Back-to-Basics Practical Pharmacology Marc Riachi, R. Ph

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

Topics to be covered in this lecture
Antibacterials Antimycobacterials Antifungals Narcotic analgesics Autonomic nervous system Anti seizure drugs Migraines Antidepressants Antianxiety agents Agents for insomnia Antidiabetics Antilipemics Antihypertensives Diuretics Nitrates 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

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 action

Bactericidal 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.

Penicillins Pen V/G: covers G+ (strep), oral anarobes, T. Pallidum
(Lacks efficacy vs BL’ase, B. fragilis, G-, atypicals) Develop agent vs BL’ase producing staph (MSSA) Develop agent vs Enterococcus and “easy to kill” G- (no resistance to BL’ase) Cloxacillin Ampicillin Amoxicillin Add resistance to BL’ase, cover MSSA and B. fragilis 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 Amoxicillin + Clavulanate Ampi + sulbactam Cover “hard to kill” G- Piperacillin, ticarcillin Add resistance to BL’ase 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) Piperacillin/tazobactam ticarcillin/clavulanate

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

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

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

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

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

ABX 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 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 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?
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 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): 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

Antifungals 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? 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 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 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 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 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 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… 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… 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 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 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…
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…
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 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

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 and 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 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

Treatment 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: seizure type or epilepsy syndrome side effect profile of AED, other medical conditions, concurrent drugs, drug interactions, cost Strive for monotherapy

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

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 … 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

Antidepressants 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?
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

Dosage 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?
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 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 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 …
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 …
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

More SNRI’s 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

Final 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 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 Up to 8 weeks for response

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

Oral antidiabetic agents
MOA Avoid Side Effects Notes Sulfonylureas: glyburide gliclazide glimepiride 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 - ↑ LFT’s – dose related (rare) - does not cause hypoglycemia by itself - ↓ digoxin levels Thiazolidinediones: Pioglitazone Rosiglitazone - 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: Repaglinide Nateglinide Stimulate insulin production like sulfonylureas -hepatic dysfunction - Hypoglycemia less than SU’s -take immed. before meals. Skip dose if meal is missed.

Relative duration of action of the various insulins

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

Sitagliptin 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 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 pathway

Statins 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

ezetimibe 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)

Resins 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

Fibrates 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)
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 … 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 lipoproteins
g/d 2 g/d 3 g/d Baseline -15% 12.5% 25% -30% HDL-C with Niaspan® TG with Niaspan® TG with crystalline niacin LDL-C with Niaspan® LDL-C with crystalline niacin 35% HDL-C with crystalline niacin

Fish 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 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 system

ACEI’s and ARB’s (angiotensin receptor 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 …
Θ ARB Direct Renin Inhibitor (aliskiren)

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 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 receptors

Βeta-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 …
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 Channels

Calcium 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 following is true?
TCA’s cause constipation, dry mouth, sedation SSRI’s cause constipation, enhanced sexual function Trazodone cause insomnia Mirtazapine cause weight loss

Sertraline + fluoxetine Venlafaxine + duloxetine
Which of the following antidepressant drug combos makes the most pharmacological sense when prescribed to a patient? Sertraline + fluoxetine Venlafaxine + duloxetine Moclobemide + nortriptyline Citalopram + venlafaxine Bupropion + escitalopram

Metformin (a biguanide) Glyburide (a sulfonylurea)
Which of the following monotherapies is most likely to cause hypoglycemia? Metformin (a biguanide) Glyburide (a sulfonylurea) Acarbose (alpha glucosidase inhibitor) Sitagliptin (DPP4 inhibitor) Pioglitazone (a Thiazolidinedione)

Which of the following is classified as a monoamine oxidase inhibitor?
Moclobemide Bupropion Trazodone Duloxetine

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

Which of the following raises HDL the most?
Ezetimibe Fenofibrate Pravastatin Nicotinic acid Cholestyramine

Atorvastatin Rosuvastatin Simvastatin Lovastatin Cilastatin
Which of the following statins is not significantly metabolized by the CYP3A4 system? Atorvastatin Rosuvastatin Simvastatin Lovastatin Cilastatin

Which of the following might raise blood potassium?
Hydrochlorothiazide Ramipril Spironolactone Amlodipine (b) and (c)

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

Which of the following may cause reflex tachycardia?
Amlodipine Verapamil Diltiazem Felodipine (a) and (d)

Carvedilol Ramipril Verapamil Amlodipine Candesartan
Which of the following should not be used to control hypertension in HF patients? Carvedilol Ramipril Verapamil Amlodipine Candesartan

Hydrochlorothiazide Chlorthalidone Furosemide Metolazone (a) and (b)
Which of the following is ineffective as a diuretic at low creatinine clearance (< 50 mL/min)? Hydrochlorothiazide Chlorthalidone Furosemide Metolazone (a) and (b)

Site of action of diuretics

Loop 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 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

K+-sparing diuretics MOA
Spironolactone Θ

K+-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 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 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-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)

Antiplatelets 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 according to body weight?
Warfarin Low-molecular weight heparins Unfractionated heparin Clopidogrel ASA

Which of the following requires a diet free in vitamin K?
Warfarin Low-molecular weight heparins Unfractionated heparin Clopidogrel None of the above

Anticoagulants 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 - 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 relationship to LMWH’s
Enzymatic depolymerization LMWH

Anticoagulants - 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 factors

UFH 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 mechanism

Anticoagulants - 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 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 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 Asthma
Mast Cells IL-5 Eosinophils Leukotrienes Θ Θ Θ Θ Cromolyn, nedocromil, ketotifen corticosteroids LTRA’s block LT receptors in airway LTRA’s: montelukast & zafirlukast. Serve as alternatives or adjuncts to increased ICS or when ICS are not tolerated. 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. Mast cell stabilizers need a few weeks to work, have to be used regularly, excellent safety profile. 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

Which of the following requires months to relieve prostate symptoms in BPH?
Dutasteride Finasteride Tamsulosin Pseudoephedrine (a) and (b)

Drugs 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

Carbamazepine Rifampin Clarithromycin Phenytoin None of the above
If sildenafil (Viagra) is metabolized by CYP3A4, which of the following would reduce its metabolism? Carbamazepine Rifampin Clarithromycin Phenytoin None of the above

Erectile dysfunction and premature ejaculation
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 of action

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

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

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: Absorbed in tact without exposure to acid enter the acid-producing parietal cells get protonated undergo intramolecular rearrangement (activation) 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 action

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 … 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 problems Need for pharmacotherapy Exists Does not exist
Drug is prescribed 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

A 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 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 information regarding antibacterial agents …

Antibacterial 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-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-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-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 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-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-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-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 & clindamycin
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/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-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 dosing
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 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

Back-to-Basics Practical Pharmacology Marc Riachi, R. Ph

Similar presentations

Presentation on theme: "Back-to-Basics Practical Pharmacology Marc Riachi, R. Ph"— Presentation transcript:

Similar presentations

About project

Feedback

Log in

Auth with social network:

Back-to-Basics Practical Pharmacology Marc Riachi, R. Ph

Similar presentations

Presentation on theme: "Back-to-Basics Practical Pharmacology Marc Riachi, R. Ph"— Presentation transcript:

Similar presentations

About project

Feedback