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Back to Basics Practical Pharmacology Dr. Roland Halil, BSc(Hon), BScPharm, ACPR, PharmD Assistant Professor, Dept of Family Medicine, University of Ottawa.

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Presentation on theme: "Back to Basics Practical Pharmacology Dr. Roland Halil, BSc(Hon), BScPharm, ACPR, PharmD Assistant Professor, Dept of Family Medicine, University of Ottawa."— Presentation transcript:

1 Back to Basics Practical 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) 1.Efficacy 2.Toxicity 3.Cost 4.Convenience

8 1. Efficacy – Ask About… 1.Which HARD Outcomes a)Mortality benefit? b)Morbidity benefit? 2.Which SURROGATE Outcomes Clinically relevant? 3.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… BothersomeSevere CommonNot legal RareWho cares 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? 1.Frequency of administration? – Daily vs QID? 2.Special restrictions? (eg. bisphosphonates) – PO vs IV? – Home vs Office vs Hospital therapy? 3.Many interactions? 4.Special monitoring requirements?

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

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

15 Toxicity 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?

16 Cost & Convenience 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

17 Comments, Questions & Requests? rhalil@bruyere.org Monday & Fridays: – 613-230-7788 ext 238 Tuesday, Wednesday, Thursday: – 613-241-3344 ext 327 Twitter: @Roland Halil, PharmD

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 1.Map the Bugs – “Know your enemy” 2.Map the Drugs – “Save your ammo” 3.Map the Battlefield

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

22 AerobesAnaerobes Gram PositiveGram 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 Map the Bugs

23 Anaerobes Above & below the diaphragm Oral Simple organisms Easily handled by penicillins (beta-lactams) – Eg. Actinomyces Bifidobacterium Fusobacterium Lactobacillus Peptococcus Peptostreptococcus Propionibacterium etc Gut Approx the same, except: Human pathogens: Bacteroides fragilis (B.frag) Clostridium difficile (C.diff) – More virulent bugs requiring ‘bigger guns’…

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

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

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

27 Aerobes Gram Positive Gram Negative Cocci Bacilli (Listeria) β-L[+] β-L[-] b-L[+] b-L[-] β-L[+] β-L[-] 1 2 3 4 5 6 Map the Bugs Anaerobes Below diaphragm B.Frag C.Diff 7.

28 Gm[-] Cocci Not usually pathogenic – Major Exceptions: Neisseria gonorrhea Neisseria meningitidis and Moraxella catarrhalis – (formerly thought to be a type of Neisseria)

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

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

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

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

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. 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 Haemophilus influenza – (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 poresGm[+]: molecules < 100kDa pass easily. Gm[-]: b-lactamases concentrated in periplasmic spaceGm[+]: b-lactamases diffuse outside cell ;

37 Map the Bugs Summary 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 Anaerobes : Oral Gut – Bfrag & Cdiff Atypicals : Mycoplasma pneumo Chlamydia pneumo Legionella pneumo

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” Penicillins Tetracyclines Clindamycin Vancomycin Aminoglycosides Fluoroquinolones Macrolides Cephalosporins Metronidazole Carbapenems

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

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

43 Beta-Lactams - Cephalosporins 1 st Generation – Cephalexin (Keflex™)(or Cefadroxil) (po) – Cefazolin (Ancef™) (iv) 2 nd Generation – Cefuroxime (po & iv) 3 rd Generation – Ceftriaxone, Cefotaxime, Ceftazidime (iv) – Cefixime (Suprax™) (po) 4 th 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 28/12http://commons.wikimedia.org/wiki/File:Antibiotics_Mechanisms_of_action.png

46 Fluoroquinolones 2 nd generation – Ofloxacin – Ciprofloxacin – Norfloxacin 3 rd generation – Levofloxacin 4 th 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. Not good enough for pyelonephritis or systemic infection

47 Fluoroquinolones The “Respiratory FQs” – Concentrate in alveolar macrophages – Greater than serum conc n 1.Levofloxacin – the more active L- enantiomer of Ofloxacin – Renal clearance 2.Moxifloxacin – Hepatic clearance Enhanced coverage of: 1.Strep pneumo 2.Oral Anaerobes 3.Atypicals – N.B. only Moxi cover 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 28/12http://commons.wikimedia.org/wiki/File:Antibiotics_Mechanisms_of_action.png

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 vs Azithro 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 28/12http://commons.wikimedia.org/wiki/File:Antibiotics_Mechanisms_of_action.png

51 Aminoglycosides 1.Gentamicin 2.Tobramycin – Reserved for Pseudomonas aeruginosa 3.Amikacin All excellent Gram[-] coverage: – PEcKSS-HiM and SPACE bugs Efficacy: excellent Gm[-] Toxicity: – Nephrotoxicity – Ototoxicity – Less now with daily dosing Cost: – Cheap, old meds Convenience – Now Once daily IV/IM

