Back-to-BasicsBack-to-Basics

Practical PharmacologyPractical Pharmacology

Marc Riachi, R.Ph.Marc Riachi, R.Ph.March 21, 2011 (3:00-5:00)March 21, 2011 (3:00-5:00)

March 28 and April 4, 2011 (2:30-5:00)March 28 and April 4, 2011 (2:30-5:00)

Amph DAmph D

University of OttawaUniversity of Ottawa

Topics to be covered in this lectureTopics to be covered in this lecture■ Antiplatelets and anticoagulants

■ Antiasthmatics

■ BPH

■ Erectile dysfunction

■ Dementia

■ Parkinson’s disease and schizophrenia

■ Dyspepsia, GERD and PUD

■ Antiemetics

■ IBD

■ IBS

■ Osteoporosis

■ Gout

■ OTC drugs

■ Appendix I & II

■ Antibacterials

■ Antimycobacterials

■ Antifungals

■ Narcotic analgesics

■ Autonomic nervous system

■ Anti seizure drugs

■ Migraines

■ Antidepressants

■ Antianxiety agents

■ Agents for insomnia

■ Antidiabetics

■ Antilipemics

■ Antihypertensives

■ Diuretics

■ Nitrates

Antibacterial families and their members■ 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.

Antibacterials-Site of actionAntibacterials-Site of action

Bactericidal vs. bacteriostaticBactericidal vs. bacteriostatic

Bactericidal ABX

■ Aminoglycosides

■ Fluoroquinolones

■ Penicillins

■ Cephalosporins

■ Nitrofurantoin

■ metronidazole

■ SMX+TMP

Bacteriostatic ABX

■ Tetracyclines

■ Macrolides

■ SMX

■ TMP

■ clindamycin

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.

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.

Pen V/G: coversG+ (strep), oral anarobes, T. Pallidum

(Lacks efficacy vs BL’ase,B. fragilis, G-, atypicals)

Cloxacillin AmpicillinAmoxicillin

Amoxicillin + ClavulanateAmpi + sulbactam

Piperacillin, ticarcillin

Piperacillin/tazobactamticarcillin/clavulanate

Develop agent vs Enterococcus and “easy to kill” G- (no resistance to BL’ase)

Add resistance to BL’ase, cover MSSA and B. fragilis

Add resistance to BL’ase

Develop agent vs BL’ase producing staph (MSSA)

Cover “hard to kill” G-

Penicillins

Easy to kill G- bacteria: non-BL’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)

1st gen CephsEg: cephalexin,

cefazolin

Develop agent vs BL’ase producing staph (MSSA) and “easy to kill” non-BL’ase G-

2nd gen CephsEg: cefuroxime,

cefaclor

Add resistance to “easy to kill” BL’ase G- & B. Frag, loss of some G+ coverage

3rd gen CephsEg: cefotaxime,

ceftriaxone, cefixime, ceftazidime

Add activity vs “hard to kill” G-, reduce staph coverage, retain strep coverage, loss of B. Frag coverage

3rd/4th gen CephsEg: Ceftazidime,

Cefepime

Add activity vs pseudomonas

Cefoxitin

Add activity vs B. Fragilis, and “easy to kill” G-

None are effective against enterococcus, L. monocytogenes, MRSA

Cephalosporins Pen V/G: coversG+ (strep), oral anarobes, T. Pallidum

(Lacks efficacy vs BL’ase,B. fragilis, G-, atypicals)

AminoglycosidesEg: gentamicin,

amikacin,tobramycin

Develop agent vs G- (including pseudomonas)

2nd genFluoroquinolonesEg: ciprofloxacin,

ofloxacin

Add activity to BL’ase producing G+

3rd gen FQ’sEg: levofloxacin

Add coverage to atypicals and expand G+ coverage; retain some pseudomonal coverage

4th gen FQ’sEg: moxifloxacin

Add activity vs anarobes (B. fragilis)

Don’t cover strep well. Ofloxacin does not cover strep or pseudomonas well

Fluoroquinolones & Aminoglycosides

Pen V/G: coversG+ (strep), oral anarobes, T. Pallidum

(Lacks efficacy vs BL’ase,B. fragilis, G-, atypicals)

Macrolides,Tetracyclines,

TMP/SMX

Develop agents Vs common G+, common G-, atypicals, unusual or non-bacterial organisms

