complex
(ABLC)
Pyrimidines: Disrupt fungal RNA and DNA synthesis
Flucytosine
• Cryptococcosis (with amphotericin B)
• Has broad activity but emergence of resistance limits usefulness as single-agent
therapy
• ↓ Dosage in patients with ↓ renal function
• Toxicity more frequent in patients with AIDS or azotemia
• Flucytosine may depress bone marrow, lead to leukopenia and thrombocytopenia
Imidazoles and Triazoles: Inhibit ergosterol biosynthesis
Ketoconazole
Itraconazole
•
•
•
•
•
•
•
•
Invasive aspergillosis
Blastomycosis
Coccidioidomycosis
Histoplasmosis
Pseudallescheriasis
Sporotrichosis
Ringworm
Onychomycosis
• Substrate for and potent inhibitor of CYP3A4
• Hepatotoxic
• Contraindicated in pregnancy and in women considering becoming pregnant
Drug Facts For Your Personal Formulary: Antifungal Agents (continued)
Drugs
Therapeutic Uses
Clinical Pharmacology and Tips
CHAPTER 61
Imidazoles and Triazoles: Inhibit ergosterol biosynthesis
Fluconazole
•
•
•
•
Invasive candidiasis
Cryptococcosis
Coccidioidomycosis
Prophylaxis and empirical therapy in
immunocompromised host
• Plasma concentrations are essentially the same whether the drug is given orally or
intravenously.
• Concentrations in CSF = 50%–90% of CP
• Inhibitor of CYP3A4 and CYP2C9
• Contraindicated during pregnancy
Voriconazole
• Invasive aspergillosis
• Invasive candidiasis
• Pseudallescheriasis
•
•
•
•
•
•
Oral bioavailability is 96%.
Monitor CP; serum levels of 1 to 5 mg/L maximize efficacy and minimize toxicity
Metabolized by and inhibits CYPs (2C19 > 2C9 > 3A4)
Can prolong the QTc interval
Transient visual or auditory hallucinations are frequent after the first dose.
Contraindicated in pregnancy
Posaconazole
• Oropharyngeal candidiasis
• Prophylaxis in the immunocompromised host against
aspergillosis and candidiasis
•
•
•
•
•
Oral bioavailability enhanced by food
Drugs that ↓ gastric acid ↓ posaconazole exposure
Inhibits CYP3A4
Can prolong the QTc interval
Adverse effects: headache and GI disorders
Isavuconazole
(isavuconazonium prodrug)
• Invasive aspergillosis
• Mucormycosis
• Oral bioavailability is 98%.
• Substrate of and inhibitor of CYP3A4
• Does not appear to prolong QTc
Echinocandins: Inhibit 1,3-β -d-glucan synthesis in the fungal cell wall
Caspofungin
• Invasive candidiasis
• Empirical therapy in the
immunocompromised host
• ↓ Dose in moderate hepatic impairment
Micafungin
• Invasive candidiasis
• Prophylaxis in the immuno- compromised
host
• Reduction of micafungin dose in moderate hepatic failure is not required.
Anidulafungin
• Invasive candidiasis
• No dose adjustment is needed for hepatic or renal failure.
Griseofulvin: Inhibits microtubule function, disrupts assembly of the mitotic spindle
Griseofulvin
• Ringworm
• Onychomycosis
• Absorption is reduced by barbiturates
• Induces hepatic CYPs
Allylamines: Inhibit fungal squalene epoxidase and reduce ergosterol biosynthesis
Terbinafine
• Ringworm
• Onychomycosis
• Bioavailability is ∼ 40% due to first-pass metabolism in the liver.
• The drug accumulates in skin, nails, and fat.
• The initial t1/2 is ~ 12 h but extends to 200–400 h at steady state.
Agents Active Against Microsporidia and Pneumocystis
Albendazole
• Microsporidia infection
• Anthelmintic
• Inhibitor of α-tubulin polymerization
Fumagillin
• Microsporidia infection
• Used in immunocompromised individuals with intestinal microsporidiosis due to
Enterocytozoon bieneusi unresponsive to albendazole
• Not approved for human use in the U.S.
Trimethoprimsulfamethoxazole
Pentamidine
• Pneumocystis jiroveci pneumonia
• See Chapter 56
• Pneumocystis jiroveci pneumonia
• Prophylaxis use to prevent PJP in at-risk individuals who cannot tolerate
trimethoprim-sulfamethoxazole
Imidazoles and
Triazoles Clotrimazole,
miconazole,
ketoconazole, etc.
• Dermatophytosis (ringworm),
candidiasis, tinea versicolor, piedra, tinea
nigra, and fungal keratitis
• Available for cutaneous application as creams or solutions
• Some are available as vaginal creams or suppositories or as oral troches
Tavaborole
Toenail onychomycosis due to T. rubrum
or T. mentagrophytes
• Apply daily for 48 weeks
Topical Antifungal Agents
Drug Facts for Your Personal Formulary: Antiviral Agents for Herpes Virus and
Influenza
CHAPTER 62
Drugs
Therapeutic Uses
Clinical Pharmacology and Tips
Acyclovir
Valacyclovir (Val, an ester prodrug
form of acyclovir)
• Clinical use limited to herpes
viruses
• Efficacy against:
HSV-1 > HSV-2 > VZV > EBV
> CMV = –6
• Acyclovir has low bioavailability (~20%); Val has bioavailability ~ 70%
• Concentrates in breast milk
• Clearance via renal excretion of acyclovir, requires good kidney function; t1/2
prolonged in neonates and anuric patients
• Safely used long term (10 years)
Cidofovir
Famciclovir (Fam),
a prodrug form, rapidly converted to
penciclovir (Pen)
• Active against human herpes,
papilloma, polyoma, pox,
adenoviruses
• Penciclovir similar to acyclovir
against HSV and VZV; also
inhibits HBV
• Low oral bioavailability
• Plasma t1/2 ~ 2.6 h, but active diphosphate metabolite has long t1/2 in cells, as does a
phosphocholine metabolite (t1/2 = 86 h)
• Major risk: nephrotoxicity, reduced by oral probenecid and saline prehydration
(beware interactions of probenecid and other medicines)
• Oral bioavailabilities: Pen, < 5%; Fam, ~ 75%
• Food reduces rate but not extent of Pen absorption
• Safety in pregnancy not established
Valganciclovir (Val), a prodrug valyl
ester of ganciclovor (Gan)
• Gan has inhibitory activity against
all herpesviruses, especially CMV
•
•
•
•
•
• Active against all herpesviruses and
HIV
• Poorly soluble in water; requires large volumes
• Adverse effects: neprotoxicity, hypocalcemia
• Safety in pregnancy and childhood uncertain
Fomivirsen (antisense
oligonucleotide)
• Inhibits CMV replication
• No longer available in the U.S.
Docosanol (long-chain alcohol)
• 10% cream for labial herpes
• Treatment initiation at papular or later stages provides no benefit
Idoxuridine (iodinated thymidine
analogue)
• Ophthalmic HSV keratitis (in the U.S.)
• Averse effects: pain, pruritus, inflammation, edema of eye/eyelid
Trifluridine (trifluoropyrimidine
nucleoside)
• Ocular herpes; 1° keratoconjunctivitis,
recurrent epithelial keratitis from
HSV1/2; for external use
• More active than idoxuridine and comparable to vidarabine in HSV ocular
infections
• Triphosphate form incorporated into host and viral DNA, so not used systemically
ANTIHERPES AGENTS
Guanine nucleoside analogues
Gan less active against acyclovir-resistant TK-deficient HSV strains
Active triphosphate form has long cellular t1/2
IV administration gives good levels in vitreous with long dwell time (t1/2 ~ 25 h)
Major adverse effects: myelosuppression, neutropenia
Risk in pregnancy not ruled out
Pyrophosphate analogue
Foscarnet
Other agents
ANTI-INFLUENZA AGENTS
Inhibitors of viral M2 protein function
Amantadine (Ama) Rimantadine
(Rima)
• Active only against susceptible
influenza A viruses (not B)
• Seasonal prophylaxis against
influenza A (70%–90% protective)
•
•
•
•
Rima 4- to 10-fold more active than Ama
Resistant isolates appear after 2–3 days of therapy
Virtually all H3N2 strains of influenza are resistant to these drugs
Vaccination is more cost-effective
Inhibitors of viral neuraminidase (see PK data in Table 62–3)
Oseltamivir
• Treatment and prevention of
influenza A and B
• Probenecid doubles plasma t1/2
Zanamivir
• Treatment and prevention of
influenza A and B
• Inhalable formulation
• IV formulation available as EIND
• No clinically significant drug interactions
Peramivir
• Treatment of acute uncomplicated
flu in patients ≥ 18 years and
symptomatic ≤ 2 days
• Supplied as IV infusion; for patients who cannot absorb or oral agents
• Comparable in efficacy and adverse effects to oseltamivir
• No clinically significant drug interactions reported
• Treatment of condyloma
acuminatum, chronic HCV and
HBV infection, Kaposi sarcoma
(in patients with HIV, other
malignancies, multiple sclerosis
• See Chapter 63
CYTOKINES
Interferon (recombinant α-IFNs;
natural and pegylated IFNs)
Drug Facts for Your Personal Formulary: Viral Hepatitis (HBV/HCV)
Drugs
Therapeutic Uses
Clinical Pharmacology and Tips
Pegylated interferon
alfa
• Preferred agent
• Approved for adult patients with
compensated liver disease and evidence of
viral replication and liver inflammation
• Administered SC weekly for 48–52 weeks
•
•
•
•
Entecavir
• Preferred agent
• Approved for individuals ≥ 2 years old
• Indefinite treatment for patients with cirrhosis
• Use higher dose for decompensated cirrhosis and patients with lamivudine or
telbivudine resistance
• Take on an empty stomach
• Monitor for lactic acidosis in decompensated cirrhosis
• Adverse reactions (≥3%): headache, fatigue, dizziness, nausea
Tenofovir disoproxil
fumarate
• Preferred agent
• Approved for individuals ≥ 2 years old
• Indefinite treatment for patients with cirrhosis
•
•
•
•
Adefovir
Lamivudine
Telbivudine
• Alternative agents due to high incidence of
HBV resistance with monotherapy
• Indefinite treatment for patients with cirrhosis
• Dose adjust for renal impairment
• Abrupt discontinuation causes hepatitis flares
• Common adverse reactions:
° Adefovir: asthenia and impaired renal function
° Lamivudine: ear, nose, and throat infections; sore throat; and diarrhea
° Telbivudine: increased CK, nausea, diarrhea, fatigue, myalgia, and myopathy
Hepatitis B Therapy
Adverse reactions (>40%): fatigue/asthenia, pyrexia, myalgia, and headache
May cause fatal neuropsychiatric, autoimmune, ischemic, and infectious disorders
Frequent hematologic monitoring required
Contraindicated in advanced liver disease and in pregnancy
Dose reduction in renal impairment
Monitor renal function
May decrease bone mineral density
Adverse reactions (≥10%) in decompensated cirrhosis: abdominal pain, nausea,
insomnia, pruritus, vomiting, dizziness, and pyrexia
Drug Facts for Your Personal Formulary: Viral Hepatitis (HBV/HCV)
(continued)
CHAPTER 63
Drugs
Therapeutic Uses
Clinical Pharmacology and Tips
Sofosbuvir/ledipasvir
• HCV genotype 1, 4, 5, 6 and individuals with
HIV coinfection
• Administered as fixed-dose
combination tablet for 8 or 12 weeks
• Use with ribavirin for 12 weeks in treatmentexperienced patients with cirrhosis
• Ledipasvir should not be used with potent Pgp inducers
• Ledipasvir absorption requires acid gastric pH
• Coadministration of sofosbuvir and amiodarone may cause severe bradycardia and
fatal cardiac arrest
• Avoid sofosbuvir if CrCl < 30 mL/min
• Adverse reactions (≥10%): fatigue, headache
Sofosbuvir/daclatasvir
• HCV genotype 3, HIV coinfection, and
advanced liver disease regardless of
HCV genotype
• 12-week treatment in patients without
cirrhosis
• Coadministered with ribavirin in patients
with cirrhosis for 12 weeks
• Daclatasvir should not be used with potent CYP3A inducers