52 Pharmacodynamics Relationship between Abx Concentration & Effect Concentration Dependent Killing Higher the peak, better the kill i.e. Ratio of peak drug concentration and M.I.C. determines rate of kill. Eg. FQs, AGs Time Dependent Killing Time over MIC matters i.e. Independent of peak concentration. Determined by length of time over MIC Eg. B-lactams (Pen, Ceph etc) Log [Conc] Time (h) Peak MIC Log [Conc] Time (h) MIC

53 Pharmacodynamics Relationship between Abx Concentration & Effect Concentration Dependent Killing Higher the peak, better the kill i.e. Ratio of peak drug concentration and M.I.C. determines rate of kill. Eg. FQs, AGs With renal impairment: – Maintain the peak, lengthen the interval – This ensures good rate of killing while allowing enough time to eliminate the drug and avoid toxicities – For eg: If CrCL = 90mL/min - Levofloxacin 750mg q24h po If CrCL = 30mL/min – Levofloxacin 750mg q48h po Log [Conc] Time (h) Peak MIC Log [Conc] Time (h) Peak MIC

54 Pharmacodymamics Bactericidal vs Bacteriostatic Bactericidal Abx – B-lactams (Pen, Ceph) – Aminoglycosides (AGs) – Fluoroquinolones (FQs) – Rifampin – Metronidazole – Vancomycin Bacteriostatic Abx – Tetracyclines – Macrolides – Clindamycin – Chloramphenicol Rarely a clinically important characteristic, unless the patient is immunocompromised or the risk of death with delayed/incorrect therapy is high.

55 Combination Therapy Why? – Broaden spectrum (eg. Mixed infection) – Synergistic activity for hard to kill bugs (eg. Enterococcus or pseudomonas) – Prevent resistance (eg. TB) – Reduce dose and side effects

56 Map the Drugs Pharmacology Summary Many antibiotic classes – Beta-lactams generally safest agents. Even at high doses – Some have overlapping mechanisms of action – Avoid combining similar mechanisms of action Competing effects may reduce effectiveness of one agent Eg. Penicillins + vancomycin – cell wall synthesis inhibitors Eg. Tetracyclines + aminoglycosides –protein synthesis inhibitors via 30-S subunit of the ribosome

57 Map the Drugs – Summary From: http://commons.wikimedia.org/wiki/File:Antibiotics_Mechanisms_of_action.png Accessed Dec 28/12http://commons.wikimedia.org/wiki/File:Antibiotics_Mechanisms_of_action.png For: TB, MRSA For: skin, dental infx (staph, strep, & anaerobes )

58 Part 3 – Map the Battlefield

59 Map the Battlefield Rational Prescribing Individual 1.Efficacy – Could be reduced, BUT: – Empiric tx still effective if it is well chosen (Lower risk infections, properly dosed, clinically stable, true indication etc.) 2.Toxicity – Reduced with narrow spectrum tx 3.Cost – Reduced with older tx 4.Convenience – Usually less convenient Population 1.Efficacy – Maintained long term with lower resistance rates 2.Toxicity – Reduced since lifespan of older drugs is maintained 3.Cost – Reduced insurance costs, economic losses, hospital costs dealing with superbugs 4.Convenience VS.

60 Map the Battlefield

61 Conjunctivitis: viral – no tx Sinusitis: viral – no tx Oral anaerobes: abscess drainage – no tx (Amox 2g – pre dental sx?) Pharyngitis: viral – no tx (Group A Strep – Pen VK) Bronchitis: viral – no tx Skin abscess: drainage – no tx H.pylori: triple po tx PPI + (Clarithro +/- Amox +/- Metro) Cdiff / Bfrag: Metro / po Vanco Otitis media: S.pneumo, Hi,M (Amox +/- Clav, Cef2, Septra) AECOPD: S.pneumo, Hi,M (Amox +/- Clav, Cef2, Septra) C.A.P: S.pneumo, atypicals – (Amox, Macrolides (Clarithro/Azithro)) CAP+comorb./risk factors, or NHAP: also HiM bugs (Combine AmoxClav or Cef2 + Macrolide (or use FQ)) Cellulitis: MSSA, S.pneumo – (Clox, Cef1, Clinda) UTI (Cystitis): PEcK – (Septra, Macrobid, Amox, Norflox) Pyelonephritis: PEcK – (Septra, Amox/Clav, FQ (not Norflox) Traveller’s Diarrhea : (80% bacterial): EcSS, (camphlyobacter) - Septra, FQ, (Azithro)

62 Map the Battlefield Penicillin (Group A Strep, oral anaerobes, Neisseria) Amoxicillin / AmpicillinCloxacillin (Strep & Enterococcus plus (Staph aureus, Staph epi) Easy-to-Kill Gm[-](ie. PEcKSS)) Amox/Clav(Vancomycin) (for Strep & Entero & PEcKSS-HiM)(for MRSA / MRSE) (H.flu & Moraxella can be ~35% amox resistant)(~8-10% / ~ 65% resistant)

