Back to Basics Practical Pharmacology

1. Back to BasicsPractical Pharmacology Dr. Roland Halil, BSc(Hon), BScPharm, ACPR, PharmD Assistant Professor, Dept of Family Medicine, University of Ottawa Clinical Pharmacist, Bruyere Academic Family Health Team March 2013 rhalil@bruyere.org (Partially adapted from slides by Marc Riachi, R.Ph.)

2. Objectives • Review all pharmacology in an abnormally short amount of time in preparation for LMCC • List the four steps of rational prescribing • Understand the pharmacological classes, generic examples and mechanisms of action of important tools in the practice of medicine. • Understand how the kinetics and dynamics of these agents can affect their use • Highlight clinical pearls in the proper use of these agents in practice.

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

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

5. A Process for Rational Prescribing(your new best friend) Dr Roland Halil, BSc(Hon), BScPharm, ACPR, PharmD Pharmacist, Bruyere Academic FHT Assistant Professor, Dept Family Medicine, U of Ottawa March 2013

6. Objectives • To promote an efficient process for selecting optimal drug therapy for patients • To promote a process for applying population level evidence based medicine to individual patients.

7. A Structure Requires Process To prescribe or not to prescribe? That is the question… • Rational prescribing requires a process for selecting therapy: (in order) • Efficacy • Toxicity • Cost • Convenience

8. 1. Efficacy – Ask About… • Which HARD Outcomes • Mortality benefit? • Morbidity benefit? • Which SURROGATE Outcomes • Clinically relevant? • THEN “What is the quality of the evidence to prove this?” • Meta-analysis? • Randomized Controlled Trial? • Case series? • Anecdotal evidence?

9. Efficacy • If there is no efficacy, why waste your time on the potential toxicity, cost and inconvenience of a drug? • If there is proven efficacy at the population level, then balance this against the potential toxicity to the individual.

10. 2. Toxicity – Ask About… • Age? • Newer agents= Less Safety Data • Older agents= More Safety Data

11. 3. Cost – Ask About… • Patient cost vs Societal cost • Covered under provincial formulary? • Covered under private plans?

12. 4. Convenience – Ask About… • What is the likelihood of compliance? • Frequency of administration? • Daily vs QID? • Special restrictions? (eg. bisphosphonates) • PO vs IV? • Home vs Office vs Hospital therapy? • Many interactions? • Special monitoring requirements?

13. Metformin VS Why is Metformin first line therapy? Januvia® A simple example:

14. Efficacy • HARD Outcomes • Mortality benefit • Metformin– reduction in CV events (UKPDS-34 trial) • Morbidity benefit • Metformin– reduction in microvascular complications • SURROGATE Outcomes • Hgb-A1c reduction • Metformin~ 1% - 2% • Januvia® ~ 0.5% - 0.8% • Insulin Sparing Effects • Metformin

15. Metformin Very rare risk of lactic acidosis? 0.03 cases / 1000 pt-yrs (~ 50% fatal) Never clearly implicated GI upset / diarrhea Start low, go slow! B12 / folate deficiency / anemia (6 - 8/100) Reduced absorption – easy to supplement Anorexia usually transient Januvia® ?Unknown - too new ?Pancreatitis Too few patients examined GI upset edema ?elevated risk of infection? Toxicity

16. Metformin Ontario Drug Benefit: $ 0.0587 / tab Covered by ODB Rxfiles 2012: ~ $33 / 100 days QD to TID po Januvia® Ontario Drug Benefit: $ 2.8050 / tab Covered by ODB Rxfiles 2012: ~ $315 / 100 days Once daily po Cost & Convenience

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

18. Antibiotic Review(80% of the knowledge, 80% of the time) Dr Roland Halil, BSc(Hon), BScPharm, ACPR, PharmD Pharmacist, Bruyere Academic FHT Assistant Professor, Dept Family Medicine, U of Ottawa March 2013

19. Objectives • Review clinically relevant pathogens in human disease in an ambulatory care setting • Review antibiotic classes and spectra of activity • Focus on bread and butter examples of each • Review treatment recommendations for common infections in primary care

20. Process • Map the Bugs • “Know your enemy” • Map the Drugs • “Save your ammo” • Map the Battlefield

21. Part 1 - Map the (Clinically Important) Bugs“Know your enemy” Gram Negative Aerobic β-Lactamase Negative Cocci (spheres) Bacilli (rods) Gram Positive Anaerobic β-Lactamase Positive

22. Map the Bugs Aerobes Anaerobes Gram Positive Gram Negative Gram Positive Gram Negative CocciBacilliCocciBacilliCocciBacilliCocciBacilli b-L[+] b-L[-] b-L[+] b-L[-] b-L[+] b-L[-] b-L[+] b-L[-] b-L[+] b-L[-] b-L[+] b-L[-] b-L[+] b-L[-] b-L[+] b-L[-] 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