• Daclatasvir dose reduction needed with strong CYP3A inhibitors
• Coadministration of sofosbuvir and amiodarone may cause severe bradycardia and
fatal cardiac arrest
• Avoid sofosbuvir if CrCl < 30 mL/min
• Adverse reactions (≥10%): fatigue, headache
Sofosbuvir/simeprevir
• 12-week therapy in patients without cirrhosis
• 24-week therapy in patients with cirrhosis
• Cannot be used with potent Pgp inducers
• Simeprevir: mild inhibitor of GI; contraindicated in decompensated cirrhosis CYP3A
• Coadministration of sofosbuvir and amiodarone may cause severe bradycardia and
fatal cardiac arrest
• Adverse reactions of simeprevir (≥20%): fatigue, headache, nausea, photosensitivity
(limit sun exposure)
Sofosbuvir/velpatasvir
• Approved for use in all HCV genotypes
• Administered as a fixed dose
combination tablet for 12 weeks
• Used with ribavirin for patients with
decompensated cirrhosis
• Do not use with potent Pgp or CYP3A inducers
• Velpatasvir requires acidic gastric pH
• Coadministration of sofosbuvir and amiodarone may cause severe bradycardia and
fatal cardiac arrest
• Avoid sofosbuvir if CrCl < 30 mL/min
• Common adverse reactions: fatigue and headache
Ritonavir-boosted
paritaprevir and
ombitasvir
• Fixed-dose combination tablets for HCV
genotype 4 in combination with ribavirin
Ritonavir-boosted
paritaprevir,
ombitasvir, and
dasabuvir
• HCV genotype 1b (1a in combination
with ribavirin)
• 12 weeks of therapy
• 24 weeks of therapy required for patients
with genotype 1a and cirrhosis
•
•
•
•
Grazoprevir/elbasvir
• 12-week therapy for patients without
baseline NS5A RAVs
• 16-week combined therapy with ribavirin
for patients with baseline NS5A RAVs
• Preferred treatment in renal impairment
• Should not be used with moderate and strong CYP3A and Pgp inducers
• Should not be used with OATP1B1 inhibitors
• Common adverse reactions: headache, fatigue, nausea
Ribavirin
• Used in combination with other HCV
regimens to boost therapeutic efficacy
•
•
•
•
•
Hepatitis C Therapy
High potential for CYP-mediated drug interactions
Should not be used in patients with decompensated cirrhosis
Adverse reactions (≥5%): nausea, pruritis, and insomnia
With ribavirin, the most common adverse reactions (≥10%) are fatigue, nausea,
pruritis, other skin reactions, insomnia, and asthenia
May cause hemolytic anemia
Teratogenic
Wide tissue distribution
Long half-life (7–10 days)
Dose adjustment needed for renal impairment
Drug Facts for Your Personal Formulary: Antiretroviral Agents and
Treatment of HIV Infection
Drug
Therapeutic Use
Clinical Pharmacology and Tips
Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (phosphorylated to active form to prevent infection of susceptible cells;
do not eradicate virus from cells with integrated proviral DNA): Active against HIV-1 and HIV-2 and in some cases HBV
Zidovudine
(AZT) (thymidine
analogue)
• HIV in adults and children
• Preventing mother-to-child transmission
• Adverse effects: bone marrow (anemia, neutropenia) and
muscle toxicity (myopathy); inhibits mitochondrial DNA
polymerase γ
• Do not use with stavudine
Stavudine (dT4)
• HIV in adults and children
• Adverse effects: sensory neuropathy and lipoatrophy
• Do not use with zidovudine
• Avoid use because of long-term and potentially irreversible
toxicities
Lamivudine
• HIV in adults and children ≥ 3 months
• Chronic hepatitis B (adults, children)
• Essentially nontoxic
Abacavir
(only guanosine analogue antiretroviral)
• HIV in adults and children
• Not active against HBV
• Bioavailability not affected by food
• Adverse effects: hypersensitivity syndrome (fever,
abdominal pain, rash), associated with HLA B*5701
genotype; discontinue drug immediately and never use
again as this is potentially fatal
Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (phosphorylated to active form to prevent infection of susceptible cells;
do not eradicate virus from cells with integrated proviral DNA): Active against HIV-1 and HIV-2 and in some cases HBV (continued)
• HIV infection (adults, children > 2 years, in
combination with other antiretrovirals)
• Chronic hepatitis B (adults, children > 12 years)
• HIV preexposure prophylaxis (with
emtricitabine) in adults at high risk of infection
• Nephrotoxicty: small decreases in estimated creatinine
clearance are common; Fanconi syndrome rare
• Decreases in bone mineral density with chronic use
Emtricitabine
• HIV infection (adults, children, in combination
with other antiretrovirals)
• Chronic hepatitis B (adults, children)
• HIV preexposure prophylaxis (with tenofovir) in
adults at high risk of infection
• Generally nontoxic
Didanosine
• HIV infection in adults and children
• Adverse effects: sensory neuropathy and pancreatitis
• Avoid use because of long-term and potentially irreversible
toxicities
Nonnucleoside Reverse Transcriptase Inhibitors: Do not require metabolic activation; HIV-1 specific and not active against HIV-2
Nevirapine
• HIV-1 infection in infants, children, and adults
• Single-dose prevention of mother-to-child
transmission
• Autoinducer of metabolism
• Commonly produces rash that usually resolves with
continued treatment
• Can rarely produce life-threatening skin eruptions such as Stevens-Johnson
syndrome
• Rarely produces life-threatening hepatitis
Efavirenz
• HIV-1 infection in children ≥ 3 years and adults
• Commonly causes CNS toxicity that usually resolves with continued treatment
but can be severe enough to warrant discontinuation
• Moderate hepatic enzyme inducer
Rilpivirine
• HIV-1 infection in children > 12 years and adults
• Must be given with food
• Avoid proton pump inhibitors because of reduced
absorption
• May cause prolonged QTc interval if concentrations are too
high
Etravirine
• Treatment-experienced adults and children
≥ 6 years
• Commonly produces rash that usually resolves with
continued treatment
• Can rarely produce life-threatening skin eruptions such as Stevens-Johnson
syndrome
• Moderate inducer of hepatic enzymes
Delavirdine
• Adults with HIV infection
• Rash commonly and rarely Stevens-Johnson syndrome
• Rarely used because of the requirement for thrice-daily
dosing
Protease Inhibitors: Active against HIV-1 and HIV-2; generally used as second-line agents in treatment-experienced patients
Saquinavir
• Second-line treatment of HIV in adults and
children
• Rarely used because of better-tolerated alternative PIs
Ritonavir
• Used only as a PK-boosting agent in
combination with other PIs
• Commonly causes nausea
• Associated with elevated cholesterol and triglycerides at
higher doses
• Potent inhibitor of CYP3A4
• Moderate hepatic enzyme inducer
Fosamprenavir
• HIV-infected adults, treatment-naïve children
≥ 2 years and treatment-experienced children
≥ 6 years
• Adverse effects: diarrhea, nausea, and vomiting
• Occasional skin rashes
Lopinavir
• Treatment-naïve or -experienced HIV-infected
adults and children ≥ 14 days
• Must be combined with ritonavir
• Commonly causes nausea and other GI toxicities
• Associated with elevated cholesterol and triglycerides in
adults with prolonged use
Atazanavir
• Treatment-naïve or -experienced HIV-infected
adults and children ≥ 3 months
• Usually combined with ritonavir or cobicistat
• Can be given without a PK booster at a higher dose
of 400 mg
• Absorption reduced with proton pump inhibitors
and H2 blockers
• Commonly causes unconjugated hyperbilirubinemia
• Can cause nephrolithiasis and cholelithiasis
Darunavir
• Treatment-naïve or -experienced HIV-infected
adults and children > 3 years
• Must be combined with ritonavir or cobicistat
• May cause transient rash
• Better tolerated than other PIs
SECTION VII
Tenofovir
(5′-AMP derivative;
supplied as prodrugs:
TDF or TAF)
Drug Facts for Your Personal Formulary: Antiretroviral Agents and
Treatment of HIV Infection (continued)
CHAPTER 64
Drug
Therapeutic Use
Clinical Pharmacology and Tips
Protease Inhibitors: Active against HIV-1 and HIV-2; generally used as second-line agents in treatment-experienced patients
Indinavir
• Treatment-naïve or -experienced HIV-infected
adults and children
• Must be taken with ritonavir or while fasting
• Adverse effects: crystalluria and nephrolithiasis
• Rarely used because of the availability of better-tolerated
PIs
Nelfinavir
• Treatment-naïve or -experienced HIV-infected
adults and children
•
•
•
•
Tipranavir
• Treatment-experienced HIV-infected adults and
children ≥2 years, generally those who have
failed all other PIs
• Toxicity: rare but potentially fatal hepatotoxicity; rare but
potentially fatal bleeding diathesis, including intracranial
hemorrhage
• Rarely used because of the availability of better-tolerated
PIs
The only PI that does not benefit from PK boosting
Must be taken with food
Adverse effects: diarrhea and other GI toxicity
Rarely used because of the availability of better-tolerated
PIs
Entry Inhibitors: Generally reserved for second-line or salvage therapy
Maraviroc
• Treatment-naïve or -experienced HIV-infected
adults who have evidence of predominantly
CCR5-tropic virus
• CYP3A4 substrate susceptible to drug interactions with
other antiretrovirals
• Adverse effect: dose- and concentration-dependent
orthostatic hypotension
Enfuvirtide
• Treatment-experienced HIV-infected adults and
children > 6 years
• Generally reserved for those with no other
treatment options
• Injected subcutaneously twice daily
• Adverse effects: injection site reactions and subcutaneous
nodules are common
• Not active against HIV-2
Integrase Inhibitors: Widely used in treatment-naïve patients because of excellent tolerability, safety, and antiretroviral
activity
Raltegravir
• HIV-infected adults and children > 4 weeks of
age
• Given twice daily without the need for a PK boosting agent
• Reduced bioavailability if given concurrently with divalent
cations
• Generally well tolerated
Elvitegravir
• HIV-infected adults and children > 12 years of
age
• Requires cobicistat as a PK booster
• Should be taken with food
• Reduced bioavailability if given concurrently with divalent
cations
• Generally well tolerated
Dolutegravir
• HIV-infected adults and children > 12 years of
age
• Given once daily without the need for a PK-boosting agent
• Reduced bioavailability if given concurrently with divalent
cations
• Generally well tolerated
Drug Facts for Your Personal Formulary: Cytotoxic Drugs
Drug
Therapeutic Use
Clinical Pharmacology and Tips
Section I: Alkylating Agents and Platinum Coordination Complexes
Mechanism of action: covalent modification of DNA. Adverse effects of all alkylating drugs: myelosuppression and immunosuppression; toxicity to dividing mucosal
cells and hair follicles (e.g., oral mucosal ulceration, intestinal denudation, alopecia); delayed pulmonary fibrosis; reproductive system toxicity (premature menopause,
sterility); and leukemogenesis (up to 5%, highest for melphalan, procarbazine, nitrosoureas).