63 Beta-Lactams - Cephalosporins 1 st Generation – Cephalexin (Keflex™) or Cefadroxil (po) – Cefazolin (Ancef™) (iv) 2 nd Generation – Cefuroxime (po & iv) 3 rd Generation – Ceftriaxone, Cefotaxime, Ceftazidime (iv) – Cefixime (Suprax™) (po) 4 th Generation – Cefipime (iv) Increasing Gram[-] coverage MSSA and Strep & PEcKSS (same as Amox) N.B. never Enterococcus! To boost: for PEcKSS-HiM (same as Amox/Clav) SPACE bugs: The Big Guns

64 SPACE bugs The Big Guns: – 3 rd and 4 th generation Cephalosporins – Carbapenems (Meropenem) – Piperacillin/Tazobactam – Aminoglycosides (Gentamicin, Tobramicin) – Fluoroquinolones (Levofloxacin, Moxi, Cipro)

65 Reserved for Pseudomonas Ciprofloxacin (FQ) – The only PO agent! – (Use Norfloxacin for UTI if a FQ is needed) Ceftazidime (Cef3) Cefipime (Cef4) Tobramycin (AG) Piperacillin/Tazobactam Meropenem

66 Need for Bigger guns There is a higher risk of Gram negative SPACE bugs with: – More risk factors / comorbidities – COPD, HIV, Diabetes, CKD etc – More institutionalized settings Community  Retirement Home  Nursing Home  Hospital ward  ICU  ventilated pt in ICU.

67 Map the Battlefield PEN – for Group A Strep, oral anaerobes, Neisseria ?What to do for Strep/Entero? – Amox po / Amp iv (also good for PEcKSS) – How to boost? Amox/clav (for HiM-PEcKSS) ?What to do for Staph? – Clox (MSSA, MSSE); Else Vanco (MRSA, MRSE) What about Cef1? (cephalexin / cefadroxil po or cefazolin iv) – Maps to Amox/Amp for PEcKSS and strep N.B. NOT Enterococcus (Cef’s never cover enterococcus!) – How to boost? Cef2 (cefuroxime) for HiM-PEcKSS What about SPACE bugs? – FQs, AGs, Cef3, Cef4, Pip/Tazo, Meropenem) – Reserved for Ps aureginosa:(cipro, tobra, ceftazidime, cefipime, pip/tazo, meropenem) What about gut anaerobes? (Metro/PO Vanco) What about atypicals? (Macrolides, Tetracyclines (doxy)) Where does Septra fit? (with Amox/Clav and Cef2)

68 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 (>2 grams) single dose metronidazole Chloramphenicol (at term or during labour): limited glucuronidating capacity of the newborn’s liver Ref: Marc Riachi, RPh

69 Antibiotics Preferred in Pregnancy Penicillins Including those in combination with ß-lactamase inhibitors (clavulanic acid, sulbactam, and tazobactam) Cephalosporins Erythromycin base Azithromycin Clindamycin Metronidazole (regular dose 250-500 mg BID) Ref: Marc Riachi, RPh

70 Summary This is far from an exhaustive review Some parts have been highly simplified for use in clinical practice Some memorization is needed with regular review of the material to retain this knowledge Doing so will allow you to choose empiric antibiotics with greater comfort in difficult situations and unfamiliar settings.

71

72 Comments, Questions & Requests? rhalil@bruyere.org Monday & Fridays: – 613-230-7788 ext 238 Tuesday, Wednesday, Thursday: – 613-241-3344 ext 327 Twitter: @Roland Halil, PharmD

73 TB drugs Adapted from: Marc Riachi, RPh

74 Mycobaterium tuberculosis The Consumption Mostly latent, asymptomatic infection (90-95%) – Activation risk ~ 10% – Usually pulmonary; can occur anywhere – Spreads via air droplet – One third of world population infected! Europe:, TB rates rose from 1600s to peak in the 1800s (caused ~25% of all deaths) Organism has "waxy" hard to penetrate cell wall – Acid-fast bacilli – Combinations of drugs needed to treat Slow growing – Therefore requires extended treatment period Treatment: – Multiple side effects = reduced compliance by patient = further emergence of resistant strains – MDR, XDR strains Adapted from: Marc Riachi, RPh

75 Available antimycobacterials First-line: – Isoniazid (INH) – Rifampin (RIF) or Rifampicin (RMP) – Pyrazinamide (PZA) – Ethambutol (ETB) Second-line: – Amikacin – FQs (Ciprofloxacin / Levofloxacin / Moxifloxacin) – Clarithromycin / Azithromycin Ref: Marc Riachi, RPh

76 Treatment - Active Pulmonary TB “4 drugs x 2 months, then 2 drugs x 4 mo” (N.B. 2x/weekly dosing must be D.O.T.) Ref: PHAC. Canadian Tuberuclosis Standards, 6th Ed. 2007 p. 130 http://www.phac-aspc.gc.ca/tbpc-latb/pubs/pdf/tbstand07_e.pdf Access March 14, 2013.http://www.phac-aspc.gc.ca/tbpc-latb/pubs/pdf/tbstand07_e.pdf Access March 14

