Marc Riachi, R.Ph.
March 21, 2011 (3:00-5:00)
March 28 and April 4, 2011 (2:30-5:00)
Amph D
University of Ottawa

■ Antibacterials
■ Antiplatelets and anticoagulants
■ Antimycobacterials
■ Antiasthmatics
■ Antifungals
■ BPH
■ Narcotic analgesics
■ Erectile dysfunction
■ Autonomic nervous system
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Anti seizure drugs
Migraines
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Dementia
Parkinson’s disease and schizophrenia
■ Antidepressants
■ Dyspepsia, GERD and PUD
■ Antianxiety agents ■ Antiemetics
■ Agents for insomnia ■ IBD
■ Antidiabetics
■ IBS
■ Antilipemics ■ Osteoporosis
■ Antihypertensives ■ Gout
■ Diuretics ■ OTC drugs
■ Nitrates ■ Appendix I & II

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Penicillins: penicillin, cloxacillin, amoxicillin, ampicillin, piperacillin, ticarcillin
Cephalosporins: all the agents starting with “Ceph-” or “Cef-”: don’t cover atypicals or enterococcus
Fluoroquinolones: cipro-, nor-, o-, levo-, and moxi-floxacin. Di-, tri-, or polyvalent cations reduce absorption of FQ’s
Aminoglycosides: gentamicin, amikacin, tobramycin
Macrolides: erythromycin, clarithromycin, azithromycin. E and C inhibit CYP3A4; A much less so.
Tetracyclines: tetracycline, minocycline, doxycycline. Di-, tri-, or polyvalent cations reduce absorption. Phototoxicity rxns.
Sulfamethoxazole+trimethoprim, trimethoprim
Clindamycin, metronidazole
Vancomycin
Nitrofurantoin: for UTI’s only. Avoid if CrCl < 50 ml/min.

Bactericidal ABX
■ Aminoglycosides
■ Fluoroquinolones
■ Penicillins
■ Cephalosporins
■ Nitrofurantoin
■ metronidazole
■ SMX+TMP
Bactericidal ABX are preferred when:
• Host defences are poor
• Infection involves heart, CNS, blood
Better not to combine with bacteriostatic
ABX because bactericidals require bacterial cells to be actively growing/dividing.
Bacteriostatic ABX
■ Tetracyclines
■ Macrolides
■ SMX
■ TMP
■ clindamycin
Bacteriostatics give the immune system enough time to clear the offending organism. Therefore it is important to dose those ABX long enough. They also require a healthy immune system.

Penicillins
Develop agent vs
BL’ase producing staph (MSSA)
Pen V/G: covers
G+ (strep), oral anarobes, T. Pallidum
(Lacks efficacy vs BL’ase,
B. fragilis, G-, atypicals)
Develop agent vs Enterococcus and
“easy to kill” G- (no resistance to BL’ase)
Cloxacillin
Easy to kill G- bacteria: nonBL’ase
H. Flu, P. mirabilis, salmonella, shigella, E. coli
Hard to kill G- bacteria: klebsiella, enterobacter, citrobacter, serratia, morganella, pseudomonas, providencia
Oral penicillin is called Pen VK.
Injectable penicillin is available as the long acting benzathine penicillin G or the short acting benzylpenicillin (aka, pen G)
Ampicillin
Amoxicillin
Add resistance to BL’ase, cover MSSA and B. fragilis
Amoxicillin + Clavulanate
Ampi + sulbactam
Cover “hard to kill” G-
Piperacillin, ticarcillin
Add resistance to BL’ase
Piperacillin/tazobactam ticarcillin/clavulanate

Cephalosporins
Develop agent vs BL’ase producing staph (MSSA) and
“easy to kill” non-BL’ase G-
Pen V/G: covers
G+ (strep), oral anarobes, T. Pallidum
(Lacks efficacy vs BL’ase,
B. fragilis, G-, atypicals)
Add activity vs B. Fragilis, and “easy to kill” G-
1 st gen Cephs
Eg: cephalexin, cefazolin
Add resistance to “easy to kill”
BL’ase G- & B. Frag, loss of some
G+ coverage
2nd gen Cephs
Eg: cefuroxime, cefaclor
Add activity vs “hard to kill” G-, reduce staph coverage, retain strep coverage, loss of B. Frag coverage
3 rd gen Cephs
Eg: cefotaxime, ceftriaxone, cefixime, ceftazidime
Add activity vs pseudomonas
3 rd /4 th gen Cephs
Eg: Ceftazidime,
Cefepime
Cefoxitin
None are effective against enterococcus, L. monocytogenes, MRSA

Fluoroquinolones &
Aminoglycosides
Pen V/G: covers
G+ (strep), oral anarobes, T. Pallidum
(Lacks efficacy vs BL’ase,
B. fragilis, G-, atypicals)
Develop agent vs G-
(including pseudomonas)
Aminoglycosides
Eg: gentamicin, amikacin, tobramycin
Add activity to BL’ase producing G+
2 nd gen
Fluoroquinolones
Eg: ciprofloxacin, ofloxacin
Don’t cover strep well. Ofloxacin does not cover strep or pseudomonas well
Add coverage to atypicals and expand G+ coverage; retain some pseudomonal coverage
3 rd gen FQ’s
Eg: levofloxacin
Add activity vs anarobes
(B. fragilis) 4 th gen FQ’s
Eg: moxifloxacin

Macrolides,
Tetracyclines
TMP/SMX
Pen V/G: covers
G+ (strep), oral anarobes, T. Pallidum
(Lacks efficacy vs BL’ase,
B. fragilis, G-, atypicals)
Develop agents Vs common G+, common
G-, atypicals, unusual or non-bacterial organisms
Macrolides,
Tetracyclines,
TMP/SMX
TMP/SMX does not cover atypicals but it covers community acquired
MRSA

Vancomycin, metronidazole, clindamycin
Develop agent Vs B. fragilis and other anaerobes
Pen V/G: covers
G+ (strep), oral anarobes, T. Pallidum
(Lacks efficacy vs BL’ase,
B. fragilis, G-, atypicals)
Develop agent vs Staph
Epidermidis and MRSA
Metronidazole
Add coverage for MSSA and community acquired MRSA
Clindamycin
Vancomycin
Note:
Use PO vancomycin or PO/IV metronidazole to treat C. difficile infections

Commonly prescribed ABX in the community setting
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Oral infections: penicillin, clindamycin, erythromycin, amoxicillin, cephalexin
UTI: ciprofloxacin, SMX/TMP, nitrofurantoin
RTI’s, sinusitis: clarithromycin, azithromycin, 2 nd or 3 rd gen Cephs, amoxi/clav, levo-
/moxifloxacin
Skin/nail/bites: cephalexin, cloxacillin, amoxi/clav
Travellers’ diarrhea: azithromycin, ciprofloxacin, norfloxacin
H. pylori: amoxi+clarithromycin, metronidazole+clarithromycin, tetracycline+metronidazole
Bacterial vaginosis, trichomoniasis: metronidazole, clindamycin
Chlamydia: single dose azithromycin, 7-day course doxycycline, ofloxacin
Gonorrhea: cefixime, ceftriaxone
Acne: tetracyclines, erythromycin
Acute otitis media: Macrolides, amoxicillin, amoxi/clav, 2 nd gen Cephs
Patients with penicillin allergy: clindamycin or erythromycin (choice depends on indication) are useful
Intraabdominal infections: ciprofloxacin, metronidazole, 3 rd gen Cephs
C. difficile diarrhea: metronidazole, vancomycin
MRSA-CA: high dose SMX+TMP, doxycycline, clindamycin

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Tetracyclines (also in children < 9 y.o.): are incorporated into fetal skeleton/unerupted teeth
Fluoroquinolones
Erythromycin estolate (may cause toxic liver reaction), clarithromycin
TMP: in 1st trimester because it is a folate antagonist
Sulfonamides: last trimester or if delivery is imminent because they interfere with the bile conjugating mechanism of the neonate and may displace bilirubin bound to albumin which may lead to jaundice and kernicterus
Nitrofurantoin (during labor and delivery only ): can affect glutathione reductase activity and hence can cause hemolytic anemia (analogous to the problems it causes in patients with glucose-6-phosphate dehydrogenase deficiency) and hemolytic crises have been documented in newborns and fetuses
Aminoglycosides : nephrotoxic and ototoxic to the fetus
High single dose metronidazole
Chloramphenicol (at term or during labour): limited glucuronidating capacity of the newborn’s liver

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■ Penicillins, including those in combination with ß-lactamase inhibitors (clavulanic acid, sulbactam, and tazobactam)
Cephalosporins
Erythromycin base
Azithromycin
Clindamycin
Metronidazole (regular dose 250-500 mg BID)

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

■ First-line:
– Isoniazid (INH)
– Rifampin (RIF)
– Pyrazinamide (PZA)
– Ethambutol (ETB)
■ Second-line (for drug-resistant TB and M Avium-
Intracellulare):
– Amikacin
– Ciprofloxacin/levofloxacin/moxifloxacin
– Clarithromycin/azithromycin

■ Pulmonary or extrapulmonary disease:
– INH+RIF+PZA+ETB
■ If resistant to INH:
– RIF+PZA+ETB (+FQ if severe)
■ If resistant to RIF:
– INH+ETB+FQ+PZA
■ if resistant to INH and RIF:
– PZA+ETB+FQ+amikacin
■ If resistant to INH, RIF and PZA or ETB
– ETB (or PZA)+FQ+amikacin+two 2 nd line agents

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INH (inhibits formation of fatty acids found in the cell wall):
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Bactericidal; penetrates cavitations
Hepatotoxicity (↑ with alcohol & rifampin)
 monitor LFTs
■ peripheral neuropathy (give B6 to help)
GI symptoms, skin rash
↑ phenytoin, carbamazepine & benzodiazepine blood levels
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RIF (inhibits RNA synthesis):
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Bactericidal; penetrates cavitations
Hepatotoxicity (↑ with alcohol & rifampin)
 monitor LFTs
GI symptoms, skin rash
Pancytopenia
Colors urine, feces, saliva, tears orange
 may permanently stain contact lenses
– Induces CYP450
PZA (may inhibit mycobacterial metabolism):
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Bactericidal in acid environment (in macrophages)
Hepatotoxicity (↑ with alcohol & rifampin)  monitor LFTs
Hyperuricemia  monitor uric acid
– GI symptoms and arthralgias
ETB (may inhibit cell wall synthesis):
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Bacteriostatic
GI symptoms, hyperuricemia
Ocular toxicity and change in color perception
 monitor at high doses

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Oral
– Itra, flu, vori-, posa- and ketoconazole
– terbinafine
■ Topical
– Ciclopirox (cream, lacquer, shampoo), nystatin
(cream, pv, oral suspension), clotrimazole (cream, pv), miconazole (cream, pv), ketoconazole (cream shampoo), terbinafine (cream, spray), tolnaftate
(powder  good for skin folds)
■ Injectables: usually require infectious disease consult

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Onychomycosis: oral terbinafine, oral itraconazole, ciclopirox lacquer
Fungal skin: topical clotrimazole, topical miconazole, topical terbinafine, topical ketoconazole. Nystatin is ineffective vs. dermatophytes.
Candidal skin infections respond to nystatin. Use topical azoles for tinea versicolor
(not terbinafine).
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Seborrheic dermatitis: topical ciclopirox, ketoconazole
Oral candidiasis: Oral nystatin swish and swallow ( not absorbed from GI tract ). Oral fluconazole.
■ Vulvovaginal candidiasis: topical azoles, po fluconazole one dose (now available without a prescription), boric acid pv suppositories (very irritative)
■ Diaper rash: Topical nystatin, clotrimazole, miconazole, or ketoconazole.