TMP/SMX does not cover atypicals but it covers community acquired MRSA

Macrolides,

Tetracyclines

TMP/SMX

Pen V/G: coversG+ (strep), oral anarobes, T. Pallidum

(Lacks efficacy vs BL’ase,B. fragilis, G-, atypicals)

Metronidazole

Develop agent Vs B. fragilis and other anaerobes

Vancomycin

Develop agent vs Staph Epidermidis and MRSA

Note:

Use PO vancomycin or PO/IV metronidazole to treat C. difficile infections

Vancomycin, metronidazole, clindamycin

Clindamycin

Add coverage for MSSA and community acquired MRSA

Pen V/G: coversG+ (strep), oral anarobes, T. Pallidum

(Lacks efficacy vs BL’ase,B. fragilis, G-, atypicals)

Commonly prescribed ABX in the community settingCommonly prescribed ABX in the community setting

■ Oral infections: penicillin, clindamycin, erythromycin, amoxicillin, cephalexin

■ UTI: ciprofloxacin, SMX/TMP, nitrofurantoin

■ RTI’s, sinusitis: clarithromycin, azithromycin, 2nd or 3rd 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, 2nd gen Cephs

■ Patients with penicillin allergy: clindamycin or erythromycin (choice depends on indication) are useful

■ Intraabdominal infections: ciprofloxacin, metronidazole, 3rd gen Cephs

■ C. difficile diarrhea: metronidazole, vancomycin

■ MRSA-CA: high dose SMX+TMP, doxycycline, clindamycin

Antibiotics contraindicated in pregnancy Antibiotics contraindicated in pregnancy (category X)(category X)■ 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

ABX generally regarded as safer options in ABX generally regarded as safer options in pregnancypregnancy

■ 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)

ABX and warfarinABX and warfarin

■ All antibiotics have the theoretical potential to increase INR

■ Penicillins, cephalosporins, azithromycin, aminoglycosides, clindamycin, nitrofurantoin and vancomycin generally do not necessitate INR monitoring

Anti-TB agentsAnti-TB agents

■ Organism has "waxy" hard to penetrate cell wall

■ Slow growing (requires extended treatment period)

■ Combinations of drugs needed to treat

■ Available agents have unpleasant side effects leading to reduced compliance by patient contributes to the emergence of resistant strains

Available antimycobacterialsAvailable antimycobacterials

■ 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

Which agents to use in active disease?Which agents to use in active disease?

■ 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 2nd line agents

Drug infoDrug info■ INH (inhibits formation of fatty acids found in the cell wall):

– Bactericidal; penetrates cavitations

– Hepatotoxicity (↑ with alcohol & rifampin) monitor LFTs

– peripheral neuropathy (give B6 to help)

– GI symptoms, skin rash

– ↑ phenytoin, carbamazepine & benzodiazepine blood levels

■ RIF (inhibits RNA synthesis):

– 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):

– 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):– Bacteriostatic– GI symptoms, hyperuricemia– Ocular toxicity and change in color

perception monitor at high doses

AntifungalsAntifungals■ 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

Which agents to use?Which agents to use?

■ 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).

■ 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.

Drug infoDrug info■ Terbinafine po:

– Very active vs dermatophytes– headache, GI diarrhea, dyspepsia, abdominal pain– taste disturbance (may persist post treatment)– CYP2D6 inhibitor:

● 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.

Narcotic analgesicsNarcotic analgesics

■ 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

Classes of opioidsClasses of opioids

■ 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:

– 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

General notesGeneral notes■ 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)

Examples of prescription opioidsExamples of prescription opioids■ Codeine:

– converted to the active metabolite morphine by CYP2D6– 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

Examples cont…Examples cont…■ Fentanyl: many street names including “China White”, “Apache”, “Dance fever”

– Patch: worn continuously for 72 hours. In some patients for 48 hours.– Should not be prescribed to narcotic-naïve patients– Rate of drug reaching the circulation is directly proportional to body temperature

● 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– Dosed Q4-8H for pain control– Dosed QD for management of opioid dependence– Physician has to apply for and be granted permission to prescribe methadone from the federal office of

controlled substances● 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

● 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

Examples cont…Examples cont…■ 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: – 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

Other uses of opioidsOther uses of opioids

■ Diarrhea– Lomotil (diphenoxylate + atropine)

■ Cough suppression– Codeine

● At least 15 mg per dose required● Syrup is 5 mg/mL

– Hydrocodone

■ Opioid dependence– Methadone– Sublingual Suboxone (Buprenorphine + naloxone)

