Pharmacodynamic
Drug Interactions
Mary Lynn McPherson, Pharm.D., BCPS
Professor, University of Maryland School of Pharmacy
mmcphers@rx.umaryland.edu
Drug Interactions
• Medications are used extensively to
palliate symptoms
– Patients with advanced illness take an average
of 5 medications (range 0-13)
– Increases risk for drug interactions
– Risk increased due to patient fragility, comorbid conditions, increased age
Defining a Drug Interaction
• “A measurable modification (in magnitude
or duration) of the action of one drug by
prior or concomitant administration of
another substance.”
– Drug-drug (Rx, OTC, herbal)
– Drug-food, drug-alcohol
– Drug-lab, drug-disease, drug-chemical
Wright 1992. Drug Interactions. In: Melmon and Morrelli’s
Clinical Pharmacology 1992
Drug Interactions
• Pharmacodynamics
– The study of the action and effects of
medications on physiologic function
• Pharmacodynamic drug interactions can
be:
– Additive (two or more analgesics)
– Synergistic
– Antagonistic (dexamethasone and glyburide)
Pharmacodynamic Drug Interactions
in Palliative Care
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•
•
•
•
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Anticholinergic effects
Constipation
Lowered seizure threshold
Serotonin syndrome
CNS depression
QTc prolongation
http://cwx.prenhall.com/bookbind/pubbooks/morris5/chapter2/custom1/deluxe-content.html
Muscarinic Receptor Subtypes
Receptor
Subtype
CNS Distribution
Non-CNS
Location
M1
Cerebral cortex, hippocampus,
neostriatum
Salivary glands,
sympathetic ganglia
M2
Throughout the brain
Smooth muscle,
cardiac muscle
M3
Low levels throughout brain
Smooth muscle,
salivary glands, eyes
M4
Abundant in neostriatum, cortex and
hippocampus
Salivary glands
M5
Projection neurons of substantia nigra Eyes (ciliary muscle)
pars, compacta and ventral tegmental
area and hippocampus
Antimuscarinic Pharmacologic
Effects: Peripheral
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•
•
•
Dry eyes
Urinary retention
Dry mouth
Constipation
• Heat intolerance
• Tachycardia
• Decreased
sweating
Carnahan et al. J Clin Pharmacol 2006;46:1481-1486
Antimuscarinic Pharmacologic
Effects: Central
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•
•
•
Forgetfulness
Agitation / confusion
Delirium
Paranoia
• Dizziness
• Drowsiness
• Falls
Carnahan et al. J Clin Pharmacol 2006;46:1481-1486
Evoking Antimuscarinic Effects
Overactive bladder
Anticholinergic /
Antiparkinson’s
Antivertigo /
antiemetic
• Oxybutynin (Ditropan)
• Toleradine (Detrol)
• Trospium (Sanctura)
• Solifenacin (Vesicare)
• Darifenacin (Enablex)
• Trihexyphenidyl (Artane)
• Benztropine (Cogentin)
• Amantadine (Symmetrel)
• Meclizine (Antivert)
• Scopolamine (TransDerm Scop)
Evoking Antimuscarinic Effects
Gastrointestinal /
Antispasmodics
Antisecretory /
Drying Agents
Bronchospasm
• Diphenoxylate (Lomotil)
• Dicyclomine (Bentyl)
• Hyoscyamine (Levsin)
• Atropine (ophthalmic given PO)
• Ipratroptium (Atrovent)
• Tiotroptium (Spiriva)
Antimuscarinic Adverse Effects
Sedating
Antihistamines
• Diphenhydramine (Benadryl)
• Hydroxyzine (Vistaril)
Tricyclic
Antidepressants
• Amitriptyline (Elavil)
• Nortriptyline (Pamelor)
• Desipramine (Norpramin)
• Doxepin (Sinequan)
• Chlorpromazine (Thorazine)
• Olanzapine (Zyprexa)
• Clozapine (Clozaril)
• Thioridazine (Mellaril)
Antipsychotic
Agents
Antimuscarinic Adverse Effects
Phenothiazines
• Prochlorperazine (Compazine)
• Promethazine (Phenergan)
Antiarrhythmic
Agents
• Disopyramide (Norpace)
Muscle relaxants
• Cyclobenzaprine (Flexeril)
• Orphenadrine (Norflex)
Anticholinergic Activity of 107
Medications Commonly Used by Elders
• Radioassay used to measure the
anticholinergic activity of 107 medications
• Categories included:





0 (non-detectable)
0/+ (no or minimal)
+ (0.5-5 pmol/ml)
++ (5-15 pmol/ml)
+++ (> 15 pmol/ml)
Chew et al. JAGS 2008;56:1333-1341.