77 Treatment – Latent TB INH – monitor LFTs – Hepatitis (rare 2% in >50y.o.) – Drug interactions! RIF – GI toxicities, major drug interactions! – Huge inducer of cytochrome P450 Ref: PHAC. Canadian Tuberuclosis Standards, 6th Ed. 2007 p. 148 http://www.phac-aspc.gc.ca/tbpc-latb/pubs/pdf/tbstand07_e.pdf Access March 14, 2013.http://www.phac-aspc.gc.ca/tbpc-latb/pubs/pdf/tbstand07_e.pdf Access March 14

78 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+PZA+ETB+FQ if resistant to INH and RIF: – PZA+ETB+FQ+amikacin If resistant to INH, RIF and PZA or ETB – ETB (or PZA)+FQ+amikacin+two 2 nd line agents Ref: Marc Riachi, RPh

79 Comments, Questions & Requests? rhalil@bruyere.org Monday & Fridays: – 613-230-7788 ext 238 Tuesday, Wednesday, Thursday: – 613-241-3344 ext 327 Twitter: @Roland Halil, PharmD

80 Anti-fungals Adapted from: Marc Riachi, RPh

81 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 vit B6) – GI symptoms, skin rash – ↑ phenytoin, carbamazepine & benzodiazepine blood levels RIF (inhibits mRNA synthesis): – Bactericidal; penetrates cavitations – Hepatotoxicity (↑ with alcohol)  monitor LFTs – GI symptoms, skin rash – Pancytopenia – Colours 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 Ref: Marc Riachi, RPh

82 Antifungals Oral – Azole anti-fungals Itra- (Sporanox), flu- (Diflucan), vori-, posa- ketoconazole (Nizoral) active vs. yeast and dermatophytes – Terbinafine (Lamisil) active vs. yeast and dermatophytes – Nystatin active vs. yeast only Topical – Ciclopirox (cream, lacquer, shampoo), – nystatin (cream, pv, oral suspension), – clotrimazole (cream, pv), – miconazole (cream, pv), – ketoconazole (cream shampoo), – terbinafine (cream, spray), – tolnaftate (powder  suitable for skin folds) Injectables – usually require I.D. consult Ref: Marc Riachi, RPh

83 Which agents to use? Onychomycosis: – oral terbinafine, oral itraconazole, ciclopirox lacquer (use lacquer only for mild distal form; expensive) 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. Ref: Marc Riachi, RPh

84 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. Ref: Marc Riachi, RPh

85 Comments, Questions & Requests? rhalil@bruyere.org Monday & Fridays: – 613-230-7788 ext 238 Tuesday, Wednesday, Thursday: – 613-241-3344 ext 327 Twitter: @Roland Halil, PharmD

86 Hypertension and BP Meds (The ABCD’s of HTN) Dr Roland Halil, BSc(Hon), BScPharm, ACPR, PharmD Pharmacist, Bruyere Academic FHT Assistant Professor, Dept Family Medicine, U of Ottawa March 2013

87 Objectives List first line classes of medication for the treatment of essential hypertension Explain how co-morbid indications may change your choice in therapy Apply a rational approach in selecting therapy Understand the dosing, monitoring and titration of key examples from each class of medication

88 Rational Prescribing Rational prescribing requires a process for selecting therapy: (in order) 1.Efficacy 2.Toxicity 3.Cost 4.Convenience

89 AABCD ARBACEinhB-blockersCCB (DHP-type) Diuretics (Thiazide type) Angiotension Receptor Blocker Angiotensin Converting Enzyme Inhibitor Beta-BlockerCalcium Channel Blocker (dihydropyridine type) -sartan-pril-olol-dipine Losartan Valsartan Candesartan Etc Ramipril Enalapril Perindopril Etc Bisoprolol Metoprolol Atenolol Etc Amlodipine Nifedipine Felodipine Etc Chlorthalidone Hydrochlorothiazide Indapamide Etc Blocks conversion of AT1 to ATII (ACEinh) or blocks ATII receptors (ARB) = Inhibition of vasoconstriction, aldosterone, catecholamine, and arginine vasopressin release, water intake, and hypertrophic responses Reduced sympathetic outflow, and heart rate (b1 receptor – in heart) (cardioselective ~ A-M) (b2 receptor – in lungs) (Non-selective ~ N-Z) (“one heart; two lungs”) Relaxation of coronary & peripheral arterial smooth muscle (not AV node!) Inhibits Na+ & Cl- reabsorption in the cortical- diluting segment of the ascending loop of Henle = diuresis. Reduction in systemic vascular resistance Efficacy: 1 st line1 st line1 st line (< 65y.o.)1 st line