Nitrogen Mustards: DNA alkylation
• Hodgkin lymphoma
• Topical: cutaneous T-cell lymphoma
• Vascular damage during injection due to vesicant properties
Cyclophosphamide
• Acute and chronic lymphocytic
leukemia; Hodgkin lymphoma; nonHodgkin lymphoma; multiple myeloma;
neuroblastoma; breast, ovary, Wilms
tumor; soft-tissue sarcoma
• Autoimmune disease (Wegener
granulomatosis, rheumatoid
arthritis, nephrotic syndrome)
• Oral or intravenous administration
• Active alkylating moieties generated through hepatic metabolism
• Nephrotoxic and urotoxic metabolite, acrolein; severe hemorrhagic
cystitis in high-dose regimens; prevented by MESNA
• Provide vigorous hydration during high-dose treatment
• Elimination not affected by renal dysfunction; reduce dose in patients
with hepatic dysfunction
Ifosfamide
• See cyclophosphamide
• Can cause neurotoxicity (including seizures)
• Methylene blue treatment of CNS toxicity possibly useful
Melphalan
• Germ cell testicular cancer
• Pediatric and adult sarcoma
• High-dose chemotherapy with bone
marrow
rescue
• Multiple myeloma
Chlorambucil
• Chronic lymphocytic leukemia
• Oral administration
Bendamustine
• Non-Hodgkin lymphoma
• Chronic lymphocytic leukemia
• Lacks cross-resistance with other classical alkylators
• Chronic myelogenous leukemia
• High-dose chemotherapy regimen with
bone marrow transplantation
• Oral administration
• Adverse effects: prolonged (up to years) pancytopenia; suppression of
stem cells; seizures; ↑ clearance of phenytoin; hepatic VOD
Carmustine (BCNU)
• Malignant gliomas
• Hodgkin lymphoma; non-Hodgkin
lymphoma
• Vascular damage during injection due to vesicant properties
• Profound and delayed myelosuppression
Streptozocin (streptozotocin)
• Malignant pancreatic insulinoma
• Carcinoid
• Frequent renal toxicity, sometimes renal failure
• Oral and intravenous administration
Alkyl Sulfonate: DNA alkylation
Busulfan
Nitrosoureas: DNA alkylation
Methylhydrazine Derivatives: Monofunctional DNA alkylation
Procarbazine (N
methylhydrazine, MIH)
• Hodgkin lymphoma
• Gliomas
• Greater capacity for mutagenesis and carcinogenesis than bifunctional
alkylators (e.g., cyclophosphamide)
Triazenes: Methyl transfer to DNA
Dacarbazine (DTIC)
• Hodgkin lymphoma; soft-tissue sarcomas
• Melanoma
•
•
•
•
Intravenous administration
Activation by hepatic CYPs
Adverse effects: nausa, vomiting
Rare hepatotoxicity and neurotoxicity
Temozolomide
• Malignant gliomas
• Oral administration
• Combined with radiation therapy
• Greater capacity for mutagenesis and carcinogenesis than bifunctional
alkylators; more active in MGMT-deficient tumors
Platinum Coordination Complexes: Form covalent metal adducts with DNA
Cisplatin
• Testicular, ovarian, bladder, esophageal,
gastric, lung, head and neck, anal, and,
breast cancer
• Intravenous administration
• Adverse effects:
• Nephrotoxicity (reduce by forced pretreatment hydration, diuresis, and
use of amifostine)
• Ototoxicity (tinnitus, high-frequency hearing loss)
• Nausea and vomiting (antidote, aprepitant)
• Peripheral sensory and motor neuropathy (may worsen after
discontinuation; may be aggravated by taxane treatment)
• Drug resistance due to loss of mismatch repair proteins
SECTION VIII
Mechlorethamine
Drug Facts for Your Personal Formulary: Cytotoxic Drugs (continued)
Drug
Therapeutic Use
Clinical Pharmacology and Tips
Platinum Coordination Complexes: Form covalent metal adducts with DNA
Carboplatin
• Same as above
• Less nausea, neuro-, oto-, and nephrotoxicity than cisplatin
• Dose-limiting toxicity: myelosuppression
• May cause hypersensitivity reaction
Oxaliplatin
• Colorectal, gastric, and pancreatic cancer
• Peripheral neuropathy is dose limiting
• Some nausea
• Efficacy not dependent on intact mismatch repair
CHAPTER 66
Section II: Antimetabolites
Folic Acid Analogues: Inhibit dihydrofolate reductase
Methotrexate (amethopterin)
• Acute lymphocytic leukemia;
choriocarcinoma; breast, head and neck,
ovary, bladder and lung cancers;
osteogenic sarcoma
• Noncancer use: psoriasis, rheumatoid
arthritis
• Oral, intravenous, or intramuscular administration
• Adverse effects: myelosuppression, GI toxicity
• Leucovorin can reverse toxic effects; used as “rescue” in high-dose
therapy
• Glucarpidase, a methotrexate-cleaving enzyme, is approved to treat
toxicity
• ↓ Dose in renal insufficiency
Pemetrexed
• Mesothelioma, lung cancer
• Similar effects and side effects as methotrexate
• Attenuate toxicity with folate and Vit B12 supplementation
5-Fluorouracil (5FU)
Thymidylate synthase inhibitor
• Breast, colon, esophageal, stomach, anal
cancer
• In FOLFOX or FOLFIRINOX combination to
treat pancreatic or colorectal cancer
• Combined with cisplatin in head and neck
cancer
• Premalignant skin lesion (topical)
•
•
•
•
Capecitabine
Thymidylate synthase inhibitor
• Metastatic breast, colorectal cancer
• Orally administered prodrug of 5FU
• Similar adverse effects as 5FU; hand and foot syndrome more frequent
than with 5FU
Cytarabine
(cytosine
arabinoside) Interferes with
base pairing in DNA; inhibits
DNA polymerase
• Acute myelogenous and acute lymphocytic
leukemia; non-Hodgkin lymphoma
• Intravenous administration
• Myelosuppressive; can cause acute, severe leukopenia,
thrombocytopenia, anemia
• GI disturbances
• Noncardiogenic pulmonary edema
• Dermatitis
Gemcitabine (difluoro
analogue of deoxycytidine)
Inhibits DNA polymerase; causes
strand termination
• Pancreatic, ovarian, lung, bladder cancer
• Intravenous administration
• Female and elderly patients clear the drug more slowly
• Myelosuppression, hepatic toxicity
• Rare posterior leukoencephalopathy syndrome; sometimes interstitial
pneumonitis
• Radiosensitizer; should be used with caution in radiotherapy
5-Azacytidine
Inhibits DNA cytosine
methyltransferase
• Myelodysplasia
• Subcutaneous or intravenous administration
• Myelosuppression and mild GI symptoms
• After intravenous administration severe nausea possible
Pyrimidine Analogues
Intravenous administration
Nausea, mucositis, diarrhea, myelosuppression, hand-foot syndrome
Combined with leucovorin to enhance efficacy
Enhanced toxicity with DPD deficiency; may rescue with uridine
Purine Analogues and Related Inhibitors
6-Mercaptopurine
Inhibits purine nucleotide synthesis
and metabolism
• Acute lymphocytic and myelogenous
leukemia; small cell non-Hodgkin
lymphoma
• Noncancer: Crohn disease, ulcerative
colitis
• Oral absorption incomplete, thus intravenous administration
• Reduce oral dose by 75% in patients receiving allopurinol; no
adjustment needed for intravenous administration
• Myelosuppression; anorexia, nausea, vomiting; GI side effects less
frequent in children than adults
• Secondary malignancy: SCC of the skin, AML
Fludarabine
A chain terminator when
incorporated into DNA; inhibits
RNA function and processing
• Chronic lymphocytic leukemia
• Follicular B-cell lymphoma
• Allogeneic bone marrow transplant
•
•
•
•
•
Oral or intravenous administration
Frequently myelosuppression
Less frequent: nausea, vomiting; altered mental status; seizures
Secondary myelodysplasia and acute leukemias
Adjust dose for renal dysfunction
Purine Analogues and Related Inhibitors (continued)
•
•
•
•
Hairy cell leukemia
Chronic lymphocytic leukemia
Low-grade lymphoma
CTCL, Waldenström macroglobulinemia
• Intravenous administration
• Adjust dose for renal dysfunction
• Myelosuppression, opportunistic infections, nausea, high fever, tumor lysis
syndrome
• Acute myelogenous or lymphocytic leukemia
• T-cell leukemia, lymphoma
•
•
•
•
•
•
•
Intravenous administration
Adjust dose to creatinine clearance
Myelosuppression
Capillary leak syndrome: discontinue drug
Nausea, vomiting, diarrhea
Intravenous administration
Myelosuppression; liver function abnormalities; infrequent neurologic sequelae
Pentostatin
(2′-deoxycoformycin)
Inhibits adenosine
deaminase; causes
immunodeficiency (T
and B cells)
• Hairy cell leukemia; chronic lymphocytic
leukemia; small cell non-Hodgkin lymphoma
•
•
•
•
Intravenous administration
Adjust dose for renal dysfunction
Myelosuppression, GI symptoms, skin rashes, opportunistic infections
Renal, neurologic, pulmonary toxicity
Section III: Natural Products
Vinca Alkaloids: Inhibit tubulin polymerization and microtubule formation
Vinblastine
•
•
•
•
Hodgkin and non-Hodgkin lymphoma
Breast, bladder, lung, testicular cancer
Kaposi sarcoma, neuroblastoma
Part of ABVD combination with doxorubicin
(adriamycin, bleomycin, dacarbazine) for
Hodgkin lymphoma
• Intravenous administration; extravasation causes irritation and
ulceration