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Terbinafine po:
– Very active vs dermatophytes
– headache, GI diarrhea, dyspepsia, abdominal pain
– taste disturbance (may persist post treatment)
– CYP2D6 inhibitor:
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Decreases formation of active metabolites of tamoxifen
May ↓ breakdown of TCA’s, fluoxetine, paroxetine, fluvoxamine, sertraline, tamsulosin, mirtazapine, haloperidol, some beta blockers
Azole antifungals po:
– Itraconazole and ketoconazole particularly are strong inhibitors of CYP3A4 and so many drug interactions. Also hepatotoxic. Ketoconazole > itraconazole
> terbinafine wrt hepatic toxicity. Itra may worsen heart failure symptoms.
Ketoconazole is rarely used and is poorly tolerated; anorexia, nausea, vomiting high doses, and effects sexual function/sex hormones and steroidogenesis.
– Fluconazole is considered a moderate inhibitor of CYP3A4 and so less clinically important drug interactions. Strong CYP2C9,2C19 inhibitor. QT prolongation with amiodarone, clarithromycin, TCA’s. Bioavailability of PO similar to IV; use PO if possible.

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Morphine is the prototype and the standard opiate
Treatment of moderate to severe pain
Neuropathic pain may respond to higher doses of opioids . Standard treatment of this kind of pain is with antidepressants and anticonvulsants
All opioids have the same basic side effects:
– euphoria
– constipation
– N&V
– somnolence
– respiratory depression (especially important if patient is not awake)
– potential for addiction
– hypotension
– skin itchiness
– seizures

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■ codeine, hydromorphone, levorphanol, morphine, oxycodone, hydrocodone, and pentazocine meperidine and fentanyl methadone
If truly allergic to codeine (anaphylaxis), may consider an opioid from a different class such as:
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– meperidine fentanyl (Warning: not for narcotic naive or narcotic inexperienced patients)
– methadone (not every physician is licensed to prescribe it. Usually reserved for severe pain)
– all opioids have the potential to cause skin itchiness which is not considered an allergic reaction
– in all cases, monitor patient for possible cross-allergic reactions

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Considered to not have a “ceiling dose” (except for pentazocine)
Have “ceiling dose” when combined with other analgesics (e.g., acetaminophen) in the same dosage form
“Contin” in the name of the medication means that the drug lasts 8 to 12 hours and therefore is dosed q8-12h
If the Contin wears off before the 8 to 12 hours have passed, the dose (NOT the dosing frequency) should be increased
Most patients should be able to tolerate very high doses if the dose is increased slowly fentanyl and hydromorphone are the opioids of choice for use in renal or hepatic impairment . Use codeine, morphine, or oxycodone with caution in these patients
Most opioids are either contraindicated or not recommended for use with monoamine oxidase inhibitors (MAOIs)

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Codeine:
– converted to the active metabolite morphine by CYP2D6
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– some Caucasian, Asians, and Arabs have poorly functioning
CYP2D6 while others may have more efficient CYP2D6
CYP2D6 inhibitors: bupropion, duloxetine, paroxetine, moclobemide, escitalopram, fluoxetine, citalopram, quinidine, terbinafine
– CYP2D6 inducers: rifampin, dexamethasone
Morphine:
– The metabolite morphine-3-glucuronide may build up in elderly and in those with renal insufficiency causing myoclonus and interfering with analgesia
Oxycodone:
– Highly abused and dealt on the streets
Hydromorphone

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Fentanyl : many street names including “China White”, “Apache”, “Dance fever”
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Patch: worn continuously for 72 hours . In some patients for 48 hours.
Should not be prescribed to narcoticnaïve patients
– Rate of drug reaching the circulation is directly proportional to body temperature
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● patients should treat fever and should avoid exposure to heating pads, sunbathing, hot showers, saunas, vigorous exercise, etc…
Patients with low fat tissue mass may need lower doses than those recommended by conversion tables
May take up to 24 hours to attain adequate and stable blood levels and pain control
Drug may still leech into circulation from fat depot even after patch is removed
Gel patch should not be cut
Fentanyl is metabolized by CYP3A4 and therefore should monitor patients carefully if they receive
CYP3A4 inhibitors (e.g., azole antifungals, erythromycin, clarithromycin, ritonavir) or inducers
(rifampin, phenytoin, carbamazepine, phenobarbital, St. John’s Wort)
Methadone :
– Last resort for pain control
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Dosed Q4-8H for pain control
Dosed QD for management of opioid dependence
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Physician has to apply for and be granted permission to prescribe methadone from the federal office of controlled substances
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Having authority to prescribe methadone for pain ≠ authority to prescribe as part of methadone maintenance program (MMT) for opioid/heroin dependence and vice versa
Produces less euphoria than heroin.
– Patients start off by drinking methadone dose daily at the pharmacy
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If urine tests show no use of illicit drugs, patient may be allowed by prescriber to “carry” some doses home for convenience
– Pharmacist has the authority to deny patient his/her methadone dose if patient shows s/sx of intoxication

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Hydrocodone : mainly used as anti-tussive
Meperidine :
– 10 times less potent than morphine with shorter duration of action
– Should only be used for acute pain
– Contraindicated for treatment of chronic pain
– Risk of accumulation of toxic metabolite normeperidine which could lead to anxiety, tremors, myoclonus, seizures with repeated doses
– Limit its use to less than a day or two
– Not useful for cough or diarrhea
Tramadol : Parent compound and its metabolite bind to mu receptors AND inhibit reuptake of serotonin and NE. Contraindicated with MAOIs and may cause seizures if mixed with
SRIs. Only partially antagonized by the opiate antagonist naloxone. Laws for prescribing narcotics do not apply to tramadol, i.e., tramadol can be refilled.
Pentazocine :
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Brand name = Talwin
Mixed agonist-antagonist at mu receptor and therefore has “ceiling dose”
– Exceeding maximum dose does not give added benefit
– May cause withdrawal symptoms if given to patients taking pure agonists such as morphine , etc…
– Causes hallucinations, confusion and vivid dreams which renders it as an unacceptable option in most patients
– Absolute contraindication in chronic pain

■ Diarrhea
– Lomotil (diphenoxylate + atropine)
■ Cough suppression
– Codeine
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At least 15 mg per dose required
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Syrup is 5 mg/mL
Hydrocodone
■ Opioid dependence
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Methadone
Sublingual Suboxone (Buprenorphine + naloxone)
● naloxone is an opioid antagonist but is not absorbed orally; purpose is to deter patient from injecting Suboxone

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Constipation
– Tolerance does not develop with repeated doses of opioid
– Stimulant laxatives :
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● senna 8.6 mg tabs: 2 to 12 tabs bid or hs bisacodyl 5 mg tabs: 2 to 12 tabs bid or hs
Cathartics such as 15 to 45 ml of milk of magnesia daily
Osmotics such as 15 to 30 ml of lactulose qd to tid
Oral naloxone or SQ methylnaltrexone (peripheral opioid antagonists)
Fiber will not help and in fact may compound the problem and lead to impaction
Stool softeners such as docusate are generally not helpful and may delay patient from getting proper laxative

■ Nausea & Vomiting
– Tolerance usually develops with repeated doses
– Seen mostly if the up-titration of dose is too rapid
– First, try reducing the dose of the opioid to minimize fluctuation in blood levels
– Dimenhydrinate (Gravol) 25 to 50 mg q4-6h
– Metoclopramide or domperidone 10 to 40 mg qid
– Prochlorperazine 5 to 10 mg q4-6h
– If N/V persistent, consider switching to another opioid

■ Respiratory depression
– Seen mostly if the up-titration of dose is too rapid or in case of overdose
– Sudden, severe sedation often precedes respiratory depression
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Respiratory depression is due to decreased responsiveness of respiratory center in brain stem to increases of Pco
2
Death from opioid poisoning is usually due to respiratory arrest
Serious respiratory depression is managed by injections naloxone
– From the LMCC exam objectives:
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"Contrast respiratory depression caused by opioids to the respiratory rate of six to eight breaths per minute of the dying patient who is not receiving opioids (i.e., the respiratory depression is not caused by opioids but is actually a natural part of the dying process)."

■ The law prohibits adding refills for opioids
– Eg: Oxycontin 20 mg q12h x60 tabs + 2 refills  pharmacist can only fill 60 tabs and the refills are ignored
■ Prescriptions can be written as part-fills
– Eg: Oxycontin 20 mg q12h x180 tabs, dispense in portions of 60 tabs every 30 days (indicating an interval is not mandatory but strongly recommended)

■ Muscarinic agonists:
– Direct: pilocarpine (glaucoma management; constricts pupil allowing aqueous humor to leave eye), bethanechol
(contracts urinary bladder)
– Indirect (AChEIs): pyridoand neostigmine (myasthenia gravis), rivastigmine, donepezil, galantamine
■ Muscarinic antagonists:
– Direct: atropine, oxybutynin, tolterodine, trospium, solifenacin, darifenacin (inhibit contraction of urinary bladder; useful in urge incontinence), ipratropium or tiotropium
■ Nicotinic agonists: nicotine at low doses and with short-term exposure
■ Nicotinic antagonists: nicotine at large doses and with longterm exposure

Carbidopa -

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Selegiline
(MAO type B inhibitor)
Entacapone, tolcapone
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Alpha agonists:
– Phenylephrine, oxymetazoline, xylometazoline, clonidine, methyldopa, naphazoline
■ Alpha antagonists:
– Terazosin, doxazosin, tamsulosin, prazosin, alfuzosin
■ Beta agonists:
– Dobutamine, isoproterenol, salbutamol, formoterol, salmeterol, terbutaline
■ Beta antagonists:
– All the beta blockers such as propranolol, metoprolol, etc…

■ Conventional :
– carbamazepine, benzos, ethosuximide, phenobarbital, phenytoin, primidone, valproic acid
■ Second Generation :
– gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, topiramate, vigabatrin
■ Most are dosed at least BID
■ Most are started at a low dose and titrated up slowly
■ Phenytoin, phenobarbital, valproic acid, gabapentin and levetiracetam can be started with the loading or maintenance doses

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Correct underlying cause whenever possible
In general, AEDs are used when cause cannot be identified and if patient had 2 or more seizures
Partial onset seizures are often resistant ot AEDs
Generalized onset seizures usually respond to AEDs
1.
Choose AED based on: seizure type or epilepsy syndrome
2.
side effect profile of AED, other medical conditions, concurrent drugs, drug interactions, cost
Strive for monotherapy

Titrate firstline drug for seizure type ineffective
Check compliance, reconsider diagnosis, etiology
Summary:
A, A, A+A, A+B ineffective
Initiate and titrate another
1 st -line agent and taper off ineffective agent ineffective
Try combination of
1 st -line agents.
ineffective
Replace the drug with least benefit/most side effects a
2 nd -line agent

Some anti-seizure drugs prolong the inactivation of the Na+ channels, thereby reducing the ability of neurons to fire at high frequencies.