90 AABCD Toxicity : Hypotension HyperK+ Acute renal failure (ARF) Angioedema Monitor: SCr, K+, BP Toxicity : Hypotension Bradycardia Bronchoconstric tion (in brittle asthmatics with non- cardioselective bbl’s) Monitor: BP, HR, RR Toxicity : Hypotension Edema Orthostatic hypotension Toxicity : Hypotension HypoNa+ HypoK+ ARF Monitor: SCr, lytes, BP Cost: Generic - $$$ ODB covered Cost: Generic - $ ODB covered Cost: $ ODB covered Cost: Generic: $$$ ODB covered Cost: ¢ ODB covered Convenience: QD Losartan 25mg to 100mg Convenience: QD Ramipril 2.5mg to 10mg Convenience: QD Bisoprolol 2.5mg to 10mg Convenience: QD Amlodipine 2.5mg to 10mg Convenience: QAM Chlorthalidone 25mg

91 Choosing Therapy If efficacy (#1), cost (#3) and convenience (#4) are all more or less equivalent: – Choose based on potential Toxicities (#2) – Tailor the meds to the individual patient! Evidence of efficacy is population based Toxicities are individual. Some combos are additive others synergistic BP lowering – Rarely clinically relevant – Can choose between groups A or B plus C or D (synergistic) N.B. Choice will also be guided by various comorbidites

92 Comorbidities Indication ARBACEinhBCD HTN (ALLHAT) MI(HOPE trial)(VALIANT) ( CAPRICORN, BHAT) CHF ( CONSENSUS, SOLVD, ATLAS) (MERIT-HF, CIBIS II, COPERNICUS ) DM2 (HOPE) (IDNT, IRMA-2, RENAAL) CVA (HOPE, PROGRESS) (LIFE, SCOPE, MOSES) (ALLHAT, PROGRESS) PVD (HOPE) Afib (Diltiazem)

93 Second Line Therapy What if you have used all available 1 st line options? 2 nd line options: – Alpha blockers – Spironolactone – Hydralazine – Nitrates – Clonidine – Beta-blockers (> 65 y.o.) – etc. ~ Equivalent efficacy – choose based on potential toxicity, cost or convenience factors. Ensure that you balance these factors in their order of importance.

94 Second Line Therapy Alpha blockers – Eg. Terazosin, Prazosin, Doxazosin – Toxicity: Risk of orthostatic hypotension – Cost: cheap, generic – Convenience: only QD Good 1 st choice of 2 nd line tx Dual treatment of BPH & BP if also needed in male patients Spironolactone – Efficacy: mortality benefit in late stage CHF (NYHA class III or IV) – Toxicity: risk of hyperK+ esp with ARBs or ACEinh’s – Cost: cheap generic – Convenience: only QD Hydralazine – MOA: direct vasodilation of arteries – Toxicity: orthostatic hypotension – Cost: cheap, generic – Convenience: QID dosing Nitrates – eg. ISDN, ISMN, NTG – MOA: smooth muscle vasodilation of vasculature (veins > arteries); – Toxicity: headache, orthostatic hypotension, dizziness – Cost: cheap/ generic – Convenience: BID- QID dosing;

95 Process 1.Start first drug 2.Increase to moderate dose 3.Monitor for efficacy (BP) and toxicity If close to target: – increase dose If far from target: – start new drug Dose response curves – Flatten at top half – Less bang for your buck mg BP

96 Comments, Questions & Requests? rhalil@bruyere.org Monday & Fridays: – 613-230-7788 ext 238 Tuesday, Wednesday, Thursday: – 613-241-3344 ext 327 Twitter: @Roland Halil, PharmD

97 Oral Anti-hyperglycemics Dr Roland Halil, BSc(Hon), BScPharm, ACPR, PharmD Pharmacist, Bruyere Academic FHT Assistant Professor, Dept Family Medicine, U of Ottawa March 2013

98 Objectives List the classes of oral antihyperglycemic agents and understand their place in therapy. – Determine the relative efficacy, toxicity, cost and convenience of these agents before choosing therapy – Rationalize prescribing of oral hypoglycemics Describe the current approach to pharmacologic management of type 2 diabetes.

99 Diagnosis of IFG, IGT CategoryFPG And/or 2-hour after OGTT IFG6.1-6.9N/A IFG (isolated)6.1-6.9AND< 7.8 IGT (Isolated)< 6.17.8-11.0 IFG and IGT6.1-6.97.8-11.0 Can J Diabetes 2003;27(2);S11

100 MACROvascularMICROvascular Stroke Heart disease & hypertension Foot problems Diabetic eye disease (retinopathy & cataracts) Nephropathy Neuropathy Foot problems Diabetes: complications Peripheral vascular disease

101 Kumamoto Study – HgbA1c & Complications 567891011 1098765 HbA1c (%) Rate per patient-years Intensive vs. conventional insulin therapy (n=110) Median A1c - 7.1% vs. 9.4% 0 2 4 6 8 6 10 12 14 16 10 16 14 12 8 4 2 0 7% RetinopathyNephropathy

102 Prevention of Diabetes in IGT Lifestyle modification – (see Finnish Diabetes Trial) – Moderate weight loss (5%) (esp. abd fat) – Regular physical activity > 150 minutes per week – 58% RRR for type 2 Diabetes at four years Pharmacotherapy – Multiple effective trials Eg. LIFE trial - Losartan  onset of new DM2 Can J Diabetes 2003;27(2);S12