• Reduce dose in patients with impaired liver function
• Least neurotoxic Vinca alkaloid
• Myelosuppressive
• GI side effects nausea, vomiting, diarrhea
• Vinca alkaloids are substrates of the Pgp efflux pump
Vinorelbine
• Breast cancer
• Non–small cell lung cancer
•
•
•
•
Vincristine
• Acute lymphocytic leukemia; neuroblastoma;
Wilms tumor; rhabdomyosarcoma; Hodgkin and
non-Hodgkin lymphoma
• part of CHOP regimen: cyclophosphamide,
doxorubicin (H), vincristine (O), prednisone
Eribulin
• Breast cancer, liposarcoma
• Intravenous administration; extravasation causes irritation and
ulceration
• Reduce dose in patients with impaired liver function
• Least myelosuppressive Vinca alkaloid
• Dose-limiting neurotoxicity
• Better tolerated by children than adults
• Side effects overlap with vinca but less sensitive to extrusion by Pgp
Intravenous administration
Reduce dose in patients with impaired liver function
Intermediate neurotoxicity amongst the Vinca alkaloids
Myelosuppressive (granulocytopenia)
Taxanes: Stabilize microtubules, inhibit depolymerization
Paclitaxel
• Ovarian, breast, lung, prostate, bladder, head and
neck cancer
• Intravenous administration
• Metabolized by hepatic CYPs, ↓ dose in patients with hepatic
dysfunction
• Substrate of Pgp efflux pump
• Myelosuppressive, alleviated by G-CSF
• Peripheral neuropathy is dose limiting
• Mucositis
Docetaxel
• Same as above
• No effect on doxorubicin clearance
• Pharmacokinetics similar to paclitaxel’s
• ↓ Neutropenia, ↓ neuropathy than paclitaxel
Camptothecins: Inhibit topoisomerase I; DNA religation is inhibited: accumulation of single-strand breaks
Topotecan
• Ovarian cancer; small cell lung cancer
•
•
•
•
Intravenous or oral administration
Reduce dose in patients with renal dysfunction
Neutropenia, GI side effects, nausea, vomiting
Substrate for Pgp
Irinotecan
• Colorectal cancer, small cell lung cancer
• Part of FOLFIRI or FOLFIRINOX combination
for GI tumors
•
•
•
•
Intravenous administration
Prodrug activated in the liver; CYP substrate
Diarrhea and neutropenia
Acetylcholinesterase inhibition results in cholinergic syndrome: treat
with atropine
• Wilms tumor; rhabdomyosarcoma; Ewing,
Kaposi, and other sarcoma; choriocarcinoma
• Intravenous administration; severe injury on extravasation
• Nausea, vomiting; myelosuppression; GI side effects; erythema,
inflammation of the skin
Antibiotics
Dactinomycin
(actinomycin D)
Intercalates between GC
base pairs of DNA
SECTION VIII
Cladribine
Incorporated into DNA,
produces strand breaks;
inhibits conversion of riboto deoxyribonucleotides
Clofarabine (mechanism as
above)
Nelarabine
Incorporated into DNA,
terminates DNA
synthesis
Drug Facts for Your Personal Formulary: Cytotoxic Drugs (continued)
Drug
Therapeutic Use
Clinical Pharmacology and Tips
Anthracyclines and Anthracenediones: Inhibit topoisomerase II and intercalate DNA
Daunorubicin
(daunomycin,
rubidomycin)
Doxorubicin
CHAPTER 66
Mitoxantrone (an anthracenedione)
• Acute myelogenous and acute lymphocytic
Leukemia
• Soft-tissue, osteogenic, and other sarcoma;
Hodgkin and non-Hodgkin lymphoma; acute
leukemia; breast, genitourinary, thyroid, and
stomach cancer; neuroblastoma
• Acute myelocytic leukemia; breast and
prostate cancer
•
•
•
•
Intravenous administration
Impart a red color to the urine
Myelosuppression, GI side effects
Most important long-term side effect is cardiotoxicity, including
tachycardia, arrhythmias, congestive heart failure
• Alopecia
• Similar side effects as above
• Less cardiotoxic
Epipodophyllotoxins: Inhibit topoisomerase II and religation of cleaved DNA strand
Etoposide
• Testicular and lung cancer; Hodgkin lymphoma;
non-Hodgkin lymphomas; acute myelogenous
leukemia; Kaposi sarcoma
•
•
•
•
Oral and intravenous administration
Reduce dose in patients with renal dysfunction
Leukopenia, GI side effects; hepatic toxicity after high doses
Secondary leukemia
Teniposide
• Acute lymphoblastic leukemia in children;
glioblastoma, neuroblastoma
• Intravenous administration
• Myelosuppression, nausea, vomiting
Drugs With Diverse Mechanism of Action
Bleomycin
Binds to DNA, generates free
radicals, and induces DNA cleavage
via deoxyribose ring damage
• Testicular cancer; Hodgkin and non-Hodgkin
lymphoma; local treatment of bladder cancer
• Part of the ABVD regimen (doxorubicin
[Adriamycin], Bleomycin, Vinblastine, and
Dacarbazine)
•
•
•
•
•
l-Asparaginase
• Acute lymphocytic leukemia
• IV and IM administration
• Hypersensitivity reactions, anaphylaxis
• Hyperglycemia, clotting abnormalities
Hydroxyurea
Inhibits RNR (conversion of riboto deoxyribonucleotides)
• Chronic myelogenous leukemia; polycythemia
vera; essential thrombocytosis; sickle cell disease
in adults
• Oral administration
• Reduce dose in patients with renal dysfunction
• Myelosuppression; some GI side effects
Tretinoin (all-trans retinoic acid)
Promotes degradation of PMLRARA fusion protein
• Acute promyelocytic leukemia
• Oral administration
• CYP substrate
• Leukocyte maturation syndrome, pulmonary distress, effusions,
fever, dyspnea
• Dry skin, cheilitis
• Hypercalcemia and renal failure
Arsenic trioxide
Inhibits thioredoxin and
generates reactive oxygen
species
• Acute promyelocytic leukemia
• Oral or intravenous administration
• Leukocyte maturation syndrome as above with ATRA
• QT prolongation; rare torsade de pointes
Hydrolyzes asparagine; deprives
leukemia cells that lack
asparagine synthase
IV, IM or SC administration; instilled into bladder
Reduce dose in patients with renal dysfunction
Most serious: pulmonary toxicity
Cutaneous toxicity (erythema, ulcerations)
Less myelosuppression than other cytotoxics
Drug Facts for Your Personal Formulary: Pathway-Targeted Therapies
Drug
Therapeutic Use
Clinical Pharmacology and Tips
Section I: Inhibitors of Growth Factors and Receptors
Epidermal Growth Factor Receptor Inhibitors
Small-Molecule EGFR Kinase Inhibitors: Oral Administration
• Advanced NSCLC with mutant EGFR (del exon 19; L858R)
• Advanced pancreatic cancer in combination with
gemcitabine
•
•
•
•
Skin rash, stomatitis, diarrhea, interstitial lung disease
CYP3A4 substrate
Anticoagulant effect of warfarin enhanced
Concurrent use of PPI ↓ bioavailability
Gefitinib
• Advanced NSCLC with mutant EGFR (del exon 19; L858R)
• Side effects similar to erlotinib, but bioavailability not affected by
PPI
Afatinib
• Irreversible inhibitor EGFR > HER2
• Advanced NSCLC with mutant EGFR (del exon 19; L858R)
• Side effects similar to gefitinib; can cause hepatotoxicity
• Not affected by CYP3A4 modulation
• ↓ Dose with renal impairment or Pgp inhibitors
Osimertinib
• Advanced NSCLC that is resistant to other EGFR kinase inhibitor
and positive for T790M-mutant EGFR
• Similar to gefitinib but less intense side effects; can ↑ QTc interval
Monoclonal Antibody EGFR Inhibitors: Intravenous Administration
Cetuximab
(chimeric
human/
mouse IgG1)
• Metastatic colorectal cancer with wild-type KRAS in
combination with chemotherapy
• Head and neck SCC in combination with radiation or
cisplatin
• Skin rash, diarrhea, interstitial lung disease
• Rare: infusion reaction, cardiopulmonary arrest, hypomagnesemia
Panitumumab (human
IgG2)
• Metastatic colorectal cancer with wild-type KRAS in
combination with chemotherapy
• Side effects similar to cetuximab
Necitumumab (human
IgG1)
• Metastatic NSCLC in combination with chemotherapy
• Side effects similar to cetuximab
Human Epidermal Growth Factor Receptor 2 Inhibitors
Small-Molecule HER2 Kinase Inhibitors: Oral Administration, Also Inhibit EGFR
Lapatinib
• HER2-positive breast cancer in combination with
capecitabine
• HER2-positive, hormone receptor–positive breast
cancer in combination with letrozole (AI)
• Skin rash, diarrhea
• Some cardiotoxicity (less than trastuzumab, the HER2 antibody), QT
interval prolongation
• CYP3A4 substrate
Neratinib
• Irreversible inhibitor of EGFR and HER2
• HER2-positive breast cancer in addition to
chemotherapy
• Diarrhea is major adverse effect with 1/3 of patients severe grade
3–4
Monoclonal Antibody HER2 Inhibitors: Intravenous Administration
Trastuzumab
(humanized
IgG1)
• HER2-positive breast cancer and gastric cancer
• Combination with taxanes possible as chemotherapy
• Congestive heart failure (<5% reduced LVEF; < 1% symptomatic); ↑
to 20% in combination with doxorubicin due to cardiotoxicity;
monitor LVEF during and after
• Acute infusion reaction, nausea, dyspnea, rashes
Pertuzumab
(humanized
IgG1)
• HER2-positive breast cancer in combination with
trastuzumab and taxane
• Targets different HER2 domain than trastuzumab; prevents