23. AnaerobesAbove & below the diaphragm Oral • Simple organisms • Easily handled by penicillins (beta-lactams) • Eg. ActinomycesBifidobacteriumFusobacterium Lactobacillus PeptococcusPeptostreptococcusPropionibacterium etc Gut • Approx the same, except: • Human pathogens: • Bacteroidesfragilis(B.frag) • Clostridiumdifficile(C.diff) • More virulent bugs requiring ‘bigger guns’…

24. Map the Bugs Anaerobes Above & Below diaphragm B.Frag C.Diff 9 . Aerobes Gram Positive Gram Negative CocciBacilli CocciBacilli b-L[+] b-L[-] b-L[+] b-L[-] b-L[+] b-L[-] b-L[+] b-L[-] 1 2 3 4 5 6 7 8

25. Map the Bugs Anaerobes Below diaphragm B.Frag C.Diff 9 . Aerobes Gram Positive Gram Negative CocciBacilli CocciBacilli b-L[+] b-L[-] b-L[+] b-L[-] b-L[+] b-L[-] b-L[+] b-L[-] 1 2 3 4 5 6 7 8

26. Gram[+] Bacilli • Not usually pathogenic • Major Exception: Listeria monocytogenes • Listeriosis – enteritis, sepsis, meningitis +/- encephalitis

27. Map the Bugs Anaerobes Below diaphragm B.Frag C.Diff 7 . Aerobes Gram Positive Gram Negative Cocci Bacilli CocciBacilli (Listeria) β-L[+] β-L[-] b-L[+] b-L[-] β-L[+] β-L[-] 1 2 3 456

28. Gm[-] Cocci • Not usually pathogenic • Major Exceptions: • Neisseria gonorrhea • Neisseriameningitidis and • Moraxellacatarrhalis • (formerly thought to be a type of Neisseria)

29. Map the Bugs Anaerobes Below diaphragm B.Frag C.Diff 5 . Aerobes Gram Positive Gram Negative Cocci Bacilli CocciBacilli (Listeria)(Neisseria & Moraxella) β-L[+] β-L[-] β-L[+] β-L[-] 1 2 3 4

30. β-Lactamase Enzymes • First penicillinase described in 1940’s even before penicillin was clinically available. • Most bugs produce some type of β-lactamase enzyme that destroys β-lactam antibiotics (pen’s, ceph’s, carbapenems) • Gm[+]cocci & β-lactamase [-]: only Group A strep give Penicillin

31. Map the Bugs Anaerobes Below diaphragm B.Frag C.Diff 4 . Aerobes Gram Positive Gram Negative Cocci Bacilli CocciBacilli (Listeria)(Neisseria & Moraxella) β-L[+] β-L[-] β-L[+] β-L[-] 1 (GrpAStrep) 2 3

32. Map the Bugs Anaerobes Below diaphragm B.Frag C.Diff 3 . Aerobes Gram Positive Gram Negative CocciBacilli β-L[+] both β-L[+]&[-] 1 2

33. Map the Clinically Important Bugs Atypicals Legionella pneumonia Chlamydia pneumonia Mycoplasma pneumonia 3 . Anaerobes (esp. Gut organisms) Eg. C-Diff & B-frag 4 . Aerobes Gram [+] Gram [-] Cocci Bacilli 1 2

34. 1 - Gram [+] Cocci Staphylococcus • S. aureus • Methicillin resistant (MRSA) • Methicillin sensitive (MSSA) • S. epidermidis • Methicillin resistant (MRSE) • Methicillin sensitive (MSSE) • Skin commensal • Rarely pathogenic Streptococcus • Group A (pyogenes) (β-Lact[-]) • Group B (agalactiae) • Neonates, v. elderly, obstetrics • S. pneumonia etc. etc. Enterococcus • (Formerly thought to be ‘Strep D’) • E. faecalis • E. faecium

35. 2 - Gram [-] Bacilli Easy to Kill • Proteus mirabilis • Escherichia coli • Klebsiella pneumonia • Salmonella • Shigella • Haemophilusinfluenza • (Moraxella catarrhalis) (actually a Gm[-] coccus) PEcKSS-HiM Hard to Kill • Serratia • Pseudomonas • Acinetobacter • Citrobacter • Enterobacter SPACE bugs

36. Gram Negative vs Gram Positive Gm[-]: red on stain. (ie. Don’t retain stain) Gm[+]: blue-purple on stain; Gm[-]: must pass through pores Gm[+]: molecules < 100kDa pass easily. Gm[-]: b-lactamases concentrated in periplasmic space Gm[+]: b-lactamases diffuse outside cell;