103 Pharmacological Prevention Studies StudyDrugDuration (years) RRR (%) DPP Metformin 850mg BID 2.831 STOP- NIDDM Acarbose 100mg TID 3.330 DREAM Rosiglitazone 8mg daily 3.055 XENDOS Orlistat 120mg TID 4.037

104 Non-Pharmacologic Tx Mainstay of therapy! Nutrition therapy – ↓ A1c 1-2% – CDA recommends counseling by a dietician for all type 2 diabetics – www.cvtoolbox.com diet for Type 2 diabetes Can J Diabetes 2003;27(2);S27

105 Pharmacotherapy Comparison of antihyperglycemics

106 Drug Classes SensitizersSecretagogues Other

107 Drug Classes Sensitizers Metformin Glitazones – Rosiglitazone (AVANDIA) – Pioglitazone (ACTOS) Secretagogues Sulfonylureas – Eg. Glyburide, Gliclazide Meglitinides – Eg Repaglinide (GLUCONORM) Other Alpha glucosidase inhibitors (Acarbose) DPP4 inhibitors (Gliptins) Incretin Analogues Sitagliptin (JANUVIA) * Liraglutide (VICTOZA) (sc inj) Saxagliptin (ONGLYZA) * Exenatide (BYETTA) (sc inj)

108 Drug Classes Sensitizers Metformin Glitazones – Rosiglitazone (AVANDIA) – Pioglitazone (ACTOS) Sensitizers – reduce insulin resistance Increase glucose uptake & utilization in muscle and adipose tissue Reduce hepatic glucose output

109 Drug Classes ↑Basal & prandial insulin secretion, ↓hepatic gluconeogenesis Doesn’t correct impaired 1 st phase insulin secretion; primarily affects 2 nd phase Beta-cell sensitizer – primes glucose mediated insulin secretion (1 st phase) Secretagogues Sulfonylureas – Eg. Glyburide, Gliclazide Meglitinides – Eg Repaglinide (GLUCONORM)

110 Drug Classes Other Alpha glucosidase inhibitors (Acarbose) Competitive inhibitor of pancreatic α-amylase and intestinal brush border α- glucosidases, resulting in delayed hydrolysis of ingested complex carbohydrates and disaccharides and absorption of glucose; Dose-dependent reduction in postprandial serum insulin and glucose peaks; inhibits the metabolism of sucrose to glucose and fructose DPP4 inhibitors (Gliptins) – (Sitagliptin (Januvia), Saxagliptin (Onglyza)) Prolongs the action of endogenous incretin hormones by blocking their breakdown by the enzyme, dipeptidyl peptidase-4 (DPP-4). This leads to more insulin release after eating. Incretin Analogues – (Liraglutide (Victoza), Exenatide (Byetta)) (sc inj) mimic endogenous incretin hormones

111 Rational Prescribing FOUR steps to Rational Prescribing: 1.EFFICACY 2.TOXICITY 3.COST 4.CONVENIENCE

112 EFFICACY – Ask… 1.HARD Outcomes a)Any mortality benefit? b)Any morbidity benefit? Then, 2.SURROGATE Outcomes a)Clinically relevant?

113 EFFICACY 1.HARD Outcomes – Mortality benefit » Metformin » Metformin – UKPDS-34 trial – Morbidity 2.SURROGATE Outcomes a)Hgb-A1c Blood glucose levels – Fasting or Prandial b)Insulin Sparing Effects

114 Effect of Metformin on Event Rates in the UKPDS Diabetes-related endpoint  32% p=0.002 All-cause mortality  36% p=0.011  MI / CVA Diabetes-related death  42% p=0.017 – But.. When added early to sulfonylurea  risk of DM-related death (?statistical anomaly?)

115 EFFICACY A) Surrogate Outcome - Hgb-A1c – ~ 1% to 2% METFORMIN (1% - 2%) SULFONYLUREA’s (1% - 2%) REPAGLINIDE (1% - 1.5%) GLITAZONE’s (0.4% - 1.5%) – ~ 0.5% to 0.8% ACARBOSE DPP4 inhibitors (‘GLIPTINS) NATEGLINIDE Nathan DM, et al. Diabetes Care 2008 (Dec);31:1-11.Diabetes Care 2008 (Dec);31:1-11

116 EFFICACY B) Surrogate Outcome - Insulin Sparing Effect – METFORMIN – ACARBOSE – GLITAZONE’s (Pioglitazone) – Gliptins (Sitagliptin, Saxagliptin) – Incretin Analogies (Liraglutide, Exenatide) = Weight neutral or weight negative = Reduction of hyperinsulinemia

117 TOXICITY – Ask… 1.Serious / Fatal Side Effects 2.Bothersome / Common s.e. 3.Age? Newer agents = Less Safety Data Older agents = More Safety Data

118 TOXICITY – Serious / Fatal Glitazones – CHF – Fractures – M.I. (rosiglitazone) – Bladder Cancer (pioglitazone) Secretatgogues (Sulfonylureas & Meglitinides) – Severe Hypoglycemia

119 TOXICITY – Serious / Fatal Metformin ?Risk of Lactic Acidosis – 0.03 cases / 1000 pt-yrs – ~ 50% fatal – When implicated: Metformin plasma levels are usually >5 μg/mL Cases - primarily diabetics w/ significant renal insufficiency, both intrinsic renal disease and renal hypoperfusion, w/ multiple medical/surgical problems and multiple medications.