dimerization with other HERs
• Side effects similar to trastuzumab
Platelet-Derived Growth Factor Receptor Inhibitors
Olaratumab (fully
human
IgG1)
• Soft-tissue sarcoma in combination with doxorubicin
• Nausea, fatigue, GI toxicity
• Neutropenia, thrombocytopenia, elevated aPTT, hypokalemia,
hypophosphatemia
Section II: Inhibitors of Intracellular Protein Kinases
Mutant B-RAF Kinase Inhibitors
Vemurafenib
• BRAFV600E/K mutant melanoma
• Not effective in wild-type BRAF melanoma
•
•
•
•
Cutaneous adverse effects up to 60%, with SCC in > 20%
Arthralgia, fatigue, nausea less frequently
Can cause QT prolongation
CYP3A4 substrate; CYP1A2 inhibitor
Dabrafenib
• BRAFV600E/K mutant melanoma also in combination
with the MEK inhibitor trametinib
• BRAF V600E mutant NSCLC with trametinib
• Not effective in wild-type BRAF melanoma
• Cutaneous adverse effects include hyperkeratosis and papilloma
• cuSCC in ~ 10% of patients
• Combination with trametinib ↓ incidence of cuSCC to 3% and
delays onset
• CYP2C8 and CYP3A substrate
SECTION VIII
Erlotinib
Drug Facts for Your Personal Formulary: Pathway-Targeted Therapies (continued)
Drug
Therapeutic Use
Clinical Pharmacology and Tips
Mitogen-Activated Protein Kinase Kinase Inhibitors
CHAPTER 67
Cobimetinib
• BRAFV600E/K mutant melanoma
• Diarrhea, photosensitivity, nausea common
• Risk of hemorrhage, cardiomyopathy
• CYP3A4 substrate
Trametinib
• BRAFV600E/K mutant melanoma & BRAF V600E
mutant NSCLC: with dabrafenib
• Ineffective in patients who developed resistance to
BRAF inhibitor treatment
• Cutaneous rash, acneiform dermatitis, diarrhea most frequent;
serious skin toxicity in 6%
• Risk of cardiomyopathy, hypertension, hemorrhage, interstitial lung
disease
• Reduced absorption after high-calorie meal
Janus-Associated Protein Kinase Inhibitors
Ruxolitinib
• Polycythemia vera
• Myelofibrosis
•
•
•
•
Thrombocytopenia, anemia most frequent
Rare basal cell carcinoma or SCC
↓ Dose in renal or hepatic impairment
CYP3A4 substrate
Cyclin-Dependent Kinase 4/6 Inhibitors
Palbociclib
• Advanced ER-positive, HER2-negative breast cancer
• Combination with AI or antiestrogen (fulvestrant)
• In clinical trial for other cancers
• Common: neutropenia, leukopenia, infections, stomatitis, anemia,
thrombocytopenia, nausea, diarrhea
• Substrate and inhibitor of CYP3A4
Abemaciclib and
Ribociclib
• In clinical trials for use as above
• Side effects same as palboclib
Ibrutinib
• Mantle cell lymphoma, CLL, SLL, Waldenström
macroglobulinemia
Bruton Tyrosine Kinase Inhibitors
•
•
•
•
•
Neutropenia, thrombocytopenia, diarrhea, anemia, musculoskeletal pain
Slow onset of hypertension possible: monitor blood pressure
Atrial fibrillation: monitor and treat
Secondary malignancies mostly skin, nonmelanoma
CYP3A4 substrate
BCR-ABL, PDGFR, KIT Kinase Inhibitors
Imatinib
• Chronic-phase CML; mucosal and acral lentigenous
melanoma (KIT-mutation positive), GIST (KITmutation-positive), dermatofibrosarcoma
protuberans,
chronic myelomonocytic leukemia
•
•
•
•
GI tract adverse effects: diarrhea, nausea, vomiting
Fluid retention, edema
Rare myelosuppression, hepatotoxicity
CYP3A4 substrate
Dasatinib
• CML resistant to imatinib after prior therapy
•
•
•
•
•
Adverse effects: diarrhea, nausea, vomiting
Fluid retention, edema, pleural effusions
Rare myelosuppression, hepatotoxicity
Bioavailability ↓ after antacids or H2 blockers
CYP3A4 substrate
Nilotinib
• CML resistant to imatinib after prior therapy
•
•
•
•
•
•
Adverse effects: diarrhea, nausea, vomiting, fluid retention, edema
May ↑ QT interval; beware vascular events, including ischemia
Rare myelosuppression, hepatotoxicity
Bioavailability ↑ in the presence of food
CYP3A4 and Pgp substrate
Inhibitor of the Pgp
Bosutinib
• CML with resistance to prior therapy
• Diarrhea, nausea, thrombocytopenia, vomiting, rash
Ponatinib
+
• Resistant CML and Ph ALL
• Major adverse effects: thrombosis, hepatotoxicity, pancreatitis
• Absorption ↓ by elevated gastric pH (H2 antagonists, antacids, PPIs)
• CYP3A4 substrate
Anaplastic Lymphoma Kinase Inhibitors
Alectinib
•
Advanced NSCLC with gene rearrangement
containing the ALK kinase fusion gene
•
Advanced NSCLC with gene rearrangement
containing the ALK kinase fusion gene and disease
progression on crizotinib
• Fatigue, constipation, and edema, myalgia are common adverse
effects
• Pneumonitis, GI and hepatic toxicity; bradycardia and prolonged QT
intervals observed
Ceritinib, Crizotinib
• As above
• As above
PI3K (Phosphatidylinositol-4,5-Bisphosphate 3-Kinase) Inhibitors
Idelalisib
• Relapsed or refractory B-cell malignancies: CLL
(with rituximab), FL, SLL
• Not indicated for first-line treatment
• Serious and sometimes-fatal adverse effects: hepatotoxicity,
colitis, pneumonitis, intestinal perforations, skin toxicity
• CYP3A substrate
mTOR (Mechanistic or Mammalian Target of Rapamycin) Inhibitors
• Renal cell carcinoma
• Adverse effects: frequent rash, mucositis, anemia, fatigue (30%–50%);
rare leukopenia, thrombocytopenia, interstitial lung disease
• Metabolized to a longer-lived active metabolite (sirolimus) by CYP3A4:
avoid CYP3A4 inhibitors, including grapefruit juice
Everolimus
• Renal cell carcinoma
• Breast cancer: advanced ER positive, HER2 negative
in combination with AI exemestane after failure of
other AIs (letrozole, anastrazole)
• PNETs
• Progressive, well-differentiated,
nonfunctional neuroendocrine GIST
• Adverse effects overlap with temsirolimus (see above)
• CYP3A4 substrate
Cabozantinib
• Advanced renal cell carcinoma
• Lung adenocarcinoma with MET gene alteration
• Diarrhea, fatigue, nausea, abdominal pain
• Hypertension: monitor blood pressure
• Not indicated in patients with recent bleeding history or
thromboembolic event
• Discontinue in patients with GI perforation, fistulas
• CYP3A4 substrate; ↓ dose with hepatic impairment
Vandetanib
• Progressing, locally advanced medullary thyroid
cancer
•
•
•
•
Multikinase Inhibitors
Diarrhea, colitis, rash
QT interval prolongation, torsades des pointes, sudden death
Do not use in patients with hepatic impairment, long QT syndrome
CYP3A4 substrate
Section III: Inhibitors of Tumor Angiogenesis
Vascular Endothelial Growth Factor Inhibitors
Bevacizumab
(humanized
IgG1)
• Metastatic colorectal cancer combined
with chemotherapy (FOLFOX or FOLFIRI)
• NSCLC combined with carboplatin and paclitaxel
• Ovarian cancer combined with chemotherapy
• Renal cell carcinoma combined with interferon α
• Glioblastoma following prior therapy
• Hypertension, related congestive heart failure: monitor blood pressure
and treat hypertension
• Impaired wound healing: delay elective surgery for 1 month after the last
dose; do not resume treatment for at least 1 month after surgery
• Spontaneous GI perforation
Ramucirumab (fully
human
IgG1 to VEGFR2)
• Metastatic colorectal cancer, advanced gastric
adenocarcinoma, and NSCLC with disease
progression on or after prior therapy as a single
drug or in combination with chemotherapy
• Hypertension, diarrhea
• Hemorrhage, GI perforations
• Impaired wound healing
Aflibercept
(extracellular domain
of VEGFR1/2 fused to
Fc portion of human
IgG1)
• Metastatic colorectal cancer in combination with
FOLFIRI chemotherapy following FOLFOX
•
•
•
•
Sunitinib
•
•
•
•
Sorafenib
• Hepatocellular carcinoma (currently the only
approved
drug)
• Metastatic renal cell cancer (however, sunitinib is
the first choice)
• Adverse vascular effects match with those of sunitinib
• More common: fatigue, diarrhea, anorexia, rash
• Less common: bone marrow suppression, GI perforation,
cardiomyopathy
Axitinib
• Inhibition of VEGFR1–3
• Advanced renal cell cancer after failure of prior
systemic therapy
• Adverse effects overlap with those of anti-VEGF: hypertension,
thrombotic and hemorrhagic events, GI perforation
• CYP3A4/5 substrate
Lenvatinib
• Inhibition of VEGFR1–3, FGFRs, PDGFR
• Recurrent or metastatic differentiated thyroid cancer
• Renal cell cancer in combination with everolimus
• Adverse effects overlap with those of anti-VEGF: hypertension,
thrombotic and hemorrhagic events, GI perforation
• In addition: hepatotoxicity, QT prolongation
• CYP3A substrate
Soluble trap for VEGF receptor ligands
Hypertension, diarrhea
Increased risk of hemorrhage, GI perforation
Impaired wound healing
Inhibitors of Intracellular Kinases Participating in Angiogenesis
VEGFR2 and multiple other kinases inhibited
Metastatic renal cell cancer
GIST after imatinib resistance
Pancreatic neuroendocrine tumors
• Adverse effects shared with anti-VEGF: bleeding, hypertension,