Some anti-seizure drugs reduce the flow of Ca 2+ through T-type Ca 2+ channels thus reducing the pacemaker current seen in generalized absence seizures.

GABA opens the GABA receptor (structure on left) allowing an influx of Cl resulting in hyperpolarization. Some anti-seizure drugs act by reducing the metabolism of
GABA. Others act at the
GABA receptor to enhance
Cl influx in response to
GABA. Gabapentin promotes GABA release.
Red structures are GABA molecules; GABA-T =
GABA transaminase; GAT-
1, GABA transporter.

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50% of patients achieve complete seizure control and additional 25% experience reduced seizure frequency
Treat with AEDs until patient is seizure free for at least 2 years then graduallt decrease dose over months
New onset of nystagmus (except with PHT), ataxia and unsteady wide gait signal intoxication
Phenytoin: small increases in dose may raise blood levels dramatically due to saturation of hepatic enzyme clearance
Carbamazepine: induces its own hepatic breakdown  large increases in dose result in small increases of blood levels
Don’t increase drug dose if patient is seizure free even if blood drug levels are below therapeutic range

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Carbamazepine is chemically related to TCAs  D/C MAOIs 2 weeks before starting CBZ
CYP inducers: CBZ, PHT, phenobarbital  ↓↓ LMT, TPM, effectiveness of estrogen in OCP’s
CYP inhibitors: VPA
High protein binding: PHT, VPA
Renally eliminated AEDs: levetiracetam, gabapentin (not metabolized at all), vigabatrin, topiramate (exhibits carbonic anhydrase inhibition and hyperthermia)
Supplement women of child bearing age with folate if they are on VPA
CBZ and vigabatrin may worsen absence or myoclonic seizures
VPA is not the same as divalproex
Tolerance to clobazam can occur after 3-6 months  drug holiday required
Pseudoephedrine, gingko, meperidine, bupropion, antipsychotics may exacerbate seizures

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Primary generalized seizures: VPA, LMT, topiramate, levetiracetam
Tonic-clonic: CBZ, PHT, VPA
Absence: Ethosuximide, VPA
Myoclonic, atonic: VPA
Infantile spasms: vigabatrin
Partial onset seizures (including secondarily generalized): CBZ,
PHT but all conventional AEDs are effective (except ethosuximide)
– all new AEDs are good alternatives but most are approved only as add-on agents
2 or more types of seizures: VPA is a good choice

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Acute attacks:
– Antiemetics: can be useful analgesics. E.g., prochlorperazine, metoclopramide or domperidone
– NSAIDs: mild-moderate attacks. Need high doses. E.g., ibuprofen (max 3.2 g/day), naproxen (1.5 g/day)
– Triptans: Nara-, riza-, suma-, zolmi-, ele-, almo- and frova-triptan
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Serotonin receptor type 1 agonists; vasoconstrictors
For moderate-severe attacks; should be taken at earliest sign of pain; if no partial or complete relief within 1-2 hours then do not redose
Not helpful in up to 40% of attacks; also high recurrence rate
Avoid these agents if patient has cardiac or cebreovascular disease
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Decrease dose or avoid in hepatic impairement
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Tightness of chest, neck or throat, facial flushing, tingling
Possible serotonin syndrome if taken with MAOI’s before NSAID/triptan consider an antiemetic
Butorphanol nasal spray: narcotic; dependency potential. Reserve for rescue treatment or when triptans ineffective or contraindicated

■ Prophylaxis:
– Consider if migraines severe enough to impair quality of life or patient has 3 or more severe attacks per month
– use one prophylactic agent at a time; start low & titrate up
– benefits usually seen after 1-2 months
– Beta blockers (propranolol, atenolol, metoprolol)
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Calcium channel blockers (verapamil)
TCA’s (amitriptyline, nortriptyline)
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Anticonvulsants (valproic acid, gabapentin, topiramate) if single agent ineffective, may try a combination (eg beta blocker + TCA)
– discontinue gradually to prevent rebound

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■ Classified as:
– TCA’s : include amitriptyline, desipramine, imipramine, nortriptyline  desipramine and nortriptyline are most tolerated
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SSRI’s : citalopram, escitalopram, fluoxetine, paroxetine, fluvoxamine, sertraline
NDRI’s : bupropion
SNRI’s : venlafaxine, desvenlafaxine, duloxetine
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Misc : trazodone, mirtazapine
MAOI’s :
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Irreversible: phenelzine, tranylcypromine
Reversible: moclobemide
TCA=tricyclic antidepressant
NDRI=Norepinephrine and dopamine reuptake inhibitor
SNRI=serotonin and NE reuptake inhibitor

■
Factors to consider include:
– TCA’s are less well tolerated ( anticholinergic SE’s )
– Try to avoid TCA’s and MAOI’s in elderly
– Ingestion of 10 day supply of 200 mg TCA
( avoid in patients with suicidal ideation ) at once could be lethal
– Use a sedating agent if patient also has insomnia mirtazapine)
(trazodone or
–
–
–
Moclobemide and bupropion have lowest rates of sexual dysfunction
MAOI’s are usually reserved as last resort
–
With atypical features of depression (over-eating, weight gain or oversleeping), use fluoxetine, sertraline, moclobemide
If patient has OCD, use SSRI’s or clomipramine
–
–
If hypertensive, avoid high dose venlafaxine, desvenlafaxine or duloxetine
If cardiac conduction abnormalities or dementia, avoid TCA’s

■
■

■ Response could begin in the first 1-2 weeks but would be optimal most probably after at least 3-4 weeks
■ If no response after 4 weeks, alter treatment in some way (raise dose, switch to another agent, combine two agents with different mechanisms of action)
■ Treat major depression for at least 9 months
■ To avoid relapse D/C therapy gradually and not abruptly ( venlafaxine is particularly difficult to
D/C ).

■ With most agents, there is no need for a washout period
■ One option is to taper down one agent while tapering up its replacement
■ If switching from an IRReversible MAOI to another agent: 2 week washout of MAOI
■ If switching from a REversible MAOI to another agent: 3 day washout
■ If switching from one agent to an MAOI: washout the first agent for a period of 5 half-lives then start the
MAOI ( fluoxetine has a very long half life ~ 1 week )

■
■
■
■
TCA’s: anticholinergic , sedation (tolerance usually develops after 1-
2 weeks), weight gain, orthostatic hypotension , dizziness, reflex tachycardia, prolong conduction time of electrical current in heart (avoid in heart block or MI), lower seizure threshold, sexual dysfunction
SSRI’s: diarrhea, N /V, insomnia , sedation (especially with fluvoxamine), headache, sexual dysfunction (especially with paroxetine)
Irreversible MAOI’s: constipation, anticholinergic , drowsiness
(phenelzine), insomnia (tranylcypromine), orthostatic hypotension, hypertensive crisis (occipital headache, stiff neck, N/V, high BP) if combined with tyramine containing foods (aged cheese, cured meats, broad been pods, sauerkraut, soy, tap beer)
Reversible MAOI: dry mouth, N, sedation, headache, dizziness. NO
FOOD RESTRICTION REQUIRED .

■ Venlafaxine (Effexor):
–
–
Doses
Doses
< 150 mg
> 150 mg
: behaves like an
: additional
SSRI (N/V)
NE reuptake inhibition which may lead to hypertension
– Doses > 300 mg : additional weak DA reuptake inhibition (it’s like adding low dose bupropion to an SSRI)
– So, venlafaxine has the potential to inhibit the reuptake of serotonin + NE + DA
– nausea, dry mouth, constipation, fatigue, decreased appetite, somnolence or insomnia, increased sweating

■ Trazodone (Desyrel): SEDATION , DRY mouth , orthostatic hypotension, priapism (1 in 6000 male patients)
■ Bupropion (Wellbutrin): stimulation ( insomnia , agitation), headache, higher risk of seizures if daily dose > 450 mg or if >150 mg per single dose of the
SR version
– SR formulation is dosed BID (at least 8 hours between the two doses)
– XL formulation is dosed QD
■ Mirtazapine (Remeron): SEDATION and WEIGHT
GAIN

■ Duloxetine (Cymbalta):
– Similar mechanism of action to venlafaxine, i.e., it is another SNRI
– Also indicated for management of diabetic peripheral neuropathy
–
–
Like venlafaxine, it may increase BP
May cause nausea, dry mouth, constipation, fatigue, decreased appetite, somnolence or insomnia, increased sweating
– Twice the cost of venlafaxine effective for major depression but not more

■
■
■

■ Benzodiazepines:
■
■
For short term use/PRN
Rapid onset of action
■ Buspirone:
■ For long term use
■ Low abise potential and is less sedating than benzos
■ Up to 3 weeks for response
■ Antidepressants:
■
■
■ Example: escitalopram, paroxetine, sertraline, venlafaxine, bupropion
For long term use
Up to 8 weeks for response

■
■
■
■
■
■
■
■
■
■
Long acting: chlordiazepoxide, clonazepam, clorazepate, nitrazepam, diazepam, flurazepam.
Intermediate acting: alprazolam, bromazepam, lorazepam, oxazepam, temazepam
Toxicity is due to decreased respiratory rate and decreased LOC  often a problem when prescribed with opioids
Can also cause cognitive/memory impairment, confusion, hallucinations, worsening sleep apnea
Ethanol enhances toxicity
Doses should be tapered down gradually if patient has been using them chronically
Can cause dependence; high potential for abuse
L orazepam, o xazepam and t emazepam (LOT) do not undergo hepatic microsomal oxidation and therefore are best options for elderly patients
Any BZ can cause falls
Avoid BZ in dementia

■ Benzodiazepines or their agonists are generally first line if nonpharmacological treatment fails
■ BZ: flurazepam, nitrazepam, temazepam and triazolam are officially indicated for treatment of insomnia
■ BZ agonist: zopiclone (Imovane) is officially indicated for insomnia
■ Different medications are used to address the different types of insomnia
■ Avoid triazolam since it is associated with behavioural changes
■ Flurazepam and nitrazepam have long half lives and accumulate with repeated dosing; they also cause more pronounced hangover effects
■ Triazolam and lorazepam may cause rebound insomnia

■ Zopiclone has a short half life and causes bitter or metallic aftertaste
■
■
Sedating antihistamines, aka, 1st generation antihistamines: diphenhydramine , dimenhydrinate, hydroxyzine , chlorpheniramine
 anticholinergic side effects are a problem.
Antidepressants: trazodone , mirtazapine, TCA’s . Low doses are sufficient.
■ Melatonin (use is controversial and more studies are needed)
■ Secobarbital, pentobarbital. Abuse potential.