Anticholinergic Activity of 107
Medications Commonly Used by Elders
• +++ (> 15 pmol/ml)
– Amitriptyline, doxepin
– Clozapine, thioridazine
– Atropine, dicyclomine, hyoscyamine
• ++ (5-15 pmol/ml)
–
–
–
–
Nortriptyline, paroxetine
Diphenhydramine
Chlorpromazine, olanzapine
Oxybutynin
Chew et al. JAGS 2008;56:1333-1341.
Anticholinergic Activity of 107
Medications Commonly Used by Elders
• + (0.5-5 pmol/ml)
– Citalopram, escitalopram, fluoxetine,
mirtazpine
– Quetiapine
– Tempazepam
– Ranitidine
– Lithium
Chew et al. JAGS 2008;56:1333-1341.
Anticholinergic Activity of 107
Medications Commonly Used by Elders
• 0/+ (no or minimal)
– Celecoxib, fentanyl, hydrocodone,
propoxyphene
– Duloxetine, metformin
– Amoxicillin, cephalexin, levofloxacin
– Diazepam, donepezil
– Digoxin, furosemide
– Phenytoin, topiramate
– Diphenoxylate, lansoprazole
Chew et al. JAGS 2008;56:1333-1341.
Anticholinergic Activity of 107
Medications Commonly Used by Elders
• 0 (non-detectable)
– Acetaminophen, aspirin, codeine, ibuprofen,
morphine, tramadol
– Bupropion, sertraline, trazodone, venlafaxine
– Glipizide, pioglitazone, rosiglitazone
– Cetirizine, fexofenadine, loratadine
– Ciprofloxacin, sulfamethoxazole, trimethoprim
– Aripiprazole, haloperidol, perphenazine,
risperidonem ziprasidone
Chew et al. JAGS 2008;56:1333-1341.
Anticholinergic Activity of 107
Medications Commonly Used by Elders
• 0 (non-detectable)
– Alprazolam, buspirone, lorazepam, oxazepam,
zaleplon, zolpidem
– Beta-blockers, CCB, statins, ACE inhibitors,
ARBs, nitroglycerin
– Galantamine, memantine, rivastigmine
– Bisacodyl, famotidine, loperamide,
omeprazole, pantoprazole, rabeprazole
Chew et al. JAGS 2008;56:1333-1341.
Anticholinergic Activity of 107
Medications Commonly Used by Elders
• 0 (non-detectable)
– Baclofen, carbidopa, clopidogrel, darbepoetin,
dipyridamole, epietin, levodopa, levothyroxine,
megestrol, warfarin
– Carbamazepine, gabapentin, lamotrigine,
valproate
Chew et al. JAGS 2008;56:1333-1341.
Estimated Anticholinergic Activity (AA) for
Therapeutic Doses of Nortriptyline at
Estimated Mean Peak Concentrations (Cmax)
in a Typical Geriatric Patient
Total Daily
Dose (mg)
10
25
50
100
150
Cmax
(ng/ml)
12
29
59
117
175
In Vitro AA
(pmol/ml)
0.8
3.5
8.2
18.0
29.0
Chew et al. JAGS 2008;56:1333-1341.
Cognitive Impact of Anticholinergics
• 27 studies reviewed
• Consistent correlation seen between SAA
and worsening performance on cognitive
testing
– Acute (delirium)
– Chronic (mild cognitive impairment)
• Deficits in processing, speed, psychomotor
performance, concentration/attention,
problem solving and language skills
Campbell et al. Clinical Interventions in Aging 2009;4:225-233.
Cognitive Impact of Anticholinergics
• Delirium - identified by disorientation,
altered consciousness, disorganized
thinking, fluctuating alertness
• Variable deficits in recalls identified
• Minimal changes in global measures of
cognitive functioning with exposure to
anticholinergics
Campbell et al. Clinical Interventions in Aging 2009;4:225-233.