● naloxone is an opioid antagonist but is not absorbed orally; purpose is to deter patient from injecting Suboxone

Management of opioid side effectsManagement of opioid side effects■ Constipation

– Tolerance does not develop with repeated doses of opioid– Stimulant laxatives:

● 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

Management of opioid side effects cont…Management of opioid side effects cont…

■ 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

Management of opioid side effects cont…Management of opioid side effects cont…

■ 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 – Respiratory depression is due to decreased responsiveness of

respiratory center in brain stem to increases of Pco2

– Death from opioid poisoning is usually due to respiratory arrest– Serious respiratory depression is managed by naloxone

injections– From the LMCC exam objectives:

● "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)."

Opioid prescriptionsOpioid prescriptions

■ 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)

Autonomic nervous system pharmacology

ACh

Examples of useful cholinergic agonists & antagonists

■ Muscarinic agonists:– Direct: pilocarpine (glaucoma management; constricts pupil

allowing aqueous humor to leave eye), bethanechol (contracts urinary bladder)

– Indirect (AChEIs): pyrido- and 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 long-term exposure

NE, E and dopamine

Carbidopa -

Breakdown of NE and E

Entacapone, tolcapone

-Selegiline (MAO type B inhibitor)

-

Examples of useful adrenergic agonists Examples of useful adrenergic agonists and antagonistsand antagonists■ 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…

Anti-seizure drugsAnti-seizure drugs

■ 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

TreatmentTreatment

■ 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

■ Choose AED based on:

1. seizure type or epilepsy syndrome

2. side effect profile of AED, other medical conditions, concurrent drugs, drug interactions, cost

■ Strive for monotherapy

TreatmentTreatment

Titrate first-line drug for seizure type

Check compliance, reconsider diagnosis, etiology

ineffective

Initiate and titrate another 1st-line agent and taper off ineffective agent

Try combination of 1st-line agents.

ineffective

Replace the drug with least benefit/most side effects a 2nd-line agent

ineffective

ineffective

Summary:

A, A, A+A, A+B

Mechanism of action

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

Mechanism of action

Some anti-seizure drugs reduce the flow of Ca2+ through T-type Ca2+ channels thus reducing the pacemaker current seen in generalized absence seizures.

Mechanism of action

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.

Practical info■ 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

Practical info■ 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

Which AEDs to use

■ 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

Migraine■ 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● 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● Decrease dose or avoid in hepatic impairement● 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

Migraine continued …Migraine continued …

■ 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)

– Calcium channel blockers (verapamil)

– TCA’s (amitriptyline, nortriptyline)

– Anticonvulsants (valproic acid, gabapentin, topiramate)

– if single agent ineffective, may try a combination (eg beta blocker + TCA)

– discontinue gradually to prevent rebound

AntidepressantsAntidepressants

■ Classified as:– TCA’s: include amitriptyline, desipramine, imipramine,

nortriptyline desipramine and nortriptyline are most tolerated

– SSRI’s: citalopram, escitalopram, fluoxetine, paroxetine, fluvoxamine, sertraline

– NDRI’s: bupropion– SNRI’s: venlafaxine, desvenlafaxine, duloxetine– Misc: trazodone, mirtazapine– MAOI’s:

● Irreversible: phenelzine, tranylcypromine● Reversible: moclobemide

■ TCA=tricyclic antidepressant

■ NDRI=Norepinephrine and dopamine reuptake inhibitor

■ SNRI=serotonin and NE reuptake inhibitor

How to decide which agent to use?How to decide which agent to use?■ 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 at once could be lethal

(avoid in patients with suicidal ideation)– Use a sedating agent if patient also has insomnia (trazodone or

mirtazapine)– 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 over-

sleeping), 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

DosageDosage

■ Start low and increase dosage slowly until optimal therapeutic dose is reached

■ Use lower doses in elderly and hepatic dysfunction

When do you see a response?When do you see a response?■ 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).

Switching between agentsSwitching between agents

■ 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)

Side EffectsSide Effects

■ 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.

