Back-to-Basics Practical Pharmacology Marc Riachi, R.Ph. March 29, 2010 University of Ottawa

1. Back-to-BasicsPractical PharmacologyMarc Riachi, R.Ph.March 29, 2010University of Ottawa

2. Antibacterials Narcotic analgesics Antidepressants: MAOIs, SSRIs, TCAs, NDRIs, SNRIs Agents used for anxiety and sleep disorders Antidiabetics: alpha-glucosidase inhibitors, biguanides, meglitinides, sulfonylureas, thiazolidinediones, dipeptidyl peptidase inhibitors, insulins Antilipemic agents: statins, cholesterol absorption inhibitors (ezetimibe), resins, fibrates, niacin, omega-3 fatty acids ACEI’s, ARB’s, direct renin antagonists, Beta blockers, calcium channel blockers Diuretics: loop, thiazide, and potassium-sparing Agents used in heart failure Nitrates Antiasthmatics Agents for benign prostatic hyperplasia Agents for Urinary Incontinence Agents for Dementia Appendix I Appendix II Topics to be covered in this lecture

3. Which of the following is a macrolide antibiotic? • Clindamycin • Tobramycin • Vancomycin • Azithromycin • Gentamicin

4. Which of the following ABX most commonly causes skin photosensitivity manifested by an exaggerated sunburn reaction, commonly used to manage acne vulgaris and should not be taken with Al3+, Ca2+, Mg2+ or Fe2+ products? • Clindamycin • Minocycline • Penicillin • Ciprofloxacin • Metronidazole

5. Which of the following ABX is least likely to affect INR when a patient is on warfarin? • Amoxicillin • Levofloxacin • SMX+TMP • Erythromycin

6. Which of the following ABX most commonly affects drug metabolism at CYP3A4? • Cloxacillin • Cephalexin • Erythromycin • Clindamycin • Metronidazole

7. Which of the following groups is the least likely to prolong QTc interval? • Macrolides • Penicillins • Fluoroquinolones

8. Antibacterial families and their members • Penicillins: penicillin, cloxacillin, amoxicillin, ampicillin, piperacillin, ticarcillin • Cephalosporins: all the ABX starting with “Ceph-” or “Cef-” • Fluoroquinolones: cipro-, nor-, o-, levo-, and moxi-floxacin • Aminoglycosides: gentamicin, amikacin, tobramycin • Macrolides: erythromycin, clarithromycin, azithromycin • Tetracyclines: tetracycline, minocycline, doxycycline • SMX/TMP • Clindamycin, metronidazole • vancomycin

9. Antibacterials-Site of action

10. Bactericidal vs. bacteriostatic • Bacteriostatic ABX • Tetracyclines • Macrolides • SMX • TMP • chloramphenicol • Clindamycin • Bactericidal ABX • Aminoglycosides • Fluoroquinolones • Penicillins • Cephalosporins • Nitrofurantoin • Metronidazole • SMX+TMP 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. • Bactericidal ABX are preferred when: • Host defences are poor • Infection involves heart, brain, blood • Better not to combine with bacteriostatic ABX because bactericidals require bacterial cells to be actively growing/dividing.

11. Pen V/G G+ (strep), oral anarobes, T. Pallidum (Lacks efficacy vs BL G+, G-, B. fragilis, atypicals) Add Enterococcus and “easy to kill” G- (non-BL’ase) coverage Add MSSA coverage Ampicillin Amoxicillin Cloxacillin Add MSSA, M. Catarrhalis, BL H. Flu and B. fragilis Amoxicillin + Clavulanate Ampi + sulbactam Piperacillin, ticarcillin Add MSSA & BL resistance to “easy to kill” bacteria Piperacillin/tazobactam ticarcillin/clavulanate Penicillins Easy to kill G- bacteria: non-BL’ase H. Flu, P. mirabilis, salmonella, shigella, E. coli, Listeria monocytogenes Hard to kill G- bacteria: klebsiella, enterobacter, citrobacter, serratia, morganella, pseudomonas, providencia Coverage for “hard to kill” G- & B. Frag