proteinuria (frequent); thromboembolism, GI perforations (rare)
• Adverse events distinct from anti-VEGF:
• Fatigue (50%–70%), hypothyroidism (40%–60%)
• Common: bone marrow suppression and diarrhea
• Less common: hepatotoxicity, congestive heart failure
• Check blood pressure, blood counts, and thyroid functions at regular
intervals
• Elimination t1/2 ~ 4 days: regimen in some cancers is 4 weeks on, 2 weeks
off versus continuous daily administration for other cancers
SECTION VIII
Temsirolimus
Drug Facts for Your Personal Formulary: Pathway-Targeted Therapies (continued)
CHAPTER 67
Drug
Therapeutic Use
Clinical Pharmacology and Tips
Pazopanib
• Inhibition of VEGFR1–3, FGFRs, KIT, PDGFR
• Advanced renal cell carcinoma and advanced softtissue sarcoma after prior chemotherapy
• Adverse effects overlap with those of anti-VEGF: hypertension,
thrombotic and hemorrhagic events, GI perforation
• In addition: hepatotoxicity, QT prolongation
• CYP3A substrate
Regorafenib
• Inhibition of RET, VEGFR1, PDGFR, FGFR, TIE2, RAF1,
BRAF, ABL
• Metastatic colorectal cancer after previous
chemotherapy and anti-VEGF or anti-EGFR
• Advanced GIST after imatinib or sunitinib
• Major adverse effects: hepatotoxicity, hypertension, thrombotic and
hemorrhagic events, GI perforation, and wound-healing complications
• CYP3A substrate
Section IV: Drugs Targeting the Immune System
Immune Checkpoint Inhibitors
Ipilimumab (antiCTLA-4 fully human
IgG1)
• Metastatic melanoma as single agent or in combination
with nivolumab (anti-PD1)
• Clinical trials with different cancers are ongoing
• Autoimmune inflammatory toxicities in majority of patients (>70%)
• Most frequent: skin (pruritus, rash, vitiligo), GI tract (diarrhea, colitis)
• Less frequent: hepatitis, pneumonitis, hypophysitis, hypo- or
hyperthyroidism, myocarditis
Tremelimumab (antiCTLA-4 fully human
IgG2)
Nivolumab (anti-PD-1
fully human IgG4)
• Clinical trials with different cancers are ongoing
• See above
• Advanced melanoma that progressed after ipilimumab
(anti–CTLA-4)
• Previously treated NSCLC
• Advanced renal cell carcinoma
• Relapsed/refractory Hodgkin lymphoma
• Adverse effects: rash, fatigue, dyspnea, musculoskeletal pain, decreased
appetite, cough, nausea, constipation
• Immune-related serious adverse effects include pneumonitis, colitis,
hepatitis, nephritis, renal dysfunction, hypophysitis, hypo- and
hyperthyroidism
Pembrolizumab (antiPD-1 humanized IgG4)
• Advanced melanoma that progressed after ipilimumab
(anti–CTLA-4)
• NSCLC that express PD-L1 and progressed under
chemotherapy
• NSCLC with wild-type EGFR and ALK and disease
progression after chemotherapy
• HNSCC with disease progression after chemotherapy
• Adverse effects: rash, fatigue, dyspnea, musculoskeletal pain, decreased
appetite, cough, nausea, constipation
• Immune-related serious adverse effects include pneumonitis, colitis,
hepatitis, nephritis, renal dysfunction, hypophysitis, hypo- and
hyperthyroidism
Atezolimumab (antiPD-L1 fully human
IgG1)
• NSCLC that is treatment resistant
• Urothelial cancer that is locally advanced or metastatic
• Adverse effects: fatigue, decreased appetite, dyspnea, cough, nausea,
musculoskeletal pain, constipation
• In patients with urothelial cancer: urinary tract infections
• Immune-related pneumonitis, colitis, hepatitis, nephritis, renal
dysfunction, hypo- and hyperthyroidism, hypophysitis, adrenal
insufficiency, pancreatitis, Guillain-Barré syndrome, severe infections
Section V: Inhibitors of Other Targets
Poly(ADP-Ribose) Polymerase Inhibitor
Olaparib PARP (poly
(ADP-ribose)
polymerase)
inhibitor
• Ovarian cancer after three or more prior lines of
treatment in patients with germline mutant BRCA
• Adverse effects: nausea, vomiting, loss of appetite, muscle and joint
pain, anemia; leukemia (rare), potentially fatal myelodysplastic (rare)
syndrome pneumonitis
• CYP3A4 substrate
BCL2 (Antiapoptotic Protein): Orally Available Inhibitor
Venetoclax
• CLL with 17p deletion (poor prognosis)
• Neutropenia, thrombocytopenia, diarrhea, nausea
• Absorption ↑ 3- to 5-fold with a meal
• CYP3A substrate
Thalidomide and Lenalidomide
Thalidomide
• Newly diagnosed multiple myeloma
• Relapsed or refractory, pretreated multiple myeloma
• Most serious adverse effect: sensory neuropathy in 10%–30% of
patients; may not be reversible after discontinuation of treatment;
patients with preexisting neuropathy at higher risk
• Teratogenic; do not use in pregnancy
• Causes sedation, fatigue, constipation
• Sedation enhanced by alcohol, chlorpromazine, barbiturates;
counteracted by methylphenidate or methamphetamine
Thalidomide and Lenalidomide (continued)
Lenalidomide
• Bone marrow function suppression and leukopenia (20% of patients),
rare hepatic or renal toxicity
• Tumor lysis in some patients with CLL ⇒ lymph node swelling and
tumor flare: start at lower dose in patients with CLL
• Downregulates CD20, a target for monoclonal antibody therapy
• In contrast to thalidomide: little neuropathy, sedation, or constipation; lack
of teratogenicity
• Dose reduction recommended in patients with reduced renal function
• Multiple myeloma: initial therapy and after relapse
• Mantle cell lymphoma: relapsed or refractory
•
•
•
•
Proteasome Inhibitors
Bortezomib
Thrombocytopenia (28%), fatigue (12%), peripheral neuropathy (12%)
Neutropenia, anemia, vomiting, diarrhea, limb pain, weakness
Rare: congestive heart failure and prolonged QT intervals
Metabolized by CYP3A4; drug exposure of patient affected by
coadministration of inhibitors or inducers of CYP3A4
Antibodies Targeting Cell Surface Antigens
Rituximab (chimeric
murine/human IgG1
anti-CD20)
• Non-Hodgkin lymphoma
• Chronic lymphocytic leukemia
• Rheumatological and other autoimmune disease,
including multiple sclerosis
• Infusion-related toxicity with fever, rash, and dyspnea; B-cell depletion;
late-onset neutropenia risk of hypersensitivity reaction: use slow increase
in infusion rate and antihistamines
• Rare: severe mucocutaneous skin reaction, including Stevens-Johnson
syndrome
• Risk of tumor lysis syndrome in patients with high tumor burden in the
circulation: use lower dose initially
• Reactivation of hepatitis B virus or JC polyoma virus
Ofatumumab (fully human
IgG1 anti-CD20)
• CLL after treatment failure
• Immunosuppression and opportunistic infections, hypersensitivity
reaction during infusion and myelosuppression: monitor blood counts
during treatment
Obinutuzumab
(humanized IgG1
anti-CD20)
• CLL in combination with chemotherapy
• Frequent adverse effects: cytopenia, fever, cough, musculoskeletal
disorders
Alemtuzumab (Campath
or Lemtrada; humanized
IgG1 anti CD52)
• CLL (label: Campath)
• Multiple sclerosis (label: Lemtrada)
• Infusion-related toxicity, T-cell depletion with increased infection;
myelosuppression with pancytopenia
• Antibiotic prophylaxis
Dinutuximab (chimeric
mouse/human anti-GD2)
• High-risk neuroblastoma
• Infusion reaction
• Nerve damage
Daratumumab (human
IgG1 anti-CD38)
• Multiple myeloma in combination with lenalidomide or
bortezomb
• Infusion reactions
• Peripheral sensory neuropathy, upper respiratory tract infection
Elotuzumab (humanized
IgG1 anti-CD319) (SLAMF7)
• Multiple myeloma after one to three prior therapies
• Infusion reaction
Blinatumomab (bispecific
anti-CD19 and anti-CD3)
• Ph-negative relapsed or refractory B-cell precursor ALL
• Cytokine release syndrome, neurologic toxicity, neutropenic fever
SECTION VIII
• Multiple myeloma
• Myelodysplastic syndrome (5q- MDS)
• Chronic lymphocytic leukemia (CLL)
Drug Facts for Your Personal Formulary: Hormones and Related Agents in
Cancer Therapy
Drug
Therapeutic Use
Clinical Pharmacology and Tips
• Treatment of malignant hematologic disorders (e.g.,
ALL, CLL, MM, HL, NHL)
• Symptom palliation in various cancer types (e.g.,
antiemetic; reduce edema due to spinal cord
compression, brain metastases)
• Major toxicities: Cushing syndrome, glucose intolerance,
immunosuppression, osteoporosis, psychosis, insomnia
• Acute reduction in dosing can lead to recurrence of
symptoms
Glucocorticoid Receptor Agonists
Dexamethasone
Prednisone
Others
Selective Estrogen Receptor Modulators: Antiestrogens in breast cancer therapy
Tamoxifen
• Adjuvant therapy for pre- and postmenopausal
women with HR(+) breast cancer
• Treatment of advanced or metastatic HR(+) breast
cancer in pre- and postmenopausal women
• Breast cancer prevention in pre- and postmenopausal
women
• SERM with partial agonist and antagonist action. Antagonist of
ER in breast. Long t1/2 . Steady-state levels reached
3–4 weeks.