Anticholinergics Conclusion
• Patients at risk
– Older adults, advanced disease, fall risk
– BPH, asthma
– Taking other medications with similar adverse
effects
– Alzheimer’s disease and other dementias
(anticholinergics antagonize cholinesterase
inhibitors)
• Consider non-drug interventions
Constipation
• 40% of all ADR affect the GI tract
• Drug-induced constipation occurs at therapeutics
doses of drugs and is dose-related
• Medications most likely to cause constipation
include:
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–
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Antispasmodics (11.6%)
Antihistamines (9.2%)
Antidepressants (8.2%)
Diuretics (5.6%)
Aluminum antacids (3.0%)
Opioids (2.6%)
Talley NJ et al. Amer J Gastroenterology 2003;98:1107-1111.
Drug-Induced Constipation
Therapeutic
Category
Examples
Analgesics
Opioids (morphine), NSAIDs (ibuprofen)
Anticholinergics
TCA, antipsychotics (haloperidol), antiparkinsonian agents
(benztropine), antihistamines (H1; diphenhydramine),
antispasmodics (dicyclomine)
Cation-containing
agents
Aluminum (antacids, sucralfate), calcium (antacids, supplements),
bismuth, iron supplements, lithium
Chemotherapy
Vinca alkaloids (vincristine), alkylating agents (cyclophosphamide)
Antihypertensives
CCB (verapamil, nifedipine), diuretics (furosemide), centrally-acting
(clonidine), antiarrhythmics (amiodarone), beta blockers (atenolol)
Bile acid
sequestrants
Colestyramine, colestipol
5HT3-receptor
antagonists
Ondansetron
Laxatives
Chronic abuse
Branch RL, Butt TF. Drug-induced constipation. Adverse Drug Reaction Bulletin 2009;257.
Drug-Induced Constipation
Therapeutic
Category
Examples
Excess fiber
Dietary or prescribed
Other
antidepressants
Monoamine amine oxidase inhibitors
Other
antiparkinsonian
agents
Dopamine agonists
Other
antispasmodics
Peppermint oil
Anticonvulsants
Carbamazepine
Miscellaneous
Barium sulphate, octreotide, polystyrene resins, oral contraceptives
Vitamin C tablets, 131I thyroid ablation, erythropoietin, baclofen
Pamidronate, alendronic acid, PPI and H2 antagonists
Branch RL, Butt TF. Drug-induced constipation. Adverse Drug Reaction Bulletin 2009;257.
Analgesics - Opioids
• Mediated through either μ or δ-opioid
receptors on enteric nerves, epithelial cells
and muscle.
– Reduces intestinal motility (via μ-receptors)
– Reduces intestinal secretion (via δ-receptors)
– And increases absorption of water (via μ and δreceptors)
Analgesics - NSAIDs
Inhibit cyclooxygenase, blocking production of PGE both
centrally and peripherally.
PGE Effects
Inhibition of PGE Effects
Decreases gastric acid secretion
Increased gastric acid secretion
Increases gastric mucus secretion
Decreased mucus secretion
Causes GI smooth muscle contraction
GI smooth muscle relaxation
NSAID discontinuation is
more often due to
constipation than dyspepsia.
↓
Constipation
Other Drug-Induced Constipation
• Anticholinergics
– Inhibit PSNS, preventing Ach from binding to the M2 muscarinic
receptor, resulting in decreased intestinal tone and motility.
– Leads to a delay on colonic transfer time
– Includes TCAs, MAOIs, antipsychotics, antiparkinsonian agents
• Antispasmodics (peppermint oil)
– Dose-related effect on smooth musculature caused by
interference of menthol with the movement of calcium across the
cell membrane.
– Reduces influx of extracellular calcium ions through voltagedependent channels; reduces gastroduodenal motility by
decreasing the number and amplitude of contractions.
Other Drug-Induced Constipation
• Cation-containing agents
– Aluminum has an astringent effect and may cause intestinal
obstruction in high doses.
– 17-30% of aluminum chloride produced from aluminum hydroxide
is absorbed; remainder unabsorbed from gut, producing
constipating effect.
– Calcium-containing antacids – 90% calcium carbonate is
converted to insoluble calcium salts in small intestine, not
absorbed, and cause constipation
• Bismuth (bismuth subsalicylate; BSS)
– BSS is an antidiarrheal agent; decreases flow of fluid and
electrolytes into bowel, reducing inflammation in the intestine
and killing organisms that cause diarrhea
– Reduces number of formed stools by 50%
• Iron, Lithium
Other Drug-Induced Constipation
• Chemotherapeutic agents
– Vinca alkaloids – 50% of patients treated; due to neurologic
changes in ANS or enteric NS
– Alkylating agents (cyclophosphamide); denature proteins
including in GIT. Changes in intestinal mucosa can cause
constipation or diarrhea.