12. Pen V/G G+ (strep), oral anarobes, T. Pallidum (Lacks efficacy vs BL G+, G-, B. fragilis, atypicals) Develop agent Vs BL staph (MSSA) and “easy to kill” non-BL G- Add activity vs B. Fragilis, and “easy to kill” G- 1st gen Cephs Eg: cephalexin, cefadroxil Cefoxitin Improve activity vs. H. Flu, Neisseria, M. Catarrhalis 2nd gen Cephs Eg: cefuroxime, Cefaclor, cefprozil None are effective against enterococcus, L. monocytogenes, MRSA. 3rd gen can cross BBB. 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 cefepime covers pseudomonas like ceftazidime and G+/hard to kill G- like cefotaxime and ceftriaxone 3rd gen: Ceftazidime 4th gen: Cefepime Add activity vs pseudomonas Cephalosporins

13. Pen V/G G+ (strep), oral anarobes, T. Pallidum (Lacks efficacy vs BL G+, G-, B. fragilis, atypicals) Develop agent Vs G- (including pseudomonas) Aminoglycosides Eg: gentamicin, Amikacin, tobramycin Add activity towards BL G+ 2nd gen Fluoroquinolones Eg: Ciprofloxacin, ofloxacin Don’t cover strep well. Ofloxacin also does not cover pseudomonas Add atypical coverage and expand G+ coverage but lose good pseudomonal coverage 3rd gen FQ’s Eg: levofloxacin 4th gen FQ’s Eg: moxifloxacin Add activity vs anarobes (B. fragilis) Fluoroquinolones & Aminoglycosides

14. Pen V/G G+ (strep), oral anarobes, T. Pallidum (Lacks efficacy vs BL G+, G-, B. fragilis, 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 some MRSA strains Macrolides, Tetracyclines TMP/SMX

15. Pen V/G G+ (strep), oral anarobes, T. Pallidum (Lacks efficacy vs BL G+, G-, B. fragilis, atypicals) Develop agent Vs B. fragilis and other anaerobes Develop agent vs Staph Epidermidis and MRSA Metronidazole Vancomycin Add activity vs BL staph aureus (MSSA) Clindamycin Vancomycin, metronidazole, clindamycin Note: Use PO vancomycin or PO/IV metronidazole to treat C. difficile colitis

16. 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 and sometimes levo-/moxifloxacin • Skin/nail/bites: cephalexin, cloxacillin, amoxi/clav • Traveller’s diarrhea: azithromycin, ciprofloxacin, norfloxacin • Bacterial vaginosis, trichomoniasis: metronidazole, clindamycin • Chlamydia: single dose azithromycin, 7-day course doxycycline • Gonorrhea: PO cefixime, ceftriaxone IM injection • Acne: tetracyclines • Acute otitis media: Macrolides, high dose amoxicillin, amoxi/clav, 2nd gen Cephs • Patients with penicillin allergy: clindamycin or erythromycin (choice depends on indication) • Intraabdominal infections: ciprofloxacin+metronidazole, 3rd gen Cephs • C. difficile diarrhea: metronidazole

17. Fluoroquinolones in patients < 18 y • FQ’s are usually not used in prepubertal children or pregnancy due to fear of cartilage and tendon damage • Some clinicians have no problem using FQ’s (particularly ciprofloxacin) in prepubertal children particularly for : • complicated UTI’s • pyelonephritis • typhoid fever • G- meningitis • Osteomyelitis • The concern with cartilage damage is slowly falling out of favor. • Journal Watch Pediatrics and Adolescent Medicine August 12, 2002 says “Fluoroquinolones in Children: Use Them, but Don't Abuse Them”. • Journal Watch Emergency Medicine December 21, 2007 concluded “arthropathy is usually reversible with drug withdrawal, and serious joint damage has not been reported; therefore, it is reasonable to prescribe a fluoroquinolone to a child (as is commonly done for cystic fibrosis) if other antibiotic options are unlikely to resolve the infectious process” • Based on experience and availability of safety data , cipro is probably the most trusted FQ for use in pediatrics

18. Antibiotics contraindicated in pregnancy (category X) Tetracyclines (also in children < 8 y.o.): are incorporated into fetal skeleton/unerupted teeth and may cause reduced weight and malformations Fluoroquinolones (young dogs and neonatal mice given ciprofloxacin developed arthropathy with permanent cartilage erosion in weight-bearing joints)  no evidence that same results are observed in humans 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 Chloramphenicol (pregnancy at term or during labour): gray baby syndrome, ie, cyanosis and hypothermia, owing to the limited glucuronidating capacity of the newborn infant's liver 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