• Some major toxicities due to ER agonist activity (e.g.,
endometrial carcinoma, thromboembolic events) or ER
antagonist effects (e.g., vasomotor symptoms, menstrual
irregularities).
• Other adverse effects: cataracts
Toremifene
• Metastatic HR(+) breast cancer
• Pharmacology, clinical efficacy, and adverse effects similar
to those of tamoxifen
• Rare: Prolongs QT interval, increased risk of torsades de
pointes
Selective Estrogen Receptor Downregulators: Antiestrogens in breast cancer therapy
Fulvestrant
• Advanced or metastatic HR(+) breast cancer (+/CDK4/6 inhibitors) in postmenopausal women who
have progressed after antiestrogen therapy
• Binds to ER, blocks estrogen action and causes degradation
of the ER
• No estrogen agonist effects
• IM loading then monthly dosing; steady state achieved in
first month
• Side effects: injection site reaction, nausea, weakness,
bone and back pain, fatigue, vasomotor symptoms,
headache
Aromatase Inhibitors: Antiestrogen in breast cancer therapy
Anastrozole, Letrozole
(Nonsteroidal, competitive inhibitors)
Exemestane
(steroidal, irreversible inhibitor)
• Adjuvant treatment of postmenopausal women with
HR(+) breast cancer
• Treatment of postmenopausal women with HR(+)
advanced and metastatic breast cancer
(+/- CDK4/6 inhibitors)
• Breast cancer prevention in postmenopausal women
• AIs significantly lower serum estrogens
• Contraindicated in premenopausal women with ovarian
function
• Major side effects: vasomotor symptoms, arthralgia, loss of
bone mineral density, osteoporosis, fractures, vaginal
dryness, dyspareunia
Megestrol acetate
• Treatment of endometrial cancer and rarely of breast
and prostate cancer
• Appetite stimulant in patients with AIDS or cancerassociated cachexia
• Adverse effects: weight gain, nausea, vomiting, edema,
breakthrough bleeding, shortness of breath,
thrombophlebitis, pulmonary embolism
Medroxyprogesterone acetate
• Management of advanced stage endometrial
carcinoma
• Therapy of metastatic hormone-dependent breast
cancer
• Adverse effects: hot flashes, weight gain, depression,
amenorrhea
• With long-term use, bone loss is possible
Prostate Cancer
GnRH agonists:
Leuprolide
Goserelin
Histrelin
Triptolerin
Nafarelin
• Androgen deprivation therapy: ↓ Pituitary release of LH
and FSH, ↓ testicular testosterone production
• Treatment of advanced prostate cancer
• In combination with radiation therapy or surgery
for management of moderate-/high-risk locally
confined prostate cancer
• Can cause initial testosterone surge and tumor flare.
Administered with antiandrogens to reduce initial side
effects from testosterone surge.
• Side effects related to low testosterone: vasomotor
symptoms, loss of libido, osteoporosis, fatigue, impotence,
gynecomastia, loss of muscle mass
• Small increase in risk of diabetes or development of
cardiovascular disease
GnRH antagonists:
Degarelix
(Cetrorelix)
• Treatment of advanced prostate cancer
• Cetrorelix rarely used due to risk of anaphylaxis
• No initial testosterone surge; rapid suppression of serum
testosterone and PSA levels
• Side-effect profile in men similar to GnRH agonists above
Progesterone Receptor Agonists
Gonadotropin-Releasing Hormone Analogues: Chemical castration in cancer therapy
Drug Facts for Your Personal Formulary: Hormones and Related Agents in
Cancer Therapy (continued)
Drug
Therapeutic Use
Clinical Pharmacology and Tips
Breast Cancer
GnRH agonist:
Goserelin
Leuprolide
• Suppression of ovarian estrogen and progesterone
production in pre- and perimenopausal women
• With antiestrogens as adjuvant therapy and for
metastatic disease
• Adverse effects due to hypoestrogenism: vasomotor
symptoms, ↓ libido, osteoporosis, tumor flare, fatigue,
vaginal dryness, dyspareunia
Nonsteroidal Androgen Receptor Antagonists: Antiandrogens in prostate cancer therapy
Enzalutamide
• Treatment of metastatic, CRPC in conjunction with ADT
following docetaxel therapy
• Adverse effects related to AR antagonism: sexual
dysfunction, gynecomastia, breast pain, fatigue, diarrhea,
headache, musculoskeletal pain, vasomotor symptoms, hot
flashes
• Rare: seizures (likely due to central “off-target” effects)
Bicalutamide
• Used with GnRH analogues to treat metastatic CRPC
• Adverse effects similar to enzalutamide
• Favorable toxicity and pharmacokinetic profile relative to
flutamide or nilutamide
Flutamide
• Used with GnRH analogues to treat metastatic CRPC
• Active metabolite: hydroxyflutamide
• Significant hepatotoxicity possible
Nilutamide
• Used with GnRH analogues to treat CRPC after
progression on other antiandrogens
• Rare adverse effect: interstitial pneumonitis
Inhibitors of Steroidogenesis: Antiandrogens in prostate cancer therapy
Abiraterone
• Treatment of advanced metastatic CRPC
• Used in combination with prednisone (to compensate for
adrenal insufficiency induced by abiraterone)
• Irreversibly inhibits CYP17A1, ↓ testosterone & other
androgens
• Fluid retention, hypertension, hypokalemia, hepatotoxicity,
fatigue, joint swelling, vasomotor symptoms, diarrhea,
arrhythmia
• Take on empty stomach; food ↑ uptake >10-fold
Drug Facts for Your Personal Formulary: Dermatological Agents
Drugs
Therapeutic Uses
Clinical Pharmacology and Tips
Glucocorticoids—Table 70–3 and Chapter 46
Topical
glucocorticoids
• Psoriasis
• Atopic dermatitis
• Other inflammatory skin diseases
•
•
•
•
•
Occlusion increases absorption
May cause skin atrophy, striae, periorificial dermatitis, folliculitis
Limit to ≤ 2–3 weeks of use
Avoid potent corticosteroids on face and genital areas
Systemic glucocorticoids for severe disease; see Chapter 46
Topical retinoids
(see Table 70–4)
•
•
•
•
•
• Start every-other-night application to reduce likelihood of skin irritation
• Decreased activity in presence of sunlight or BPO except adapalene and tazarotene
• Avoid concurrent application of DEET due to potential increased DEET absorption
Oral Retinoids
(see Table 70–5)
• Psoriasis (acitretin)
• Acne (isotretinoin)
• CTCL (bexarotene)
Retinoids
Acne
Facial wrinkling and photodamage
Psoriasis
Cutaneous KS (alitretinoin)
CTCL (bexarotene)
• Teratogenic: pregnancy should be avoided during and for 1 month (3 years for acitretin)
after cessation of treatment
• Multiple potential side effects, including cheilitis, dermatitis, conjunctivitis, myalgias,
arthralgias, epistaxis, decreased night vision, hyperlipidemia
Topical Vitamin D Analogues
Calcipotriene
• Psoriasis
• Potential hypercalcemia and hypercalciuria
• May cause lesional or perilesional irritation
Photochemotherapeutic Agents (see Table 70–6)
Biological Agents for Psoriasis—Table 70–10
Antihistamines for Urticaria: see Chapter 39
Topical Antimicrobial Agents for Acne and Rosacea
Azelaic acid
• Acne
• Rosacea
• MOA: comedolytic, antibacterial, anti-inflammatory
• Also useful for postinflammatory hyperpigmentation due to acne
Benzoyl peroxide
• Acne
• MOA: antibacterial, mildly comedolytic
• Skin irritation with higher concentrations
Clindamycin
• Acne
• Rosacea (off label)
• MOA: antibacterial, anti-inflammatory
• Bacterial resistance likely if used as monotherapy, use with benzoyl peroxide
Dapsone
• Acne
• MOA: anti-inflammatory
• Use with benzoyl peroxide causes orange-brown staining of skin or hair
• G6PD testing not needed
Erythromycin
• Acne
• Rosacea (off label)
• MOA: antibacterial, anti-inflammatory
• Bacterial resistance likely if used as monotherapy, use with benzoyl peroxide
Metronidazole
• Rosacea
• MOA: anti-inflammatory
Sulfacetamide ±
sulfur
• Acne
• Rosacea
• MOA: antibacterial, anti-inflammatory; sulfur also keratolytic
• Use with benzoyl peroxide causes orange-brown staining of clothing but not skin
• Sulfur may have pungent odor
Topical Antimicrobial Agents for Infection
Bacitracin,
neomycin,
polymyxin B,
gentamicin
• Superficial bacterial skin infections
•
•
•
•
•
•
See Section VI, Chemotherapy of Microbial Diseases
Topical use restricted for superficial infections
Not indicated in clean surgical wounds
May cause contact dermatitis (especially bacitracin, neomycin, mafenide)
Mafenide inhibits carbonic anhydrase and can cause metabolic acidosis
Efficacy of silver sulfadiazine questionable
Drug Facts for Your Personal Formulary: Dermatological Agents (continued)
Drugs
Therapeutic Uses
Clinical Pharmacology and Tips
Topical Antimicrobial Agents for Infection
Mupirocin, retapamulin
• Superficial bacterial skin infections due to S.