AGI = alpha glucosidase inhibitor (acarbose), biguanides = metformin
Insulin secretagogues = sulfonylureas or meglitinides, TZD = pioglitazone or rosiglitazone

Agent MOA Avoid Side Effects
Sulfonylureas: glyburide gliclazide glimepiride
Biguanides: metformin
α-glucosidase
Inhibitors: acarbose
Thiazolidinedion es:
Pioglitazone
Rosiglitazone stimulate insulin secretion
- Inhibits gluconeogenesi s
-↑ insulin sensitivity delays CHO absorption from GI tract
- PPAR-γ receptor agonist
↑ insulin sensitivity
Severe hepatic
/renal dysfxn
- Severe renal impairment
- liver impaired
heart failure
(emerging data suggests safe in HF)
- severe renal dysfunction/ liver cirrhosis
- IBD
caution in
HF
- Use with insulin may precipitate HF
- Class 3,4 HF
hypoglycemia (esp glyburide) if elderly, poor meal schedules,
weight gain (esp glyburide)
- nausea, anorexia
GI discomfort
- weight loss (mild)
- lactic acidosis (rare) stop it before using iodinated contrast media
- B12 deficiency
- GI discomfort
↑ LFT’s – dose related
(rare)
- weight gain
- edema
-Anemia
-↓ triglycerides
Notes
- take 30 min before a meal
- Alcohol ↑ risk of hypoglycemia
- β-blockers – mask hypoglycemia cardiac Sx’s
does not cause hypoglycemia
- has
↓ lipid effect
- does not cause hypoglycemia by itself
-
↓ digoxin levels
3 week onset, peak 8-
12 weeks
-with or w/o food
-Should not cause hypoglycemia if used alone
-Monitor LFT’s
Meglitinides:
Repaglinide
Nateglinide
Stimulate insulin production like sulfonylureas
-hepatic dysfunction
- weight gain
- Hypoglycemia less than SU’s
take immed. before meals. Skip dose if meal is missed.





Rapid acting:
− Lispro, aspart, glulisine: use immediately before meals
Short acting:
− Regular insulin: inject up to 30 minutes before meals
Intermediate acting
− NPH: inject bid
Long acting:
− glargine (should never be mixed with any other insulin in same syringe), insulin detemir : inject qd


*** insulin is the drug of choice for use in gestational diabetes.
Glyburide or metformin may also be used. ***
*** corticosteroids, atypical antipsychotics, thiazide diuretics, beta blockers, cyclosporine, and protease inhibitors, all may cause hyperglycemia ***

■
■
■
■
■
■
Incretins (GLP-1 and GIP) are hormones released from intestinal cells in response to ingestion of food
Incretins
–
–
–
– increase insulin synthesis decrease production of glucagon slow gastric emptying promote satiety
Type 2 diabetics have reduced post-prandial incretin levels
Incretins have a short life span because they are broken down by dipeptidyl peptidase-4 (DPP4) in circulation
Sitagliptin prolongs the life of incretin hormones by inhibiting the action of
DPP4 and increases endogenous GLP-1 and GIP levels
Exenatide is an injectable GLP-1 agonist

Liraglutide
Food ingestion
GLP1 and
GIP from GI cells
+
Increased insulin and reduced glucagon secretion from pancreas sitagliptin DPP4
Inactive incretins
Reduced hepatic glucose production and increased glucose uptake by adipose tissue and skeletal muscles

■
■
■
■
■
Reduces HbA1C similarly to acarbose by about 0.5 to 0.8% on average (metformin, sulfonylureas, thiazolidinediones, meglitinides reduce HbA1C by 1 to 1.5%)
Adverse effects include URTIs and GI upset
Since incretins stimulate insulin release in a glucose-dependent manner, sitagliptin does not cause significant hypoglycemia
Advantages: dosed once daily, no weight gain, low risk of hypoglycemia, does not appear to have significant drug-drug interactions
Disadvantages: post-marketing reports of serious hypersensitivity reactions, new class and therefore no known long term effects
(good or bad), expensive, reduces HbA1C less than other established antidiabetics, requires functioning beta-cells capable of producing insulin

■
■
■
■
■

■ HMG Co A reductase inhibitors, aka, Statins: atorva-, fluva-, lova-, prava-, rosuva-, and simvastatin.
■ Cholesterol absorption inhibitor: ezetimibe
■ Bile acid sequesterants, aka, resins: cholestyramine & colestipol
■ Fibrates: gemfibrozil, beza- & fenofibrate
■ Nicotinic acid
■ Fish oils containing eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)

■ They reduce cholesterol mainly due to upregulation of LDL receptors
■ S, A, and L are metabolized by CYP3A4
■ R is excreted by kidneys
■ R & S increase HDL the most
■ A, R & S reduce TG the most
■
■
All are dosed up to 80 mg qd but R and P are up to 40 mg qd
SE’s: abdominal cramps, flatulence, muscle tenderness/stiffness/weakness/inflammation, CK elevation
■ Avoid coadministration with fibrates if possible since the combo increases risk of myositis and rhabdomyolysis

■ Inhibits absorption of dietary and biliary cholesterol via an unknown transporter leading to increased LDL receptors on hepatocytes
■ Reduces LDL only
■ Works synergistically with statins
■ 10 mg qd
■ SE’s: abdominal pain, diarrhea, fatigue, increase in
LFT’s (monitor LFT’s especially is combined with statins)

■
■
■
■
■
■
■
■
Bind anionic bile acids in GI tract and prevent their absorption, which stimulates liver to convert more cholesterol into bile acids which leads to more LDL receptors
Not absorbed systemically
Reduce cholesterol only
May RAISE TG’s
Also used to clear leflunomide (an anti-rheumatic drug) from body within 2 weeks. Otherwise, it takes years to clear leflunomide.
Cholestyramine 4-12 g bid and colestipol 5-15 g bid
SE’s: CONSTIPATION, bloating, flatulence, dyspepsia, decreased absorption of vitamins ADEK, warfarin, digoxin
To avoid the possibility of reduced bioavailability, other medications should be taken a few hours before or after the resin

■ Reduce VLDL and hence TG’s
■ Mechanism of action not completely understood
■ Patient should stop excessive alcohol consumption before treatment
■ Use with statins should be avoided if possible since the combo increases risk of rhabdomyolysis and myositis
■ Clofibrate predisposes to gallstones and is best used in those with a cholecystectomy

■
■
Only nicotinic acid version has anti-lipemic activity
Lowers TG’s by up to 50% (same as fibrates) by inhibiting
VLDL production in liver
■ Most effective agent in raising HDL (up to 35%)
■ MOA: reduces clearance of HDL, blocks mobilization of
FFA’s from periphery to liver, and reduces synthesis of
VLDL
■ 0.5-2g daily in divided doses of SR or ER forms
■ 0.5-4g daily in divided doses of IR form
■ Start low and go slow to prevent side effects

■ SE’s: N/V, diarrhea, hyperglycemia, hyperuricemia, flushing, hypotension, headache, hepatotoxicity, worsening of peptic ulcer disease
■ To reduce SE’s: take with food, avoid alcohol and hot beverages/food, take ASA 30 minutes before niacin dose
■ Available as immediate and extended release tabs
■ IR is least hepatotoxic but causes most flushing. ER version
(Niaspan) causes less flushing.

35%
25%
12.5%
Baseline
-15%
-30%
0
HDL-C with crystalline niacin
HDL-C with Niaspan ®
LDL-C with Niaspan ®
TG with Niaspan ®
LDL-C with crystalline niacin
1 g/d
TG with crystalline niacin
2 g/d 3 g/d

■ Used to reduce TG’s. TG’s may be lowered by as much as 50% in some cases
■ May raise LDL but studies have inconsistent results
■ Need 2 to 4 g of EPA+DHA daily to lower TG’s
■ MOA: may reduce hepatic VLDL synthesis and secretion and enhance TG clearance
■ SE’s: Nausea, fishy after taste, dyspepsia, raised
LDL (up to 10% in some studies)

■ A=ACEI and ARB (and direct renin inhibitor?)
■ B=Beta blockers
■ C=Calcium channel blockers
■ D=diuretics
======================
■ < 55 y.o. and non-black  A or B
■ > 55 y.o. or black  C or D
■ If monotherapy is ineffective, combine one of A or B with one of C or D
■ Low-moderate dose of 2 drugs is preferable over maximal doses of 1 drug for control of hypertension

■
■
■
■
■
■
■
Captopril is proto-type. Others include ramipril, lisinopril, enalapril, quinapril, trandolapril, and fosinopril. They all end with “-pril”
SE’s: angioedema, cough (absent with ARB’s; caused by increased bradykinin levels), hyperkalemia, increased serum creatinine, headaches
(more with ARB’s)
Benefits of ACEIs: reduce peripheral artery resistance, increase CO, no change in heart rate, increase renal blood flow, GFR remains constant
To prevent hypotension when initiating ACEI therapy, stop diuretics for 2-3 days first, then start the ACEI. After that, diuretic could be restarted.
Warn patients not to use potassium-based salt substitutes.
Stop ACEI if serum potassium goes above 5.5 umol/L. Check K + and SCr in
1-2 weeks after starting the ACEI. D/C the ACEI if SCr increases by more than 30% from baseline value.
Contraindicated in pregnancy and bilateral renal artery stenosis in a patient with two kidneys or in unilateral renal artery stenosis in a patient with one kidney.

ARB
Θ
Θ
ACEI
Direct Renin
Inhibitor
(aliskiren)
Θ
Θ

■ Lisinopril and captopril are the only ACEI’s which are not prodrugs
■ Enalaprilat is the only ACEI available for parenteral administration
■
■
■
All ACEI dosages need to be adjusted in renal dysfunction/failure except for fosinopril
ARB’s include candesartan, irbesartan, losartan, valsartan, telmisartan, eprosartan. They are contraindicated in pregnancy. May also cause angioedema.
Both ACEI’s and ARB’s are very useful in managing HF, hypertension, and proteinuria.