120 Metformin Dosing Dosing recommendations with renal insufficiency: – (CONTROVERSIAL) CrCl 60ml/min→ – 1700 mg/day (Rxfiles) – 2.5g/day (Roland) CrCl 30ml/min→ – 850mg/day (Rxfiles) – 2.5g/day (Roland) CrCl < 30ml/min→ – Contraindicated (Rxfiles) – 1g/day (>20mL/min) (Roland) If NO other risk factors, else D/C. – Take home: assess OTHER RISK FACTORS for L.A.

121 Severe renal impairment – (caution if CrCl < 30ml/min) and Hepatic disease alcoholism CHF COPD CRF Pneumonia Ongoing acidosis – Lactic, keto etc. Risk Factors - Lactic Acidosis

122 TOXICITY - Bothersome 1) METFORMIN – GI upset / diarrhea – Start low, go slow! Initial dose 250mg QDaily to BID – B12 / folate deficiency / anemia (6 - 8/100) Reduced absorption – so, supplement – Anorexia – usually transient – Metallic taste

123 TOXICITY - Bothersome 2) Sulfonylureas: – Sulfa skin reactions Rash / photosensitivity ~1% – Weight gain (2-3kg) – Mild Hypoglycemia: Most with glyburide. Least w/ glimepiride & gliclazide Requires consistent food intake Major episodes 1-2% (esp. in elderly)

124 TOXICITY - Bothersome 3) Glitazones: – Edema 4) Meglitinides: – Hypoglycemia 5) Acarbose: – GI upset / diarrhea / bloating 6)Gliptins: GI upset, edema, ?infection 7)Incretin analogues N/V/D, ?infection

125 Cost – Ask… Patient cost vs societal cost Rx cost? ODB coverage? Covered under other plans?

126 Cost/tab – ODB covered? Metformin- $ 0.0587 - ODB Glyburide- $ 0.0574 - ODB Gliclazide- $ 0.0931 - ODB – Gliclazide MR $ 0.1405 - ODB Repaglinide- $ 0.- Section 8 (EAP) Acarbose- $ 0.3584 - ODB Sitagliptin- $ 2.8050 - ODB Saxagliptin- - No Pioglitazone- $ 0.- Section 8 (EAP)

127 Cost From Rxfiles May 2010 Cost per 100 days therapy (in Sask.)

128 Convenience PO vs IV? QD vs QID?

129 Convenience Gliptin’s - QD Glitazones - QD Sulfonylureas– QD to BID Metformin - QD to TID Meglitinides – QD to TID with meals Acarbose – QD to TID

130

131 1 st line – METFORMIN 2 nd line - SULFONYLUREA or INSULIN – Meglitinide – if poor CrCL or irregular eating 3 rd line - GLIPTINs or ACARBOSE if patients absolutely REFUSE insulin NEVER USE GLITAZONEs! Did I say, never? I meant NEVER!

132 Individualization of Drug Therapy Patient FactorConsider→ Possibly preferred drugs Renal FailureRepaglinide (Gluconorm) Also: gliclazide, insulin Hepatic DiseaseInsulin, repaglinide, acarbose Caution: glyburide, metformin, glitazones HyoglycemiaMetformin, Acarbose Also, repaglinide, nateglinide, gliclazide, glimepiride; ObeseMetformin, Acarbose Irregular MealtimesRepaglinide (may be preferred over SU) PPBG >10mmol/L and FBG minimally ↑’d Repaglinide or Acarbose Insulin lispro (Humalog) if PPBG very high www.rxfiles.ca

133 Comments, Questions & Requests? rhalil@bruyere.org Monday & Fridays: – 613-230-7788 ext 238 Tuesday, Wednesday, Thursday: – 613-241-3344 ext 327 Twitter: @Roland Halil, PharmD

134 Insulins Dr Roland Halil, BSc(Hon), BScPharm, ACPR, PharmD Pharmacist, Bruyere Academic FHT Assistant Professor, Dept Family Medicine, U of Ottawa March 2013

135 New Drugs/Drug News vol 24 (3): May/June 2006

136 Insulins - Simplified Long = Basal – NPH, (N) – Glargine (Lantus) – Detemir (Levemir) Short = Prandial – Short Regular (R) Toronto – Rapid Lispro (Humalog) Aspart (NovoRapid) Glulisine (Apidra) Which to choose? Premixed 30/70 (and 10/90, 20/80, 40/60, 50/50) Humalog Mix-25, NovoMix-30