Side effects continued …Side effects continued …

■ Venlafaxine (Effexor): – Doses < 150 mg: behaves like an SSRI (N/V)– Doses > 150 mg: additional 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

Side effects continued …Side effects continued …

■ 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 but not more effective for major depression

More SNRI’sMore SNRI’s

Final wordsFinal words

■ SSRI’s, bupropion, venlafaxine are usually used as first line agents

■ Fluoxetine’s half life is 1-3 days after acute administration up to 7 days after chronic administration

■ Paroxetine is used off-label as an agent to delay premature ejaculation

Medications for anxietyMedications for anxiety

■ 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

BenzodiazepinesBenzodiazepines■ 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

■ Lorazepam, oxazepam and temazepam (LOT) do not undergo hepatic microsomal oxidation and therefore are best options for elderly patients

■ Any BZ can cause falls

■ Avoid BZ in dementia

Medications for insomniaMedications for insomnia

■ 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

Insomnia continued …Insomnia continued …

■ Zopiclone has a short half life and causes bitter or metallic after-taste

■ 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.

Oral hypoglycemics-site of actionOral hypoglycemics-site of action

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

Oral antidiabetic agentsOral antidiabetic agentsAgent MOA Avoid Side Effects Notes

Sulfonylureas:

glyburidegliclazideglimepiride

stimulate insulin secretion

Severe hepatic /renal dysfxn

- hypoglycemia (esp glyburide) if elderly, poor meal schedules, - weight gain (esp glyburide)- nausea, anorexia

- take 30 min before a meal- Alcohol ↑ risk of hypoglycemia- β-blockers – mask hypoglycemia cardiac Sx’s

Biguanides:metformin

- Inhibits gluconeogenesis-↑ insulin sensitivity

- Severe renal impairment- liver impaired- heart failure (emerging data suggests safe in HF)

- GI discomfort- weight loss (mild)- lactic acidosis (rare) stop it before using iodinated contrast media- B12 deficiency

- does not cause hypoglycemia- has ↓ lipid effect

α-glucosidase Inhibitors:acarbose

delays CHO absorption from GI tract

- severe renal dysfunction/ liver cirrhosis- IBD

- GI discomfort- ↑ LFT’s – dose related (rare)

- does not cause hypoglycemia by itself - ↓ digoxin levels

Thiazolidinediones:PioglitazoneRosiglitazone

- PPAR-γ receptor agonist- ↑ insulin sensitivity

- caution in HF- Use with insulin may precipitate HF- Class 3,4 HF

- weight gain- edema-Anemia-↓ triglycerides

- 3 week onset, peak 8-12 weeks-with or w/o food-Should not cause hypoglycemia if used alone-Monitor LFT’s

Meglitinides:RepaglinideNateglinide

Stimulate insulin production like sulfonylureas

-hepatic dysfunction

- weight gain- Hypoglycemia less than SU’s

-take immed. before meals. Skip dose if meal is missed.

Relative duration of action of the various Relative duration of action of the various insulinsinsulins

InsulinsInsulins 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 ***

Dipeptidyl peptidase-4 inhibitors and GLP1 Dipeptidyl peptidase-4 inhibitors and GLP1 agonistsagonists■ 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

Mechanism of action of “gliptins”Mechanism of action of “gliptins”

Food ingestion

GLP1 and GIP from GI cells

Increased insulin and reduced glucagon secretion from pancreas

Inactive incretins

DPP4

Reduced hepatic glucose production and increased glucose uptake by adipose tissue and skeletal muscles

sitagliptin -

Liraglutide

+

SitagliptinSitagliptin

■ 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

Liraglutide

■ GLP-1 agonist

■ Reduces HbA1c by about 1%

■ Must be injected

■ Modest reduction in body weight

■ Nausea, vomiting, pancreatitis

Antilipemic agentsAntilipemic agents

■ 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)

Cholesterol biosynthesis pathwayCholesterol biosynthesis pathway

StatinsStatins

■ 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

ezetimibeezetimibe

■ 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)

ResinsResins■ 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

FibratesFibrates

■ 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

Niacin (nicotinic acid but NOT niacinamide)Niacin (nicotinic acid but NOT niacinamide)

■ 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

Niacin continued …Niacin continued …

■ 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.