• Antihypertensive agents
– CCB (verapamil, nifedipine) – reduce intestinal motility
– Diuretics (HCTZ) – decreased motility and excess fluid removal
– Centrally-acting (clonidine) – stimulated absorption and inhibits
secretion of fluids and electrolytes, prolongs intestinal transit
time by interacting with receptors on enteric neurons
• Amiodarone
• Bile-acid sequestrants
Drug-Induced Seizures
• 6-9% of seizures are drug-induced
• Drugs can cause seizures directly
– At or above therapeutic concentrations
• Drugs can cause seizures indirectly
– Reducing the effectiveness of AED
– Hypoglycemia, hyponatremia, hyperpyrexia
– Due to adverse effects (hypoxia, arrhythmia or
cerebral edema
Thundiyil JG et al. J Medical Tech 2007;3:15-19.
Thundiyil JG et al. J Medical Tech 2007;3:15-19.
Drug-Induced Seizures
• Cases involving TCAs, cocaine and
theophylline have shown a marked
decrease
• Newer causes of drug-induced causes have
emerged including: bupropion, tramadol,
and venlafaxine
Drug Withdrawal-Induced Seizures
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•
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•
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Anticonvulsant agents
Benzodiazepines
Barbiturates
Opioids
Baclofen
Serotonin Syndrome
• A potentially life-threatening condition
caused by excess serotonergic stimulation
of the central nervous system.
• Caused by:
– Drug interactions
– Intentional overdose
• Symptoms occur within minutes to hours
after starting a second drug
Serotonin Syndrome
• Classic triad of symptoms
– Altered mental status
– Neuromuscular hyperactivity
– Autonomic hyperactivity
• All three features are not always present
together
Clinical Features of Serotonin
Syndrome
• Neuromuscular
hyperactivity
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Akathisia
Tremor
Clonus
Myoclonus
Rigidity
Nystagmus
• Autonomic hyperactivity
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–
–
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Diaphoresis
Fever
Tachycardia
Tachypnea
• Altered mental status
– Agitation
– Excitement
– Confusion
Sun-Edelstein. Expert Opin Drug Safe 2008;7:587-596
Boyer EW et al. NEJM 352;1112-1130.
Drug-Induced Serotonin Syndrome
TheraCategory
Examples
SSRIs
Paroxetine, sertraline, fluoxetine, fluvoxamine, citalopram
SNRIs
Venlafaxine, milnacipran, duloxetine, sibutramine
TCAs
Clomipramine, imipramine
Misc Antidepress
Mirtazapine, trazodone, St. John’s Wort
Maoist
Trancylcpromine, phenelzine, isocarboxazid
Antiparkinsons
Selegilene
Anti-infectives
Linezolid, furazolidone
Opioids
Meperidine, fentanyl, methadone, tramadol, pentazocine,
dextromethorphan
Antihistamines
Chlorpheniramine, brompheniramine
CNS stimulants /
Psychedelics
Amphetamine, sibutramine, methylphenidate, cocaine, MDMA
(ectasy), LSD
Triptans (+/-)
Sumatriptan, zolmitriptan, rizatriptan, almotriptan, frovatriptan
Sun-Edelstein. Expert Opin Drug Safe 2008;7:587-596
Suspecting Serotonin Syndrome
• Was a serotonergic agent administered in the
past five weeks?
– No – stop; Yes –continue
• Experienced one of the following:
– Tremor and hyperreflexia
– Spontaneous clonus
– Muscle ridigity, temperature > 38°C and either ocular
clonus or inducible clonus
– Ocular clonus, and either agitation or diaphoresis
– Inducible clonus and either agitation or diaphoresis
• No – stop; Yes – possibly serotonin syndrome
Boyer EW et al. NEJM 352;1112-1130.