■ Rasilez or aliskiren is the first member of this class
■ Blocks renin from converting angiotensinogen to angiotensin 1
■ Metabolized by CYP3A4
■ Currently can be combined with HCTZ, ACEIs or DHPs
■
■
Reduces blood levels of furosemide by 50% through unknown mechanism
Ketoconazole and atorvastatin increase aliskiren’s levels while irbesartan decreases its levels
■ Like ACEIs/ARBs, aliskiren may cause angioedema, hyperkalemia, and is contraindicated in pregnancy
■ Most common side effect is transient diarrhea

■
■
■
■
■
■
■
All names end with “-lol”
Cardioselective (B1-selective at low doses): metoprolol, acebutolol, bisoprolol, esmolol (injectable only), betaxolol, atenolol. Could be safely tried in asthmatics who require beta blockade
Non-selective (B1 and B2 blockade): propranolol and nadolol. Also helpful in management of bleeding esophageal varices due to their ability to block the B2 receptor in blood vessels.
pindolol, acebutolol, and oxprenolol have Intrinsic Sympathomimetic Activity
(ISA). This means that they are also partial agonists at the beta receptor
 may have less negative effects on heart rate, blood lipids, and tiredness  useful agents if patient experiences bradycardia on other BB’s.
The only BB officially labelled for use in pregnancy is labetalol
Carvedilol is also a beta and alpha blocker
Carvedilol, bisoprolol abd metoprolol have the most evidence for good outcomes in heart failure

■
■
■
■
■
■
■
Esmolol has a short half life of about 10 minutes and is administered intravenously to treat intra- or post-operative hypertension, and to treat hypertensive emergencies.
Elderly have less functional cardiac beta receptors and so require smaller dosages compared to younger patients
BB’s typically reduce blood pressure by reducing vascular resistance, CO and renin production
Reduce HR at rest and during exercise (compare with digoxin which reduces heart rate only at rest)
Start at low doses and titrate up gradually
When discontinuing them, taper down gradually
SE’s: bradycardia, tiredness, dizziness, mood disturbances (particularly with the fat soluble agents such as metoprolol), may raise blood lipids, exacerbation of PAD, sexual dysfunction, worsening of asthma symptoms

■
■
■
■
■
■
Dihydropyridines (DHP): nifedipine, amlodipine and felodipine act on arteries (including coronary arteries) to induce vascular relaxation.
Therefore, they reduce afterload which may lead to reflex tachycardia 
BB’s may be helpful in this setting.
All their names end with “-dipine”.
NonDHP’s: diltiazem and verapamil act mostly on cardiac cells
(verapamil more so than diltiazem) to depress contractility, AV conduction, and heart rate  therefore avoid combining with BB’s.
MOA: block calcium channels from allowing entry of calcium into muscle cells which results in less contractility and vascular resistance  so, non-
DHP’s worsen heart failure
May cause swollen ankles and flushing (mostly DHP’s) and constipation
(especially verapamil). Swollen ankles may be resolved by using an
ACEI or by lowering the dose of the CCB.
Indications: all 3 types of angina (stable, unstable and vasospastic or Prinzmetal’s), and hypertension.

a)
b)
c)
d)

Which of the following antidepressant drug combos makes the most pharmacological sense when prescribed to a patient?
a)
b)
c)
d)
e)

a)
b)
c)
d)
e)

Which of the following is classified as a monoamine oxidase inhibitor?
a)
b)
c)
d)

Which of the following agents could be used to control gestational diabetes?
a) Insulin injections (e.g., NPH, aspart, lispro) b) Metformin c) Glyburide d) All of the above

a)
b)
c)
d)
e)

Which of the following statins is not significantly metabolized by the CYP3A4 system?
a)
b)
c)
d)
e)

a)
b)
c)
d)
e)

Which of the following beta blockers may worsen asthma control the most even in low-moderate doses?
a)
b)
c)
d)

a)
b)
c)
d)
e)

Which of the following should not be used to control hypertension in HF patients?
a)
b)
c)
d)
e)

Which of the following is ineffective as a diuretic at low creatinine clearance (< 50 mL/min)?
a)
b)
c)
d)
e)

■
■
■
■
■
■
■
■
■
■
Most powerful of all diuretics
E.g.: furosemide
50% of furosemide oral dose is typically absorbed
These agents have to be available inside the nephron tubule in order to exert their action  they’re filtered and secreted
Their secretion into the tubule is reduced by NSAIDS and probenecid
MOA: inhibit luminal Na + /K + /2Cl transporter in the thick ascending limb of Henle’s loop. This results in loss of Na + , K + , Mg ++ , and Cl -
Indications: pulmonary edema, other edematous conditions, acute renal failure, heart failure
Side effects: hypokalemic metabolic alkalosis, hypomagnesemia, dose-dependent hearing loss especially if patient is receiving the oto-toxic aminoglycosides, hyperuricemia
Hyponatremia is less common than with the thiazides
Use cautiously in heart failure

■
■
■
■
■
■
■
■
■
■
■
hydrochlorothiazide (HCTZ), indapamide, chlorthalidone (CTD), metolazone
Indapamide and metolazone are more powerful than HCTZ/CTD and are usually used for their powerful diuretic action like the loop diuretics
HCTZ and chlorthalidone are used mostly for treatment of hypertension
Reduce NaCl reabsorption by inhibiting NaCl transporter mostly in distal convoluted tubule
Enhance Ca ++ reabsorption which may unmask hypercalcemia.They could be useful in the management of kidney stones caused by hypercalciuria.
Compete with uric acid secretion which may translate into reduced clearance of urate leading to possible gout attacks
Have to be filtered into the nephron to exert their action  therefore may not be useful if GFR is too low
SE’s: erectile dysfunction, hypokalemia, hyponatremia, gout attacks, hyperglycemia and hyperlipidemia
Hypokalemia (worsened by corticosteroids and beta-agonists such as salbutamol) may enhance toxicity of digoxin
Indications: hypertension and edema
Dose of HCTZ and CTD for hypertension range from 12.5 to 25 mg qd

+
Θ
Θ
Spironolactone

+
■
■
■
■
■
■
■
■
Spironolactone: steroid competitive antagonist to aldosterone at the mineralocorticoid receptor
Triamterene and amiloride inhibit Na + influx through ion channels in luminal membrane
Spironolactone requires several days for full therapeutic effect
All 3 drugs are very weak diuretics and are not used for purpose of diuresis
Indications: 1 ° or 2° mineralocorticoid excess (Conn’s syndrome, ectopic
ACTH production, HF, hepatic cirrhosis, nephrotic syndrome), prevent or to treat hypokalemia caused by other diuretics
SE’s: hyperkalemia (especially if used with BB’s, NSAIDS, ACEI’s or
ARB’s)
Spironolactone may cause gynecomastia, BPH, impotence (also binds to progesterone and androgen receptors)
Eplerenone is more specific to aldosterone receptor  causes less gynecomastia

■
■
■
■
■
toxicity includes N/V, diarrhea, headache, dizziness, arrhythmias (especially if patient experiences hypokalemia, hypomagnesimia, or hypercalcemia). Toxicity more commonly seen if digoxin blood levels > 2 ng/ml

■
■
■
■
■
■
■
■
■
Indicated for treatment of acute angina attacks or prevention of exercise or prinzmetal’s angina
To treat an angina attack use: S/L NTG tablet or spray
To prevent an attack use: S/L nitroglycerin tablet or spray, nitroglycerin patch, NTG ointment, po isosorbide dinitrate (ISDN) or isosorbide mononitrate.
Manufacturer specifies that NTG spray could be used over or under the tongue.
To avoid nitrate tolerance, provide a nitrate-free period of 10 to 14 hours daily
ISDN is does BID-TID whereas ISMN is longer acting and dosed once daily
SE’s: headaches, flushing, dizziness, hypotension, reflex tachycardia
(minimized if also using BB)
Other drugs used to prevent angina include BBs and CCBs (DHPs or nonDHPs). Verapamil is especially useful for Prinzmetal’s angina.
Nitrates are contraindicated for use with PDE5Is such as sildenafil, tadalafil, vardenafil due to risk of life-threatening hypotension

TXA2 = vasoconstrictor and platelet aggregant
Thienopyridines = clopidogrel and ticlopidine. After activation in the liver, they covalently bind to ADP receptor and reduce platelet activation
PI = phosphodiesterase inhibitors (dipyridamole)
GP iib/iiia inhibitors = abcixi mab (block the final common pathway for platelet aggregation)

■
■
■
■
■
ASA:
– irreversible inhibitor of cyclo-oxygenase (COX) which results in inhibition of TXA
2 production in platelets and PGI
(prostacyclin) production in endothelial cells
2
– Endothelial cells (but not platelets) overcome this inhibition by producing fresh cyclo-oxygenase which raises PGI
2
:TXA
2 ratio
Dipyridamole+ASA: the combo is superior to ASA alone in reducing risk of strokes. Given as 1 cap bid. Each Capsule contains 200 mg dipyridamole + 25 mg ASA
Clopidogrel: ADP-receptor antagonist (ADP promotes platelet aggregation). Given to patients intolerant to ASA and sometimes along with ASA.
Ticlopidine: also an ADP-receptor antagonist. Generally not used anymore since it causes neutropenia  clopidogrel is safer
Prasugrel is the latest addition to this class

a)
b)
c)
d)
e)

a)
b)
c)
d)
e)

■ Thrombus may form in arteries (white: fibrin+platelets) or veins (red: fibrin+RBC’s)
■ ASA and other antiplatelets (e.g., clopidogrel) work well on white thrombi
■ Anticoagulants (e.g., warfarin, heparin, lowmolecular weight heparin) work well on red thrombi
■ Oral anticoagulants: warfarin
■ Injectable anticoagulants: unfractionated heparin & low molecular weight heparins (LMWH)

■ MW = 15000 Da
■ Can be given SC or IV
■ Adjust dose according to aPTT (aPTT measures antifactor IIa activity)
■ Mostly effects clotting factors II and X
■
■
Compared with LMWH, UFH binds more to plasma proteins, endothelium and macrophages, resulting in reduced bioavailability and greater patient variability to a given dose.
SE’s:
– Short term: bleeding (can be reversed with IV protamine sulfate ), thrombocytopenia (aka, HIT.
LMWH’s are cross reactive)
– Long term: osteopenia, alopecia, hypoaldosteronism

Heparin
Enzymatic depolymerization
LMWH

■
■
■
■
■
■
■
■
■
■
■
■
MW = 4000 to 5000 Da
Affect factor X mostly
Administered SC only
As effective as UFH
May be used in pregnancy
Dosed according to body weight
Dosage adjustment is unnecessary and aPTT is not required (since antifactor IIa activity is not affected)
Anti Xa levels could be used to determine efficacy
Lower incidence of thrombocytopenia
All names end with “-parin”.
Dalteparin, enoxaparin, nadroparin, tinzaparin. Injected once daily.
Same SE’s as heparin but to a lesser extent. Overdose could be reversed with protamine sulfate but repeated doses may be required

Endogenous anti-thrombin III
(ATIII) binds factors IIa and Xa but at a very slow rate.
UFH and LMWH’s speed this process up.