Effect of niacin on lipoproteinsEffect of niacin on lipoproteins

0 1 g/d 2 g/d 3 g/d

Baseline

-15%

12.5%

25%

-30%

HDL-C with NiaspanHDL-C with Niaspan®®

TG with NiaspanTG with Niaspan®®

TG with crystalline niacinTG with crystalline niacin

LDL-C with NiaspanLDL-C with Niaspan®®

LDL-C with crystalline niacinLDL-C with crystalline niacin

35%HDL-C with crystalline niacinHDL-C with crystalline niacin

Fish oilsFish oils

■ 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)

AB/CD of hypertensionAB/CD of hypertension

■ 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

Renin-Angiotensin-Aldosterone systemRenin-Angiotensin-Aldosterone system

ACEI’s and ARB’s (angiotensin receptor ACEI’s and ARB’s (angiotensin receptor blockers)blockers)■ 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.

ACEI’s and ARB’s continued …ACEI’s and ARB’s continued …

ACEI Θ

ΘARB

Θ

Direct Renin Inhibitor

(aliskiren)

Θ

ACEI’s and ARB’s continued …ACEI’s and ARB’s continued …

■ 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.

Direct renin inhibitors (new class of Direct renin inhibitors (new class of antihypertensives)antihypertensives)

■ 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

Beta receptorsBeta receptors

ΒΒeta-blockerseta-blockers■ 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

Beta-blockers continued …Beta-blockers continued …

■ 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

Calcium ChannelsCalcium Channels

Calcium channel blockersCalcium channel blockers

■ 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”.

■ Non-DHP’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.

Regarding side effects, which of the Regarding side effects, which of the following is true?following is true?

a) TCA’s cause constipation, dry mouth, sedation

b) SSRI’s cause constipation, enhanced sexual function

c) Trazodone cause insomnia

d) Mirtazapine cause weight loss

Which of the following antidepressant drug combos Which of the following antidepressant drug combos makes the most pharmacological sense when makes the most pharmacological sense when prescribed to a patient?prescribed to a patient?

a) Sertraline + fluoxetine

b) Venlafaxine + duloxetine

c) Moclobemide + nortriptyline

d) Citalopram + venlafaxine

e) Bupropion + escitalopram

Which of the following monotherapies is most Which of the following monotherapies is most likely to cause hypoglycemia?likely to cause hypoglycemia?

a) Metformin (a biguanide)

b) Glyburide (a sulfonylurea)

c) Acarbose (alpha glucosidase inhibitor)

d) Sitagliptin (DPP4 inhibitor)

e) Pioglitazone (a Thiazolidinedione)

Which of the following is classified as a monoamine Which of the following is classified as a monoamine oxidase inhibitor?oxidase inhibitor?

a) Moclobemide

b) Bupropion

c) Trazodone

d) Duloxetine

Which of the following agents could be used to Which of the following agents could be used to control gestational diabetes?control gestational diabetes?

a) Insulin injections (e.g., NPH, aspart, lispro)

b) Metformin

c) Glyburide

d) All of the above

Which of the following raises HDL the Which of the following raises HDL the most?most?

a) Ezetimibe

b) Fenofibrate

c) Pravastatin

d) Nicotinic acid

e) Cholestyramine

Which of the following statins is not significantly Which of the following statins is not significantly metabolized by the CYP3A4 system?metabolized by the CYP3A4 system?

a) Atorvastatin

b) Rosuvastatin

c) Simvastatin

d) Lovastatin

e) Cilastatin

Which of the following might raise Which of the following might raise blood potassium?blood potassium?

a) Hydrochlorothiazide

b) Ramipril

c) Spironolactone

d) Amlodipine

e) (b) and (c)

Which of the following beta blockers may worsen Which of the following beta blockers may worsen asthma control the most even in low-moderate asthma control the most even in low-moderate doses?doses?

a) Metoprolol

b) Bisoprolol

c) Propranolol

d) Acebutolol

Which of the following may cause reflex Which of the following may cause reflex tachycardia?tachycardia?

a) Amlodipine

b) Verapamil

c) Diltiazem

d) Felodipine

e) (a) and (d)

Which of the following should not be used to control Which of the following should not be used to control hypertension in HF patients?hypertension in HF patients?

a) Carvedilol

b) Ramipril

c) Verapamil

d) Amlodipine

e) Candesartan

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

a) Hydrochlorothiazide

b) Chlorthalidone

c) Furosemide

d) Metolazone

e) (a) and (b)

Site of action of diureticsSite of action of diuretics

Loop diureticsLoop diuretics■ 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

Thiazide diureticsThiazide diuretics■ 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

KK++-sparing diuretics MOA-sparing diuretics MOA

Spironolactone

ΘΘ

KK++-sparing diuretics-sparing diuretics

■ 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

Agents for heart failureAgents for heart failure

■ ACEI (or ARB)