19. Category B (no evidence of human fetal risk) ABX • Penicillins, including those in combination with ß-lactamase inhibitors (clavulanic acid, sulbactam, and tazobactam) • Cephalosporins • Erythromycin base • Azithromycin • Clindamycin

20. ABX and warfarin All antibiotics have the theoretical potential to increase INR Penicillins, cephalosporins, azithromycin, aminoglycosides, clindamycin, nitrofurantoin and vancomycin are generally safe with warfarin and do not necessitate INR monitoring

21. Which of the following is least likely to be beneficial in treatment of opioid-induced constipation? • Bisacodyl (Dulcolax) • Senna (Senokot) • Docusate (Soflax) • Lactulose

22. Which of the following opioids is least suitable for chronic pain management? • Pentazocine (Talwin) • Fentanyl patches (Duragesic) • Morphine • Oxycodone • Codeine

23. Which of the following also inhibits reuptake of serotonin and norepinephrine • Tramadol • Morphine • Codeine • Oxycodone • Fentanyl

24. Narcotic analgesics • These are the opioids (synthetic) or the opiates (naturally occurring) • 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

25. Classes of opioids • codeine, hydromorphone, levorphanol, morphine, oxycodone, hydrocodone, and pentazocine • meperidine and fentanyl • methadone and dextropropoxyphene • If a person is allergic to codeine but he/she still requires opioids for adequate pain control, 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) • dextropropoxyphene • In all cases, monitor patient for possible cross-allergic reactions

26. 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 patient should be able to tolerate very high doses if the dose is increased slowly • Note that 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)

27. Examples of prescription opioids • Codeine: • Available as a 5mg/mL syrup (NOT 5mg/5mL), codeine contin tablets, and in combination with other ingredients such as: • Tylenol #1 = 8 mg codeine + 15 mg caffeine + 300 mg acetaminophen (available to patients w/o a Rx) • Tylenol #2 = same ingredients as #1 but 15 mg codeine. Can be prescribed verbally. • Tylenol #3 = same ingredients as #1 but 30 mg codeine. Can be prescribed verbally. • Tylenol #4 = 300 mg acetaminophen + 60 mg codeine (NOTE there is no caffeine and therefore can’t be prescribed verbally) • Others include: Robaxacet-8, Robaxisal-C, Emtec, Mersyndol with codeine, Fiorinal-C, Dimetapp-C, CoActifed, Calmylin with codeine, Atasol-8, 222 tabs, 282 tabs, 292 tabs • Converted to the active metabolite morphine by CYP2D6 • Some Caucasian, Asians, and Arabs have poorly functioning CYP2D6 while others may have more efficient CYP2D6 • CYP 2D6 inhibitors: bupropion, duloxetine, paroxetine, moclobemide, escitalopram, fluoxetine, citalopram, quinidine, terbinafine • CYP2D6 inducers: rifampin, dexamethasone

28. Examples cont… • Morphine: • Statex: short acting • M-eslon, MS contin: long acting • The metabolite morphine-3-glucuronide may build up in elderly and in those with renal insufficiency causing myoclonus and interfering with analgesia • Oxycodone: • Percocet, oxycocet, Endocet: short acting preparations containing 5 mg oxycodone + 325 mg acetaminophen • Percocet Demi: short acting preparation containing 2.5 mg oxycodone + 325 mg acetaminophen • Oxy-IR, Supeudol: short acting 5, 10, 20 mg oxycodone. Supeudol also available as 10 and 20 mg suppositories • Oxycontin: long acting 5, 10, 20, 40, 80 mg oxycodone. • Trivia: Dr. House of the TV show “House MD” likes to take oxycodone • Hydromorphone: • Dilaudid: short acting • HydromorphContin: long acting

29. Examples cont… • Fentanyl: many street names including “China White”, “Apache”, “Dance fever” • Patch: worn continuously for 72 hours. In some patients for 48 hours. Available as: • 12 ug/hr (actually is 12.5 ug/hr but is marketed as 12 ug/hr to avoid misreading the Rx as 125 ug/hr) • 25 ug/hr • 50 ug/hr • 75 ug/hr • 100 ug/hr • 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… • Dose of patch is calculated from conversion tables • 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 • Patch should be flushed down the toilet upon removal • Fentanyl is metabolized by CYP3A4 and therefore should monitor patients carefully if they receive CYP3A4 inhibitors (e.g., azoleantifungals, erythromycin, clarithromycin, ritonavir) or inducers (rifampin, phenytoin, carbamazepine, phenobarbital, St. John’s Wort) • If skin needs cleansing before applying the patch, it should be cleaned with water only (avoid soaps, oils, alcohol)