■ Bioavailability 100%
■ Avoid in pregnancy (teratogen). Use UFH or LMWH instead.
■ Only S enantiomer is active
■ Binds to albumin
■ MOA: inhibits reduction of vitamin K required for carboxylation (thus activation) of clotting factors in the liver (II, VII, IX, X)
■
■
Onset of action is up to 5 days to allow for depletion of already synthesized factors
Heparin and LMWH’s start working in 1-2 hours. Patients are often started on heparins AND warfarin together, then heparins are stopped after 1-5 days and warfarin is continued

■ Warfarin also depletes protein C and S (anticoagulation factors)
■ Adjust dosage according to INR results (range is usually 2 to 3)
■ Tell patient to keep consumption of vitamin K from foods constant so that warfarin dosages could be adjusted easier and more consistently
■ Major drug interactions:
– Increase INR: amiodarone, TMP/SMX, metronidazole, cipro, erythromycin
– Decrease INR: rifampin, carbamazepine
■ SE’s: bleeding, skin necrosis (thigh, breast, buttocks), purple toe syndrome

■
■
■
■
■
■
■
■
■
■
Symptom relievers: inhaled short/long acting B2 agonists (SABA/LABA) & anticholinergics
Symptom preventers: inhaled corticosteroids (ICS), Leukotriene receptor antagonists
(LTRA), sodium cromoglycate & nedocromil (inhaled nonsteroidal agents)
For ICS to be effective, they would have to be used regularly and not PRN.
Usual combo therapy: ICS daily + SABA for exacerbations OR ICS daily + LABA bid ±
SABA for exacerbations
LABA’s are usually added to ICS’s  adding a LABA to ICS may be preferred in some patients over increasing dose of ICS
ICS: beclomethasone, triamcinolone, budesonide, fluticasone, flunisolide, ciclesonide.
Use regularly. Not for rescue therapy.
SABA: salbutamol, terbutaline. For rescue therapy.
LABA: salmeterol, formoterol. Used QD-BID regularly. Formoterol, however, could be used for rescue. Not for monotherapy; for use with ICS.
Anticholinergics: ipratropium (bid to qid), tiotropium (qd). Mostly reserved for COPD.
May cause dry mouth, urinary retention, increased IOP, pharyngeal irritation
SABA/LABA may cause tachycardia, palpitations, nervousness, tremor, hypokalemia
(at high doses)

Mast
Cells
Θ
Θ
IL-5 Eosinophils
Θ
Leukotrienes
Θ
Cromolyn, nedocromil, ketotifen corticosteroids
LTRA’s block
LT receptors in airway a)
LTRA’s: montelukast & zafirlukast. Serve as alternatives or adjuncts to increased ICS or when ICS are not tolerated.
b) Montelukast is preferred over zafirlukast since the latter is bid dosing, has to be on empty stomach, and interacts with other meds such as Eryc, ASA, and warfarin.
c) Mast cell stabilizers need a few weeks to work, have to be used regularly, excellent safety profile.
d)
CS’s inhibit mast cells, MØ’s, T-cells, eosinophils, epithelial cells, as well as gene transcription of the cytokines/interleukins implicated in airway inflammation

a)
b)
c)
d)
e)

■ 5-alpha reductase inhibitors (finasteride, dutasteride) reduce prostate size by inhibiting conversion of testosterone to dehydrotestosterone (DHT)  take weeks and months to show full benefit
■ Alpha blockers (tamsulosin, alfuzosin, doxazosin, terazosin) reduce smooth muscle tone by antagonizing binding of norepinephrine and epinephrine to alpha-1 receptors  relatively fast in controlling BPH symptoms
■ Terazosin & doxazosin: titrate dose up to avoid hypotension and dizziness
■ Testosterone, OTC decongestants (pseudoephedrine, phenylephrine), and anticholinergic drugs (TCA’s, 1 st generation antihistamines such as diphenhydramine) worsen BPH symptoms

If sildenafil (Viagra) is metabolized by CYP3A4, which of the following would reduce its metabolism?
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■

Erectile dysfunction and premature ejaculation
■
■
ED:
– Phosphodiesterase 5 inhibitors:
● cGMP in smooth muscle cells is broken down by PDE5
●
●
●
●
● cGMP is required to achieve tumescence
PDE5 inhibitors (sildenafil, vardenafil, tadalafil) suppress the function of PDE5 thus allowing cGMP to do its work
Sexual stimulation is required to achieve erection
PDE5I’s are contraindicated with nitrates due to increased risk of severe hypotension
Onset of action at 15 minutes with V & S and > 30 minutes for T
–
●
●
●
Duration of action up to 12 hours for S & V and 36 hours for T
Reduce dose of PDE5I’s if also using CYP3A4 inhibitors
High fat meal may delay and reduce efficacy of S & V
●
Available for episodic dosing or as lower daily dosing
PGE1 analogues:
●
●
●
●
Alprostadil injection or urethral pellets
Activates adenylate cyclase to produce cAMP from ATP which leads to smooth muscle relaxation and vasodilation
Rapid onset of action for <1 hour
Priapism is a problem with this agent
Premature ejaculation: daily regular use of SSRI’s (e.g., paroxetine)

■
■
Cholinergic hypothesis: ACh is one of the main neurotransmitters in the brain that serves to increase attention and facilitate learning
Pharmacological treatment: available agents are only mildly effective (if at all)
− Acetylcholinesterase inhibitors (AChEI):
●
●
●
Donepezil, galantamine, rivastigmine
Used in mild-moderate severity
● all should be titrated upwards slowly
Decrease HR (caution with BB’s), N/V, diarrhea, anorexia, urinary incontinence, insomnia (therefore dose in AM)
●
●
Donepezil and galantamine are metabolized by CYP3A4
Increase dose monthly if needed
− NMDA receptor antagonists:
● Memantine. May be combined with AChEI’s.
●
●
●
Used in moderate-severe disease
Start at 5 mg QD and every 1-2 weeks to maximum of 10 mg BID
Causes insomnia, dizziness, drowsiness, headaches, nausea, ↑ BP

Rough relationship between parkinson’s disease, schizophrenia & antipsychotics
Normal
Parkinson’s
Schizophrenia
EPS & pseudoparkinsonism: too much antipsychotic
ACh DA ACh DA ACh DA ACh DA ACh DA
• reduce activity of dopamine: antipsychotics
• reduce activity of
ACh: anticholinergics
• raise activity of DA by reducing dose of antipsychotic
• raise activity of dopamine: levodopa, dopamine agonists or
• reduce activity of ACh: anticholinergics
Symptoms worsen with:
• antipsychotics
• AChE inhibitors (used in treatment of dementia)
• Anticholinergics: benztropine, procyclidine, trihexyphenidyl, diphenhydramine
• dopamine agonists: bromocriptine, cabergoline, pramipexole, ropinirole

■ Proton pump inhibitors
– Omeprazole, esomeprazole, rabeprazole, pantoprazole sodium, pantoprazole magnesium, lansoprazole
–
–
All agents are equally effective
Must be:
1.
2.
Absorbed in tact without exposure to acid enter the acid-producing parietal cells
–
–
–
3.
4.
get protonated undergo intramolecular rearrangement (activation)
5.
form a disulfide bond with proton pump causing permanent pump inactivation
Proton pumps must be active for the PPI’s to work effectively and therefore it is generally advised to time the dose about ½ hour before breakfast
Available formulations are not very effective for nocturnal heartburn to prevent exposure to the stomach acid (and premature activation of the drug) upon swallowing, tablets are enteric coated  tablets must not be split or crushed

■
■
Omeprazole inhibits p-glycoprotein and CYP2C19 and therefore has important drug interactions (increased levels of diazepam, digoxin, phenytoin, some statins, tegretol, triazolam, warfarin)
All PPI’s decrease absorption of acid-requiring drugs such as ketoconazole, itraconazole, calcium carbonate, iron, vitamin B12, protease inhibitors and thyroxine
■ Linked to:
–
–
Worsening osteoporosis
Raised risk of pneumonia
–
–
Raised risk of developing C. difficile infection
–
–
Reduced activation of clopidogrel (controversial and if interaction exists it probably isn’t clinically significant)
Rebound hyperacidity when stopped
Reduced blood magnesium levels

■
■
Drugs used for dyspepsia, GERD or peptic ulcer disease continued …
H2-receptor antagonists:
–
–
Ranitidine, famotidine, cimetidine, nizatidine
Weaker than the PPI’s in reducing stomach acidity
– Suffer from tachyphylaxis
– Space by about 1 hour from antacids
– Cimetidine inhibits CYP2C19 and 2D6 and therefore effects levels of warfarin, phenytoin, etc…
Prokinetics
– Domperidone & metoclopramide are dopamine antagonists
– When dopaminergic system is inhibited in the GI tract, it leaves the cholinergic system unopposed
– Side effects include diarrhea
– Metoclopramide enters CNS and causes extrapyramidal side effects and pseudoparkinsonism  domperidone is preferred because it does not penetrate the CNS
– Sometimes used off-label to increase lactation in breastfeeding women
– Also used as antiemetics due to their antidopaminergic activity
– Most useful for gastroparesis

■
■
Prostaglandin analogues
– Misoprostol is a prostaglandin E1 analogue
– It leads to increased mucous production/mucosal blood flow and is used to prevent development of NSAID-induced peptic ulcers
– Side effects include diarrhea, abdominal pain, nausea, headache, dyspepsia, flatulence
– Contraindicated in pregnancy due to its ability to induce uterine contractions
–
–
–
–
Sucralfate
–
–
Complex of aluminum hydroxide and sulfated sucrose
Forms complex gels w/mucus → physical barrier that impairs diffusion of
HCl and prevents peptic mucus degradation
– Requires acidic pH for activation, therefore should not be used with antacids, PPI’s or H2RA’s taken on an empty stomach
Minimal absorption from GI tract
Used for treatment of duodenal ulcers may decrease the effect of warfarin, digoxin, phenytoin, ketoconazole, quinidine, ciprofloxacin, ofloxacin, and norfloxacin

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Neurotransmitters involved in the process of nausea and vomiting include:
– Acetylcholine and histamine: important in motion sickness, morning sickness
–
–
Serotonin: important in CINV, post-operative N/V
Dopamine: important in CINV, post-operative N/V, opioid-induced N/V
Anticholinergics/antihistamines
– Most useful for motion sickness and morning sickness
–
–
–
–
Diphenhydramine, dimenhydrinate, scopolamine, promethazine, doxylamine
Doxylamine is labelled for N/V in pregnancy
Dimenhydrinate is diphenhydramine covalently linked to chlorotheophylline
All cause anticholinergic side effects  blurry vision, dry mouth, constipation, urinary retention, sleepiness, dizziness  caution when using them in elderly patients
Dopamine antagonists
– Not effective for motion sickness
–
–
–
–
Chlorpromazine, prochloperazine, metoclopramide, domperidone, haloperidol
May cause CNS side effects due to their antidopaminergic action (domperidone is an exception)
Useful as adjuncts in CINV or as standalone agents for minimally emetogenic regimens
Also useful for opioid-induced N/V and N/V due to GI dysmotility
Serotonin antagonists
–
–
Ondansetron, dolasetron, granisetron
Mostly reserved for acute CINV
–
–
Not effective enough for opioid-induced N/V
Side effects are minimal but may include constipation and headaches
Anticholinergics may reduce effectiveness of prokinetics (domperidone and metoclopramide)