■ BB’s (particularly carvedilol & bisoprolol)

■ diuretics (particularly loop diuretics)

■ aldosterone antagonists (spironolactone, eplerenone)

■ Digoxin (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

Nitrates and nitroglycerinNitrates and nitroglycerin■ 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 non-DHPs). 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

Antiplatelets-MOAAntiplatelets-MOA

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 = abciximab (block the final common pathway for platelet aggregation)

AntiplateletsAntiplatelets

■ ASA: – irreversible inhibitor of cyclo-oxygenase (COX) which results

in inhibition of TXA2 production in platelets and PGI2 (prostacyclin) production in endothelial cells

– Endothelial cells (but not platelets) overcome this inhibition by producing fresh cyclo-oxygenase which raises PGI2:TXA2 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

Which of the following is dosed Which of the following is dosed according to body weight?according to body weight?

a) Warfarin

b) Low-molecular weight heparins

c) Unfractionated heparin

d) Clopidogrel

e) ASA

Which of the following requires a diet Which of the following requires a diet free in vitamin K?free in vitamin K?

a) Warfarin

b) Low-molecular weight heparins

c) Unfractionated heparin

d) Clopidogrel

e) None of the above

AnticoagulantsAnticoagulants

■ 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, low-molecular weight heparin) work well on red thrombi

■ Oral anticoagulants: warfarin

■ Injectable anticoagulants: unfractionated heparin & low molecular weight heparins (LMWH)

Anticoagulants - UFHAnticoagulants - UFH■ MW = 15000 Da

■ Can be given SC or IV

■ Adjust dose according to aPTT (aPTT measures anti-factor 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

Chemical structure of heparin and Chemical structure of heparin and relationship to LMWH’srelationship to LMWH’s

Enzymatic depolymerization

Heparin

LMWH

Anticoagulants - LMWHAnticoagulants - 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 anti-factor 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

Natural breakdown of clotting factorsNatural breakdown of clotting factors

UFH and LMWH MOAUFH and LMWH MOA

Endogenous anti-thrombin III (ATIII) binds factors IIa and Xa but at a very slow rate.

UFH and LMWH’s speed this process up.

Warfarin mechanismWarfarin mechanism

Anticoagulants - warfarinAnticoagulants - warfarin

■ 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 continued …Warfarin 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

Asthma medicationsAsthma medications■ 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)

Targets for anti-inflammatory therapy in Targets for anti-inflammatory therapy in AsthmaAsthma

Mast Cells

IL-5 Eosinophils Leukotrienes

Cromolyn, nedocromil, ketotifen

Θ

corticosteroids

Θ

LTRA’s block LT receptors in airway

Θ

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

Θ

Which of the following requires months Which of the following requires months to relieve prostate symptoms in BPH?to relieve prostate symptoms in BPH?

a) Dutasteride

b) Finasteride

c) Tamsulosin

d) Pseudoephedrine

e) (a) and (b)

Drugs for benign prostatic hyperplasiaDrugs for benign prostatic hyperplasia

■ 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, 1st generation antihistamines such as diphenhydramine) worsen BPH symptoms

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

■ Carbamazepine

■ Rifampin

■ Clarithromycin

■ Phenytoin

■ None of the above

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)

PDE5Is and prostaglandins mechanism PDE5Is and prostaglandins mechanism of actionof action

■ 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

DementiaDementia

Rough relationship between parkinson’s disease, Rough relationship between parkinson’s disease, schizophrenia & antipsychoticsschizophrenia & antipsychotics

ACh DA

Normal

ACh DA

Parkinson’s

ACh DA

Schizophrenia

• raise activity of dopamine: levodopa, dopamine agonists or• reduce activity of ACh: anticholinergics

Symptoms worsen with:• antipsychotics• AChE inhibitors (used in treatment of dementia)

• reduce activity of dopamine: antipsychotics

ACh DA

EPS & pseudoparkinsonism: too much antipsychotic

• reduce activity of ACh: anticholinergics• raise activity of DA by reducing dose of antipsychotic

ACh DA

• Anticholinergics: benztropine, procyclidine, trihexyphenidyl, diphenhydramine• dopamine agonists: bromocriptine, cabergoline, pramipexole, ropinirole