30. Examples cont… • 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 • PO liquid used for treatment of opioid dependence as part of the MMT • 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

31. Examples cont… • Hydrocodone: Tussionex, Hycodan, Ibucodon • Meperidine: • Brand name is Demerol • 10 times less potent than morphine with shorter duration of action • Should only be used for acute moderate to severe 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: Tramacet, Ralivia, Tridural, Zytram. 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, ie, tramadol can be refilled for example. • 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

32. Other uses of opioids • Diarrhea • Lomotil (diphenoxylate + atropine) • Cough suppression • Codeine • At least 15 mg per dose required • Syrup is 5 mg/mL NOT 5 mg/5 mL • Hycodan or Tussionex (Hydrocodone) • Opioid dependence • PO Methadone: see next slides • Sublingual Suboxone (Buprenorphine + naloxone) • naloxone is an opioid antagonist but is not absorbed orally; purpose is to deter patient from injecting Suboxone

33. Notes on SR or “Contins” • Idea is to deliver drug “Contin”uously over a 12 or 8 hour period • Not for use in acute pain • Not for use if short bowel, diarrhea, or renal failure • Available for codeine, morphine, oxycodone, and hydromorphone • Codeine contin and MS Contin 200 mg tabs are the only ones which could be split

34. 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 lactuloseqd to tid • 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

35. 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 • 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

36. 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)."

37. 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) • (Straight opioids) OR (opioids + one nonopioid in the same tablet) cannot be prescribed verbally; they can only be prescribed as written prescriptions and can be faxed to the pharmacy

38. Which of the following has the longest half-life? • Citalopram • Venlafaxine • Trazodone • Fluoxetine • Paroxetine

39. Which of the following antidepressants is particularly useful for management of insomnia? • Fluoxetine • Trazodone • Escitalopram • Bupropion • Venlafaxine

40. Which of the following combinations makes the most pharmacological sense? • Citalopram + venlafaxine • Bupropion + duloxetine • Escitalopram + bupropion • Nortriptyline + fluoxetine • Venlafaxine + duloxetine

41. Antidepressants • Classified as: • TCA’s: include amitriptyline, desipramine, imipramine, nortriptyline • SSRI’s: citalopram, escitalopram, fluoxetine, paroxetine, fluvoxamine, sertraline • NDRI’s: bupropion • SNRI’s: venlafaxine, duloxetine • Misc: trazodone, mirtazapine • MAOI’s: • Irreversible: phenelzine, tranylcypromine • Reversible: moclobemide • TCA=tricyclic antidepressant • NDRI=NE and DA reuptake inhibitor • SNRI=serotonin and NE reuptake inhibitor

42. How to decide which agent to use? • Factors to consider include: • Differences in efficacy based on controlled studies • TCA’s in general 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 at high risk of committing suicide) • 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 or duloxetine • If cardiac conduction abnormalities or dementia, avoid TCA’s

43. Dosage • Start low and increase dosage slowly until optimal therapeutic dose is reached • Use lower doses in elderly and hepatic dysfunction

44. 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 for a minimum of 9 months and may need to continue for at least 2 years • To avoid relapse D/C therapy gradually and not abruptly (venlafaxine is particularly difficult to D/C).

45. 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)

46. 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.

47. 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 DA reuptake inhibition (it’s like adding bupropion to an SSRI) • So, venlafaxine has the potential to inhibit the reuptake of serotonin + NE + DA

48. 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

49. More SNRI’s • Duloxetine (Cymbalta): • Similar mechanism of action to venlafaxine, ie, 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 (60 mg duloxetine vs. 225 mg venlafaxine) but not more effective

50. Final words • SSRI’s, bupropion, venlafaxine are usually used as first line agents • Fluoxetine’s half life is 1-3 days after acute administration and 4-6 days after chronic administration • With all AD’s watch out for suicide ideation or attempts especially in those < 18 y.o. • Paroxetine is sometimes used off-label as an agent to delay premature ejaculation