37. Atypicals: • Mycoplasma pneumo • Chlamydia pneumo • Legionella pneumo • Anaerobes: • Oral • Gut – Bfrag & Cdiff Map the BugsSummary • Gram positive aerobes: • Cocci • Staph • Aureus • MRSA (~8-10%) • MSSA • Epiderimidis • MRSE (~65%) • MSSE • Strep • Group A strep (pyogenes) • Group B strep (agalactiae) • Strep Viridans • Strep pneumo etc. • Enterococcus • Faecalis • Faecium • Bacilli • Listeria • Gram negative aerobes: • Bacilli • Easy to Kill • PEcKSS (Proteus, Ecoli, Klebsiella, Salmonella, Shigella) • HiM (H.flu and Moraxella (actually a Gm[-]coccus)) • Hard to Kill • SPACE bugs (Serratia, Pseudomonas, Acinetobacter, Citrobacter, Enterobacter) • Cocci • Neisseria • gonorrhaea • meningitidis • Moraxella catarhallis

38. Part 2 - Map the Drugs(Save your Ammo)

39. Map the Drugs • Arms race! • Remember: “Bigger guns breed higher walls” • Older drugs tend to be simpler drugs • More narrow spectrum • Broad spectrum drugs breed resistance • Superbugs develop • MRSA, VRE, ESBL, etc • Older drugs have more safety data • Tend to be less toxic • Learn their history • Learn their pharmacology

40. Part 2 - Map the Drugs“Save your Ammo” Fluoroquinolones Penicillins Tetracyclines Aminoglycosides Vancomycin Macrolides Carbapenems Cephalosporins Clindamycin Metronidazole

41. Antibiotics – Mechanisms of Action From: http://commons.wikimedia.org/wiki/File:Antibiotics_Mechanisms_of_action.png Accessed Dec 28/12

42. Beta-Lactams - Penicillins Penicillin Amoxicillin / Ampicillin Cloxacillin / Methicillin (po) (iv) (clinic) (lab) Amox + Clavulanic acid Anti-Staph Anti-Strep

43. Beta-Lactams - Cephalosporins • 1st Generation • Cephalexin (Keflex™)(or Cefadroxil) (po) • Cefazolin (Ancef™) (iv) • 2nd Generation • Cefuroxime (po & iv) • 3rd Generation • Ceftriaxone, Cefotaxime, Ceftazidime (iv) • Cefixime (Suprax™) (po) • 4th Generation • Cefepime (iv) Increasing Gram[-] coverage

44. Beta-Lactams – Other (FYI)(IV only, inpatient use only) • Piperacillin (plus tazobactam) • big gun, tazo = suicide substrate, like clavulanic acid • Carbapenems • Meropenem • Imipenem • Ertapenem • Monobactams • Aztreonam Broad spectrum, big gun antibiotics that cover Gm[+], both easy and hard to kill Gm[-] bugs, even some anaerobes.

45. Antibiotics – Mechanisms of Action From: http://commons.wikimedia.org/wiki/File:Antibiotics_Mechanisms_of_action.png Accessed Dec 28/12

46. Fluoroquinolones • 2nd generation • Ofloxacin • Ciprofloxacin • Norfloxacin • 3rd generation • Levofloxacin • 4th generation • Moxifloxacin • Covers: strep & Gm[-]’s • PEcKSS-HiM & SPACE bugs • Ofloxacin • Ciprofloxacin • Anti-pseudomonal – the only PO option! • Norfloxacin • Same spectrum as Cipro (even anti-Pseudomonal) – but only for cystitis UTI. • Concentrates in the G.U. system only • N.B.Notgood enough for pyelonephritisor systemic infection

47. Fluoroquinolones • The “Respiratory FQs” • Concentrate in alveolar macrophages • Greater than serum concn • Levofloxacin • the more active L-enantiomer of Ofloxacin • Renal clearance • Moxifloxacin • Hepatic clearance • Enhancedcoverage of: • Strep pneumo • Oral Anaerobes • Atypicals • N.B. only Moxicover B.frag • Neither covers C.diff • (Both will cover Clostrium non-difficile strains) • Both have 100% oral bioavailability • Therefore PO = IV dose

48. Antibiotics – Mechanisms of Action From: http://commons.wikimedia.org/wiki/File:Antibiotics_Mechanisms_of_action.png Accessed Dec 28/12

49. Macrolides • Coverage of: • Atypicals, Strep pneumo, & Hi.M. (Hflu & Mcat) • So, good for respiratory infections! • N.B. But doesn’t cover PEcKSS or SPACE bugs • Erythromycin • Efficacy: Poorer coverage of H.flu, MSSA • Toxicity: • Prokinetic – diarrhea! • Worse for QTc prolongation • Convenience: QID dosing • Clarithromycin • Better Hflu &MSSA coverage • Less QTc prolongation vs E • Shorter half-life vsAzithro • BID dosing x 7-10days • New daily ‘XL’ formulation • Azithromycin • An azalide, (not a macrolide) • Same spectrum of activity • Less QTc prolongation vs E & C! • Long t1/2 – QD dosing x 5d • BUT can breed resistant S.pneumo (since below [MIC] for long periods of time)

50. Antibiotics – Mechanisms of Action From: http://commons.wikimedia.org/wiki/File:Antibiotics_Mechanisms_of_action.png Accessed Dec 28/12