Drug-induced CNS depression
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•
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Sedation, agitation, confusion
May progress to respiratory depression
Opioids, benzodiazepines
Non-benzodiazepine sedative-hypnotics
Barbiturates, alcohol, antipsychotics
Antidepressants, antihistamines (H1)
Antiemetics, anticonvulsants, illicit drugs
Drug-induced CNS depression
• Less obvious causes:
– Cimetidine
– Anticholinergic agents
– Drugs that reduce GFR
• NSAIDs
• ACE inhibitors
• Fall risk increased with:
– Sedatives, hypnotics, antidepressants,
benzodiazepines
Opioid-Induced Sedation
• Occurs in 20-60% patients taking opioids
• Sedation is defined as “depression of brain
functioning by a medication, mainfested by
sleepiness, drowsiness, fatigue, slowed
brain activity, reduced wakefulness, and
impaired performance.”
• Dose-dependent effect
• Tolerance within a few days
• Don’t confuse with “catch-up” sleep
Opioid-Induced Respiratory
Depression
• Quantified by
– Observed changes in breathing frequency
• Severe respiratory depression considered to be
breathing rate of less than 8-10 breaths/minute
– And/or oxygen saturation
• Slowed and irregular respiration leads to
hypercapnia and hypoxia
Factors that modulate opioidinduced respiratory depression
• Drug interactions
– Propofol, midiazolam
• Sleep – obstructive sleep apnea
– Opioids increase stage 2 sleep (light sleep) and
decrease stage 4 (deep sleep) and REM sleep
– Methadone and benzodiazepines
• Pain – stimulated respiration
Pattinson KTS. Br J Anaesth 2008;100:747-758.
Factors that modulate opioidinduced respiratory depression
• Genetics
• Polymorphisms affecting MOP receptor
activity and opioid bioavailability
• Polymorphisms affecting opioid
metabolism
Pattinson KTS. Br J Anaesth 2008;100:747-758.
Atypical Opioids and Respiratory
Depression
• Tramadol
– Causes less respiratory depression than
meperidine or oxycodone at equivalent doses
– Reported in patients with renal failure
• Buprenorphine
– Partial agonist; may cause less respiratory
depression than conventional opioids at
equivalent doses
Pattinson KTS. Br J Anaesth 2008;100:747-758.
Drug-Induced QTc Prolongation
• QT interval prolongation is an abnormality of
the electrical activity of the heart that places
individuals at risk for ventricular arrhythmias.
– > 450 msec in men; > 470 msec in women
• Increase in QTc > 60 msec from baseline after
medication administration, or
• QTc values > 500 msec after medication
adminstration
– Potential risk for arrhythmia, including Torsades
de Pointes (TdP)
Risk Factors for Drug-Induced QTc
Prolongation
• Female sex
• Hypokalemia
• Severe
hypomagnesemia
• Bradycardia
• Recent conversion
from atrial fibrillation
• Congestive heart
failure
Wood AJJ. NEJM 2004;350:1013-1022.
• Subclinical long QT
syndrome (LQTS)
• Baseline QT interval
prolongation
• Ion-channel
polymorphisms
• Medications / high
serum concentrations
/ rapid infusion
Drugs that may cause TdP
• Drugs commonly involved
– Disopyramide, dofetilide, ibutilide
– Procainamide, quinidine, sotalol, bepridil
• Other drugs
– Amiodarone, arsenic trioxide, cisapride
– Erythromycin, clarithyromycin, halofantrine,
pentamidine, sparfloxacin, chloroquine
– Domperidone, droperidol
– Chlorpromazine, haloperidol, thioridazine
– Methadone
Gupta A et all Am Heart J 2007;153:891-899.
Methadone and LQTS and TdP
• Increasingly prescribed for chronic pain
• Associated mortality rising
disproportionately relative to other opioids
• Potent blocker of delayed rectifier
potassium ion channel
• Results in QT-prolongation and TdP in
susceptible individuals
Risk Factors for Methadone and
Prolonged QTc
• Dose-related
• Inappropriate initial dosing (including drug
diversion) or conversion calculation
• Sleep apnea, heart/lung/liver disease
• Use of other drugs that increase risk
www.torsades.org
• Arizona CERT – Center for Education and
Research on Therapeutics
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Drugs with known risk of TdP
Drugs with possible risks of TdP
Drugs for LQTS patients to avoid
Drugs unlikely to cause TdP
Pharmacodynamic Drug Interactions
in Palliative Care
•
•
•
•
•
•
Anticholinergic effects
Constipation
Lowered seizure threshold
Serotonin syndrome
CNS depression
QTc prolongation
Questions