Drugs used for dyspepsia, GERD or peptic ulcer disease■ Proton pump inhibitors

– Omeprazole, esomeprazole, rabeprazole, pantoprazole sodium, pantoprazole magnesium, lansoprazole

– All agents are equally effective– Must be:

1. Absorbed in tact without exposure to acid2. enter the acid-producing parietal cells3. get protonated4. 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

PPI’s-mechanism of actionPPI’s-mechanism of action

PPI’s continued …PPI’s continued …

■ 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

Drugs used for dyspepsia, GERD or peptic ulcer disease continued …■ 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

Antiemetics■ 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

IBD continued …IBD continued …■ 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

Agents for irritable bowel syndrome

■ 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)

Osteoporosis■ 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

Gout■ 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: 1st 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: 2nd line

● 0.6 mg daily

Drug related problemsDrug related problems

Need for pharmacotherapy

Exists Does not exist

No 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

Drug is prescribed

A note about drug allergiesA note about drug allergies

■ 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

Iron productsIron products■ 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 Fe2+ per 300 mg tab)

– Ferrous sulfate: 20% elemental iron (usually 60 mg Fe2+ per 300 mg tab)

– Ferrous fumarate: 33% elemental iron (usually 100 mg Fe2+ 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 Ca2+, Mg2+, Zn2+, Cu2+)

– More expensive than inorganic iron supplements

Over-the-counter drugs■ 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– 1st generation: diphenhydramine, chlorpheniramine

● Prominent anticholinergic side effects sedation, dryness (may exacerbate BPH symptoms), increased HR

– 2nd 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 1st 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 Ca2+, Mg2+ or Al3+ form a physical barrier at the esophageal sphincter– Histamine-2 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

OTC drugs continued …

■ 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

Appendix I: supplemental and more in depth Appendix I: supplemental and more in depth information regarding antibacterial agents …information regarding antibacterial agents …

Antibacterial agents-MOAAntibacterial agents-MOA■ 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.

Antibacterial agents-PenicillinsAntibacterial agents-Penicillins■ 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 + non-BL’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: non-BL’ase H. Flu, P. mirabilis, salmonella, shigella (L. monocytogenes is not a G- bacteria as was indicated here previously)

Hard to kill G- bacteria: klebsiella, enterobacter, citrobacter, serratia, morganella, pseudomonas

Antibacterial agents-CephalosporinsAntibacterial agents-Cephalosporins

■ Β-lactams continued …– Cephalosporins: divided into 1st, 2nd, and 3rd generations. 1st generation has mostly G+ coverage

while 3rd 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) 1st gen: cephalexin, cefazolin, cefadroxil. Used for (1) + (2) + E. coli, klebsiella. Do not cross BBB. Cefazolin is parenteral only. Cephalexin is PO only

● (8) 2nd 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) 3rd 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) 4th gen: cefepime. Active vs pseudomonas. Used to treat UTI’s, skin infections, pneumonia. Not advantageous over 3rd 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.

Antibacterial agents-fluoroquinolonesAntibacterial agents-fluoroquinolones

■ 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:

● 1st gen: Nalidixic acid (not used anymore)● 2nd gen: nor-, o-, and ciprofloxacin ● 3rd gen: levo-, gati-, and moxifloxacin. Gatifloxacin was discontinued Summer 2006. this

generation of drugs is commonly referred to as the “respiratory quinolones”– 2nd 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– 3rd gen agents were designed to cover more G+ bacteria than 2nd 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.

Antibacterial agents-aminoglycosidesAntibacterial agents-aminoglycosides

■ 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)

Antibacterial agents-macrolidesAntibacterial agents-macrolides

■ 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

Antibacterial agents-tetracyclinesAntibacterial agents-tetracyclines

■ 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

Antibacterial agents-metronidazole & Antibacterial agents-metronidazole & clindamycinclindamycin

■ 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)

■ 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

■ 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.

Antibacterial agents-TMP/SMXAntibacterial agents-TMP/SMX

■ 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)

Antibacterial agents-vancomycinAntibacterial agents-vancomycin

■ 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

Appendix II: Guidelines on opioid Appendix II: Guidelines on opioid dosingdosing■ Opioid naïve patient:

– 10 to 20 mg morphine q4h– 1/3 to ½ dose for breakthrough pain q1h– 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

● Total daily injected dose = 30 * 6 = 180 mg● 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:

– 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

Safe prescribing of opioidsSafe prescribing of opioids■ 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– 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)– 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– 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