Agents used in management of IBD (UC and CD)
■
■
Anti-inflammatories
– 5-AMINOsalicylic acid (5-ASA), aka, mesalamine or mesalazine
●
●
Available for rectal or oral dosing
Site of action varies
♦
Oral Pentasa releases 5-ASA starting at the duodenum
●
●
♦
♦
♦
♦
Oral Salofalk and Asacol release drug at terminal ileum
Oral Sulfasalazine & olsalazine release drug at proximal colon
Enemas could potentially reach the splenic flexure
Suppositories are limited to treating the rectum (10 cm or so)
For best results, may have to use oral AND rectal products
Good option for maintenance therapy (unlike corticosteroids)
Corticosteroids
–
–
–
–
–
–
Available for rectal, oral or parenteral dosing
E.g., prednisone, prednisolone, methylprednisolone, hydrocortisone
Useful for induction of remission
Not indicated for maintenance therapy
Many side effects typically seen with chronic or high-dose corticosteroid use
Budesonide is metabolised during hepatic first-pass metabolism and therefore exerts less systemic side effects compared to prednisone  but not as effective as prednisone

■
■
Purine antimetabolites
–
–
Azathioprine (or its active metabolite 6-mercaptopurine)
Helpful for those patients not responding to steroids or those who cannot be weaned off steroids (moderate-severe disease)
–
–
Side effects include bone marrow suppression, infections, hepatotoxicity, pancreatitis
Toxicity if combined with allopurinol  quarter the dose of AZA/6MP if combining with allopurinol
Biologic response modifiers
–
–
–
–
–
Monoclonal antibodies to TNF-alpha
Infliximab (intravenous), adalimumab (SQ), certolizumab (SQ)
Etanercept (also a TNF-alpha blocker) is ineffective
Used in moderate-severe UC & CD not responsive to standard regimens
Antibodies to these agents could develop  concomitant use AZA/6MP, MTX can ↓ formation of antibodies
– Side effects include hepatitis B and TB reactivation, malignancies, candidiasis, shingles, worsening of heart failure

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No cure and hard to treat
Treat individual symptoms as they arise
Antispasmodics:
– Hyoscine, dicyclomine, peppermint oil, oinaverium, trimebutine  not effective in most
Antidiarrheals:
– Loperamide, diphenoxylate/atropine, cholestyramine
Laxatives:
– Lactulose, senna, bisacodyl, psyllium, polycarbophil calcium, polyehtylene glycol, magnesium compounds, sodium phosphate
Abdominal pain ± diarrhea:
– TCA’s (notriptyline, desipramine are best tolerated)
Abdominal pain ± constipation:
– SSRI’s (fluoxetine, citalopram, paroxetine)

■
■
Bisphosphonates
– Etid-, alen-, risedronate (oral agents)
– Anti-resorptive. Bind to hydroxyapatite, inhibit osteoclasts, which decreases the resorption & turnover of bone, which increases BMD by up to 6%
–
–
–
Limited oral bioavailability (<1%) but half life is many years; should be taken on empty stomach before food/drink/medication (water is ok)
↓ vertebral, nonvertebral & hip fractures in HIGH risk patients
Avoid or carefully monitor patients with CrCl < 30 ml/min
– Depending on the agent, can be dosed daily, weekly, monthly or yearly
– Side effects include dyspepsia, acid regurgitation, abdominal pain, nausea, esophagitis  should not lie down for 30 minutes after oral dose
Selective estrogen receptor modulator (raloxifene), calcitonin, teriparatide, estrogen, denosumab

■
■
Acute attack or when starting allopurinol:
– Colchicine 1.2 mg stat then 0.6 mg 1 hour later, then 1-2 tabs daily thereafter for 1-2 weeks

GI side effects include diarrhea
–
–
NSAIDs: indomethacin, naproxen, ibuprofen, celecoxib x 1-2 weeks
Oral or intra-articular corticosteroids: prednisone, methylprednisolone, triamcinolone
– Do not start, stop or adjust allopurinol during an acute attack
Prophylaxis (3 or more attacks per year, increased uric acid levels):
– Allopurinol: 1
● st line
Xanthine oxidase inhibitor
 decreases uric acid production
●
●
Contraindicated in acute gout
Start at low dose and titrate up slowly
–
●
●
Wait 1-2wks after inflammation settles before initiating allopurinol
●
May need to prophylax with colchicine or an NSAID while adjusting allopurinol’s dose (may take a few months)
Colchicine: 2 nd line
0.6 mg daily

Need for pharmacotherapy
No drug is prescribed
Exists Does not exist
Drug is prescribed
Drug is prescribed
Wrong drug
Dose too low
Dose too high
Side effects or drug allergy or intolerance
Drug-drug interaction or drug-disease interaction
Patient not receiving drug from pharmacy

■ Patients might label side effects or intolerances as “allergies”
■ Always ask patient to describe his or her allergy to confirm
■ True allergies are uncommon particularly with opioids
■ Examples of intolerances or side effects that patients commonly label as “allergies”:
– nausea, constipation or somnolence while on opioids
–
– stomach pain while on NSAIDs pruritus or facial flushing when starting nicotinic acid or when dose increases
– Nausea or diarrhea while on antibiotics

■ Inorganic iron products:
–
–
Ferrous salts
Best absorbed from GI tract when in ferric state  gastric acid (and perhaps ascorbic acid) facilitates conversion to ferric form
–
–
–
Ferrous gluconate : 12% elemental iron (usually 35 mg Fe 2+ per 300 mg tab)
Ferrous sulfate : 20% elemental iron (usually 60 mg Fe 2+ per 300 mg tab)
–
Ferrous fumarate : 33% elemental iron (usually 100 mg Fe 2+ per 300 mg tab)
Some are available as delayed-release formulation  diminished absorption
– Side effects include nausea, stomach pain, constipation
■ Iron complexed with heme or polysaccharides
– In theory supposed to have less GI side effects and more predictable absorption (not affected by stomach acidity, presence of other competing polyvalent cations such as Ca 2+ , Mg 2+ , Zn 2+ , Cu 2+ )
– More expensive than inorganic iron supplements

■
■
■
■
Nasal decongestants:
– Oral: pseudoephedrine  may cause insomnia and may worsen BP and BPH symptoms. Phenylephrine
– does not work.
Intranasal: xylometazoline, oxymetazoline, phenylephrine
 all very effective but tolerance quickly develops. Often cause rebound congestion (especially with phenylephrine) if used for more than 3-5 days
Antihistamines: not very useful for sinus congestion
–
–
1 st
● generation: diphenhydramine, chlorpheniramine
Prominent anticholinergic side effects  sedation, dryness (may exacerbate BPH symptoms), increased HR
2 nd generation: cetirizine, loratadine, desloratadine, fexofenadine  all equally effective. Anticholinergic side effects and sedation are almost absent but more costly and headaches are more frequent compared to 1 st generation.
Dyspepsia and acid reflux:
– Antacids usually containing calcium, magnesium or aluminum salts
 drug interactions (reduce absorption of tetracyclines, fluoroquinolones, bisphosphonates, iron), caution with renal impairment.
–
Al3+ is constipating whereas Mg2+ is a laxative
Avoid sodium bicarbonate  increased risk of metabolic alkalosis
–
–
Alginates: with or without Ca 2+ , Mg 2+ or Al 3+ form a physical barrier at the esophageal sphincter
Histamine2 receptor antagonists (H2RA’s): ranitidine, famotidine (nizatidine and cimetidine still require a prescription)
Dermatitis:
–
–
Hydrocortisone 0.5% is ineffective for most indications. Clobetasone is more useful.
Topical diphenhydramine cream is also ineffective for pruritis and make actually cause sensitization  avoid

■
■
■
Antifungals
–
–
Topical miconazole, clotrimazole, ketoconazole shampoo, tolnaftate
Oral fluconazole  convenient single dose for vulvovaginal candidiasis but as effective as topical products
Analgesics
–
–
–
Naproxen, ASA, ibuprofen
Acetaminophen
Codeine+acetaminophen (available behind the counter and requires pharmacist’s intervention for dispensing)
Antidiarrheals:
– Loperamide
– Bismuth subsalicylate

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Beta-lactams: bind to PBP and inhibit formation of the bacterial cell wall by inhibiting peptidoglycan synthesis
Vancomycin: inhibits bacterial cell wall synthesis at a site different than beta-lactams
FQ’s: inhibit DNA gyrase in G- bacteria, and inhibit topoisomerase IV in G+ bacteria
Macrolides: inhibit protein synthesis by reversibly binding to the 50S ribosomal subunit
Clindamycin: inhibits protein synthesis by binding to the 50S ribosomal subunit (close to where macrolides bind. Note similarity in the name of clindamycin and the macrolides)
Aminoglycosides: inhibit protein synthesis by irreversibly binding to the 30S ribosomal subunit
Tetracyclines: interfere with protein synthesis by inhibiting codon-anticodon interaction on ribosomes
Chloramphenicol: attaches to ribosomes and inhibits the formation of peptide bonds between amino acids
Metronidazole: is a prodrug which needs activation in the bacterial cell via a reductive process carried out by anarobic bacterial ferredoxins. The donated electrons form reactive nitro anions which in turn damage bacterial DNA.
TMP/SMX: inhibit the formation of tetrahydrofolic acid. SMX is a structural analogue of PABA and inhibits the synthesis of dihydrofolate. TMP is a structural analogue of the pteridine portion of dihydrofolate and acts as a competitive inhibitor of dihydrofolate reductase. The combo blocks two consecutive steps in the synthesis of THF which is needed to synthesize nucleic acids.