aureus or S. pyogenes
• Intranasal decolonization of MRSA
Mafenide acetate
• Adjunctive therapy for burn wounds
Silver sulfadiazine
• Prevention or treatment in partialthickness burns or venous stasis ulcers
Topical Antifungal Agents—Table 70–8 (see Chapter 61 for oral antifungal agents)
Antiviral Agents
CHAPTER 70
Topical Antivirals:
Acyclovir
Docosanol
Penciclovir
• Orolabial HSV
• Genital HSV, initial episode (acyclovir)
Oral Antivirals:
Acyclovir
Famciclovir
Valacyclovir
• VZV
• HSV
• See Chapter 62
Agents for Infestations
Benzyl alcohol
• Head lice
• MOA: inhibits closure of respiratory spiracles, subsequent obstruction
by mineral oil vehicle causes asphyxiation of lice
Ivermectin
• Head lice
• Scabies (oral)
• MOA: binds glutamate-gated chloride channels, causing hyperpolarization of
nerve or muscle cells of parasite
Lindane
• Scabies
• Lice
• MOA: neuronal hyperstimulation, eventual parasite paralysis
• Potential neurotoxicity with prolonged use or in patients with impaired skin
barrier (e.g., atopic dermatitis)
Malathion
• Head lice
• MOA: acetylcholinesterase inhibitor causing neuromuscular paralysis
• Flammable due to high alcohol content
Permethrin
• Scabies
• Lice
Spinosad
• Head lice
• MOA: interferes with Na+ transport, causing neurotoxicity and paralysis
• Approved for infants ≥ 2 months
• May cross-react with sunflower family plants to cause allergic contact
dermatitis
• MOA: causes CNS excitation and involuntary muscle contractions leading to
parasite paralysis
Crotamiton
• Scabies
• MOA: unknown
• Less effective than other agents but has additional antipruritic effect
Precipitated sulfur
• Scabies
• MOA: unknown
• Poor odor and mild skin irritation
• Considered safe in pregnancy and infants
Systemic Cytotoxic, Immunosuppressant, and Immunomodulatory Agents
Methotrexate
• Psoriasis
• Off label for multiple inflammatory
dermatoses
• See Chapter 66
Cyclophosphamide
• CTCL
• Off label for severe autoimmune blistering
dermatoses
• See Chapter 66
Vinblastine
• Kaposi sarcoma
• CTCL
• See Chapter 66
Doxorubicin
• Kaposi sarcoma
• See Chapter 66
Azathioprine
• Off label for inflammatory and
autoimmune blistering disorders
• MOA: inhibition of de novo purine synthesis to decrease T-cell and B-cell
activation and proliferation
• TPMT enzyme activity should be measured before initiation
Mycophenolate mofetil
and mycophenolic acid
• Off label for inflammatory and
autoimmune blistering disorders
• MOA: inhibition of de novo purine synthesis to decrease T-cell and B-cell
activation and proliferation
• Most common side effect is GI upset
Cyclosporine
• Psoriasis
• Off label for multiple inflammatory
dermatoses
• MOA: calcineurin inhibition
• Potential side effects: hypertension, renal dysfunction, hypertrichosis,
gingival hyperplasia, tremor
Systemic Cytotoxic, Immunosuppressant, and Immunomodulatory Agents (continued)
mTOR inhibitors
• Off-label use in tuberous sclerosis,
complex vascular malformations,
and inflammatory dermatoses
Dapsone
• Dermatitis herpetiformis
• Leprosy
• Neutrophilic dermatoses (off label)
Thalidomide
• Erythema nodosum leprosum
• Off label for prurigo nodularis, cutaneous
lupus erythematosus, Behçet disease
• MOA: mTOR inhibition
• Potential side effects: stomatitis, mucositis, inflammatory cutaneous eruptions,
nail
changes
• See Chapter 60
• See Chapter 36
Topical or Intralesional Cytotoxic, Immunosuppressant, and Immunomodulatory Agents
5-Fluorouracil
• Actinic keratoses
• Superficial basal cell carcinoma
• Warts (off label)
• See Chapter 66
Bleomycin
• Squamous cell carcinoma (off label)
• Recalcitrant warts (off label)
• See Chapter 66
Alkylating agents
Carmustine
Mechlorethamine
• CTCL
• See Chapter 66
Podophyllum resin and
podofilox
• Genital warts
• MOA: microtubule inhibition to cause mitotic arrest in metaphase
• Side effects: irritation and ulcerative local reactions
Ingenol mebutate
• Actinic keratoses
• MOA: mitochondrial swelling and apoptosis of dysplastic keratinocytes
Imiquimod
• Genital warts
• Actinic keratoses
• Superficial basal cell carcinoma
• MOA: activates TLR-7, inducing cytokines and upregulating immune response
• Potential local skin reaction or systemic flu-like symptoms
Sinecatechins
• Genital warts
mTOR inhibitors
Topical calcineurin
inhibitors
Pimecrolimus
Tacrolimus
• Off-label use in tuberous sclerosis,
complex vascular malformations,
and some inflammatory dermatoses
• MOA: uncertain
• Potential local skin reactions, including erythema, pruritus, swelling that peaks
between
2 and 4 weeks of use
• Topical mTOR inhibitors not currently commercially available but may be
compounded
• Topical use may decrease potential for side effects seen with systemic use
• MOA: Decreased T-cell activation
• No skin atrophy
• Useful in sensitive areas such as face and skinfolds
• Common application site reactions (e.g., burning) decreases with continued use
• Psoriasis
• Atopic dermatitis
• Other inflammatory skin diseases
Targeted Immunotherapies for Psoriasis and Atopic Dermatitis
TNF-α inhibitors;
IL-12/23 inhibitors;
IL-17 inhibitors; PDE4
inhibitors; Jak inhibitors
• Psoriasis
• Atopic dermatitis: off-label use of PDE4
inhibitors, Jak inhibitors
• See Chapter 35
Targeted Antineoplastic Agents
Smoothened inhibitors
Histone deacetylase
inhibitors
• Basal cell carcinoma
• CTCL
• See Chapter 67
BRAF inhibitors; MEK
inhibitors; CTLA4
inhibitors; programmed
death 1 inhibitors
• Melanoma
• See Chapter 67
Topical Agents for Hyperkeratotic Disorders
Alpha-hydroxy acids
Glycolic acid
Lactic acid
• Hyperkeratotic disorders
• MOA: reduced keratinocyte adhesion by promoting degradation of
corneodesmosomes
• Potential skin irritation
Salicylic acid
• Hyperkeratotic disorders
• MOA: reduced keratinocyte adhesion by affecting desmosomal adhesion
proteins
• Potential skin irritation
• Potential salicylate toxicity with heavy use
Urea
• Hyperkeratotic disorders
Sulfur
• Hyperkeratotic disorders
• MOA: increased hydration of stratum corneum, enhancing desquamation
• Potential skin irritation
• MOA: possibly through interaction with cysteine, causing reduction to
hydrogen sulfide,which may break down keratin
• Pungent odor
Drug Facts for Your Personal Formulary: Dermatological Agents (continued)
Drugs
Therapeutic Uses
Clinical Pharmacology and Tips
Topical Agents for Hyperkeratotic Disorders
Propylene glycol
• Hyperkeratotic disorders
• MOA: increased hydration of stratum corneum, enhancing desquamation
Retinoids
• Hyperkeratotic disorders
• MOA: stimulation of keratinocyte turnover
• Potential skin irritation
Agents Affecting Hair Growth
Minoxidil, topical
• Androgenetic alopecia
• MOA: not fully determined; stimulates and prolongs anagen phase
• Requires continued use to sustain effect
Finasteride, oral
Dutasteride, oral
• Androgenetic alopecia
• Hirsutism (off label)
• MOA: inhibition of 5-α reductase to decrease conversion of testosterone to DHT
• Side effects: decreased libido, sexual dysfunction, hypotension
Spironolactone, oral
• Hirsutism (off label)
• Female pattern alopecia (off label)
• MOA: aldosterone antagonist with antiandrogenic activity
• Side effects: breast tenderness, menstrual irregularities, increased urination
• Feminization of male fetus
Eflornithine, topical
• Unwanted facial hair in women
• MOA: ornithine decarboxylase inhibition to decrease hair growth
• Slows hair growth; use in combination with hair removal methods
Bimatoprost, topical
• Hypotrichosis of the eyelashes
• MOA: prostaglandin analogue that increases percentage of hairs in anagen phase
• May cause brown pigmentation of eyelid and iris (permanent)
Drug Facts for Your Personal Formulary: Metal Chelators
Drugs
Therapeutic Uses
Clinical Pharmacology and Tips
CaNa2EDTA(calcium disodium
ethylenediaminetetraacetic acid)
• Acute lead poisoning
• IV or IM administration
• Not effective for chronic lead poisoning
• Nephrotoxic
• IV administration can increase intracranial pressure in patients
with lead encephalopathy and cerebral edema
• Zinc supplementation may be beneficial
Dimercaprol
• Acute arsenic, gold, and mercury poisoning
• Acute lead poisoning (in combination with
CaNa2EDTA)
•
•
•
•
Administered IM
Not effective for chronic intoxication
Increases toxicity of iron, cadmium, and selenium
Toxicity profile is worse than for succimer
Succimer
• Treatment of children with blood lead > 45 μg/dL
• Off label for adults with lead poisoning and for
arsenic and mercury poisoning
•
•
•
•
Orally bioavailable
Improved toxicity profile over dimercaprol
Reduced mobilization of lead to brain
May cause allergic reactions
Penicillamine
• Treatment of copper intoxication due to Wilson
disease
• Chelates heavy metals, but more toxic, less potent,
and less selective than other options
•
•
•
•
•
Orally bioavailable
Allergenic
Nephrotoxic
Causes hematological toxicities
Causes a variety of other side effects
Trientine
• Treatment of Wilson disease in those intolerant of
penicillamine
• Orally bioavailable
• Less potent than penicillamine
Deferoxamine
• Treatment of acute iron intoxication
• Treatment of chronic iron overload due to
transfusion
•
•
•
•
Deferasirox
• Treatment of chronic iron overload due to
transfusion
• Treatment of nontransfusion-dependent iron
overload
• Orally bioavailable
• Renal failure, hepatic failure, and GI hemorrhage are concerns
• Not recommended over deferoxamine
Deferiprone
• Treatment of chronic iron overload due to
transfusion
• Orally bioavailable
• Causes agranulocytosis and neutropenia
• Not recommended over deferoxamine
Heavy Metal Chelators
CHAPTER 71
Copper Chelators
Iron Chelators
IV, IM, or SC administration required
SC administration preferred for chronic iron overload
IV use for cardiovascular collapse or shock
IM administration for other acute iron intoxication cases