■
β -lactams:
– Penicillins
●
(1) Pen VK & Pen G: mostly for non β-lactamase producing G+ and oral anaerobes. Pen V is PO while Pen G is by injection only. Commonly used for strep throat and mouth infections. Agents of choice for syphilis even if patient is allergic to penicillins (need to desensitize patient first!). Give Pen
VK on empty stomach.
●
(2) Methicillin & cloxacillin: for what (1) covers + BL’ase producing staphylococcus (MSSA).
Commonly prescribed for skin infections. Oral and parenteral. Give on empty stomach. No dosage adjustment in renal dysfunction. Think of them as anti-staph.
●
(3) Ampicillin & amoxicillin: for what (1) covers + non BL’ase producing “easy to kill” G- bacteria & for
ENTEROCOCCUS. Ampi is PO/IM/IV and causes diarrhea while Amoxi is only PO.
●
(4) Amoxicillin+clavulanate & ampicillin+sulbactam: for what (3) covers + (2) + easy to kill BL’ase producing G- bacteria + B. Fragilis + E. coli. Amoxi/clav frequently causes diarrhea.
●
(5) Piperacillin & ticarcillin: for what (4) covers + Pseudomonas + nonBL’ase “hard to kill” G- (often used in combo with aminoglycosides). Given parenterally only. Adjust dose in renal impairement.
Think of them as mainly anti-pseudomonal.
●
●
(6) Piperacillin+tazobactam & ticarcillin+clavulanate: for what (5) covers + MSSA
Pen G, ticarcillin, and piperacillin contain sodium which should be taken into account when injecting them into patients with HF or renal insufficiency
Easy to kill G- bacteria: nonBL’ase H. Flu, P. mirabilis, salmonella, shigella (L. monocytogenes is not a Gbacteria as was indicated here previously)
Hard to kill G- bacteria: klebsiella, enterobacter, citrobacter, serratia, morganella, pseudomonas

■ Β-lactams continued …
– Cephalosporins: divided into 1 coverage while 3 rd st , 2 nd , and 3 rd generations. 1 st generation has mostly G+ has mostly G- coverage. Non are effective for enterococcus, MRSA, L. monocytogenes. Cross allerginicity with penicillins is up to 10% (less with higher generations).
●
(7) 1 st gen: cephalexin, cefazolin, cefadroxil. Used for (1) + (2) + E. coli, klebsiella. Do not cross BBB. Cefazolin is parenteral only. Cephalexin is PO only
●
(8) 2 nd gen: cefuroxime (parenteral only), cefaclor, cefuroxime axetil, (PO version of cefuroxime), cefprozil. For (7) + H. flu + Neisseria + M. catarrhalis. Give cefuroxime axetil with food while cefaclor on empty stomach
●
●
(9) 3 rd gen: ceftazidime, ceftriaxone, cefotaxime, cefixime (the only PO drug), ceftizoxime.
Retain activity versus strep species but have reduced activity vs. staph species. For (8) +
“hard to kill” G- bacteria + pseudomonas (only ceftazidime). Avoid ceftriaxone in neonates.
All parenteral agents cross the BBB and so helpful in treating meningitis
(10) 4 th gen: cefepime. Active vs pseudomonas. Used to treat UTI’s, skin infections, pneumonia. Not advantageous over 3 rd generation agents such as ceftazidime.
– Carbapenems: imipenem and meropenem. Available parenterally only. Imipenem may cause seizures and N/V. These are less common with meropenem. They cover “everything” including
C. difficile. BL ring is resistant to the BL’ases. Imipenem is renally metabolized to the stable open-lactam metabolite by a dipeptidase, dehydropeptidase I, located at the lumenal surface of the proximal tubular cells. To prevent this, imipenem is combined with cilastin.

■ Fluoroquinolones:
– may cause nausea, diarrhea, photosensitivity, dizziness, agitation, cartilage damage (based on studies of beagle puppies), glucose dysregulation (newer generation)
–
–
–
Newer generation agents are almost 100% absorbed PO
Cipro is about 80% absorbed
Polyvalent cations (Ca, Fe, Al, Mg, Zn, antacids) prevent absorption of FQ’s which requires these drugs to be spaced by a few hours
–
–
–
–
–
–
Divided into 3 generations:
●
●
●
1 st gen: Nalidixic acid (not used anymore)
2 nd gen: nor-, o-, and ciprofloxacin
3 rd gen: levo-, gati-, and moxifloxacin. Gatifloxacin was discontinued Summer 2006. this generation of drugs is commonly referred to as the “respiratory quinolones”
2 nd gen agents cover G- bacteria mainly.
Cipro is the only FQ with reliable activity against pseudomonas. It could also be used against
MSSA. Cipro does not cover strep species well.
Norfloxacin is pretty much only used to treat uncomplicated UTI’s
3 rd gen agents were designed to cover more G+ bacteria than 2 nd gen. They are very broad spectrum (including B. fragilis and atypical microorganisms) but do not cover pseudomonas reliably.
FQ’s are currently not recommended to be given to pregnant women or to patients under 18 y.o.

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Only available for parenteral administration (tobramycin is available for inhalation to treat chronic pseudomonas infections in cystic fibrosis patients; brand name is called TOBI)
Gentamicin, amikacin, tobramycin
All have very narrow therapeutic window (must monitor levels and SCr)
Toxicity: reversible nephrotoxicity (less with qd dosing), irreversible ototoxicity, rare but potentially fatal neuromuscular blockade (interfere with ACh release and binding leading to weakness of respiratory muscles which can be reversed by administering calcium gluconate)
Since all are renally cleared, dose must be adjusted in renal impairment
Active against G- bacteria including pseudomonas
Frequently used with other ABX (especially anti-pseudomonal penicillins)

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■
■
Erythromycin (E), clarithromycin (C), azithromycin (A)
E and C inhibit CYP450 enzymes while A does not. All are hepatically metabolized and cleared. Non are removed during hemodialysis.
E and C stimulate GI motility causing diarrhea, cramps, and nausea
All are PO but E and A are also parenteral
All are poorly absorbed. E should be taken on an empty stomach but because it causes
GI side effects, it is recommended to be taken with food
All may cause QT prolongation
They cover common G+ (including MSSA), common G- bacteria (A>C>E), mycoplasma, chlamydia, legionella, treponema pallidum. They are very helpful for respiratory tract infections. E is an important antibiotic to use in those allergic to penicillin.
A and C are active against mycobacterium avium-intracellulaire (MAC)
E is dosed qid, C is dosed bid or qd, A is dosed qd
A is not officially labeled as safe in pregnancy but it is often used in pregnancy without reported adverse effects

■
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■
■
■
Minocycline, doxycycline, tetracycline
All cause photosensitivities. Because they are often used in young people to treat their acne, these patients should be warned against sun tanning
Because they depress bone growth and cause permanent grey-brown discoloration of teeth, they should not be given to children < 8 y.o.
Esophageal ulceration has been reported with doxycycline (should be taken with lots of fluids)
Minocycline has been reported to cause dizziness, ataxia, and vertigo
All should be administered on an empty stomach and patients should avoid concomitant ingestion of metal cations found in milk, multivitamins, antacids
Doxy and minocycline are dosed bid. Tetracycline is dosed bid to qid
Active against many respiratory pathogens, strep pneumo, H. flu, mycoplasma, chlamydia, legionella, moraxella catarrhalis

■
■
■ Metronidazole causes a disulfiram-like reaction when taken with alcohol (N/V, abdominal cramps, hypotension, headache), metallic taste, stool and/or urine discoloration, peripheral neuropathy, seizures
■
Clindamycin causes diarrhea (sometimes due to C. difficile)
Clindamycin is active against G+ bacteria (BL’ase producing staph, strep) and anarobes (B. fragilis and C. perfringens)
Active against anarobes (B. fragilis, C. difficile). Agent used to combat C. difficile infection caused by clindamycin. Also active against trichomonas, giardia lamblia, and entamoba histolytica.

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Can cause skin reactions (rashes, Stevens-Johnson syndrome), N/V, diarrhea, hepatic necrosis, hemolytic anemia in those with G6PD deficiency, bone marrow depression
Advise patient to drink lots of fluids to prevent crystallization in kidneys
Active against G+ (including MRSA!!), and G- bacteria (salmonella, shigella, H. flu)

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Available for parenteral administration only
Rapid infusion causes flushing of face, neck and upper thorax, pruritis and hypotension (similar to side effects of nicotinic acid). This is known as the
“red man” syndrome and is not an allergic reaction
High serum levels (> 80 ug/ml) may cause ototoxicity leading to deafness
May potentiate aminoglycoside nephrotoxicity
Given PO to treat C. difficile pseudomembranous colitis or staph enterocolitis
Adjust dosage in renal dysfunction (trough levels should be 5-10 ug/ml)
Not removed by dialysis
Active against G+ bacteria mainly staph (MSSA, MRSA, and staph epidermidis), strep, C. difficile

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Opioid naïve patient:
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10 to 20 mg morphine q4h
1/3 to ½ dose for breakthrough pain q1h
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Eg: 10 mg morphine q4h, 5 mg q1h prn
Elderly should get half the doses
Previously on opioids or poorly controlled:
– Increase dose by 25 to 50% q4h
– Eg: 10 mg * 1.5 = 15 mg q4h, 7.5 mg q1h prn
Converting from injection to oral:
– Divide total 24-hour dose by 3 and dose q4h
– Eg: morphine 30 mg SC q4h
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Total daily injected dose = 30 * 6 = 180 mg
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The q4h dose = 180/3 = 60 mg
The q1h dose for BT pain = 60/2 = 30 mg
Reassess pain control every 24 hours and make adjustments until patient is stable
When you find the stable dose as outlined above, the patient could be switched from IR to “Contin” or SR preparation for convenience:
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Divide total daily dose of the IR by 2 for q12h dosing
Divide total daily dose of the IR by 3 for q8h dosing
Give 1/5 of the q12h dose for BT pain q4h
Eg: patient is stable on 120 mg/day of IR preparation. The q12h dose of MS Contin would be
120/2 = 60 mg PLUS 10 mg of the IR q4h prn

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Before prescribing opioids, consider using:
– Non-pharmacological pain therapy
– Non-opioid analgesics such as NSAIDs, acetaminophen and antidepressants or antiepileptics for neuropathic pain
If patient requires opioids:
– Prescribe small amounts
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Tell patient what you expect from him/her
Be alert for scripts not lasting expected duration or if pharmacist contacts you for an early fill of a part-fill
– Be alert when patient reports stolen pills or lost scripts (you can ask patient for a police report)
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Use prescription pads with security features
Spell out the amount of pills to dispense when writing a Rx because patients could alter digits more easily than written words. Eg: 60 (Sixty) tablets instead of 60 tablets
Be alert for evidence of drug injections
– Be alert for requests of other opioids by patient
– Patient has to inform prescriber by law that he/she received a prescription for an opioid from another prescriber within the last month: most patients do not know this and therefore may require reminding
– Be alert if patient is young and without identifiable pathology or if psychologically unstable
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Try not to be pressured by patient to prescribe an opioid you do not agree with
Include intervals on part-fills to limit how often a patient fills the Rx
– Consult with the pharmacist and ask if he/she can provide a good reference for the patient or if he/she can vouch for the patient
– Pharmacists are required by their licensing body to verify the legitimacy of questionable prescriptions with the prescriber; most diverters will attempt to prevent the pharmacist from doing that and may voice their “concern” to you during the next visit
– Inform patient of his/her own responsibilities when entrusted with drugs that have a huge potential street value