137 Basic Concepts Hyperglycemia = Chronic Hypoglycemia = Acute – So, go after Hypo’s first! Fed: 6h/24h = 25% Fasting: 18h/24h = 75% – So, go after Fastings first! AM affects PM & HS – So, go after AM first! 1.?Any hypo’s?- fix ‘em! then, 2.FBS AM 3.FBS Noon 4.FBS PM 5.FBS HS then, 6.2h PPG AM 7.2h PPG Noon 8.2h PPG PM

138 Insulins Long – Basal – NPH, (N) – Glargine (Lantus) – Detemir (Levemir) Short – Prandial – Short Regular (R) Toronto – Rapid Lispro (Humalog) Aspart (NovoRapid) Glulisine (Apidra) Now, which to choose? Premixed 30/70 (and 10/90, 20/80, 40/60, 50/50) (R + NPH) Humalog Mix-25, NovoMix-30 (Rapid + NPH)

139 Rational Prescribing FOUR steps to Rational Prescribing: 1.EFFICACY 2.TOXICITY 3.COST 4.CONVENIENCE

140 Long – Basal Insulins Efficacy: – NPH = Lantus = Levemir = NPH – Equivalent Morbidity benefits, A1c lowering effect – Despite the marketing: Kinetics don’t affect overall efficacy: – Slowest absorption: Thigh (best for basal insulins) – Fastest absorption: Abdomen (best for prandial insulins) Lots of Lantus is injected BID NPH can be used QHS for some

141 Long – Basal Insulins Toxicity: – All: Hypoglycemia – NPH: Peak effect at ~ 8hrs (4-10hrs) – Risk of hypoglycemia (~ 5%? vs “peakless” insulins) – Lantus / Levemir: Insulin analogues Increased breast cancer risk? – more research needed

142 Long – Basal Insulins Cost: – All: covered under ODB N.B. No Rx required for any insulins – all OTC – NPH: ~ $40 – Lantus: ~ $90 – Levemir: ~ $100 Convenience: – All sc injections, via penfills – All QD – BID

143 Bottom Line – Basal Insulins All equivalent Choose therapy based on cost (NPH) – For the very small proportion suffering from hypoglycemia due to the peak effect of NPH or lamenting BID dosing, consider Lantus or Levemir.

144 Starting Basal Insulin Fancy Way: – calculate unit/kg dose = 0.1 - 0.2u/kg/day sc Risk hypoglycemia on first dose – lose your patient’s buy-in forever. Primary Care Method: – Initiate 5u or 10u qhs sc – Titrate by 1-2u q3-4d until AM FBS = 4 - 7 mmol/L 10% titrations – If dose = 30’s – increase by 3 units – If dose = 40’s – increase by 4 units – etc. etc.

145 Rx 1.NPH – Sig: 5u qhs sc or ud – M: 1 box penfills – Repeat x 12 2.Needle tips – 28G - 6mm – Sig: ud – M: 1 box – r x 12 N.B. (Please teach pt pen technique)

146 Insulins Long = Basal – NPH, (N) – Glargine (Lantus) – Detemir (Levemir) Short = Prandial – Short Regular (R) Toronto – Rapid Lispro (Humalog) Aspart (NovoRapid) Glulisine (Apidra) Premixed 30/70 (and 10/90, 20/80, 40/60, 50/50) (R + NPH) Humalog Mix-25, NovoMix-30 (Rapid + NPH)

147 Short – Prandial Insulins Efficacy – Equivalent reduction in morbidity, HgbA1c

148 Short – Prandial Insulins Toxicity – Hypoglycemia – Rapid insulins better reflect physiological effect of pancreatic insulin (vs Regular insulin) More important in CKD (=longer insulin t½ )

149 Short – Prandial Insulins Cost – All covered under ODB Regular (R) / Toronto ~ $40 NovoRapid (aspart) ~ $56 Humalog (lispro) ~ $55 Apidra (glulisine) ~ $48 Convenience – All injected with meals – Regular insulin injected 30-45 min before meal – Rapid insulin can be taken with meal Reduced risk of hypo if pt injects, then forgets to eat

150 Bottom Line – Prandial Insulins All equivalent Choose therapy based on cost / familiarity – Rapid insulins reflect pancreatic insulin release better than [R]/Toronto. – The worse the CrCL, the more important this fact becomes.

151 Starting Prandial Insulin Fancy Way: – Total dose: 0.5u/kg – 40% of total dose - basal insulin qHS – 20% of total dose TID with meals (60%) – prandial insulin 15- 30 min before meals Eg. 80kg pt – 0.5u/kg = 16u basal (40%) ; 8u TID (20% x 3 = 60%) Primary Care Method: – Start 5u sc with meals Titrate AM to HS to target – Monitor 2h PPG Start injection TID or only single meal as required – If poor control: inj TID sc; If mediocre control: inj qAM sc Still aim for ~ 2/3 rds split (40% basal / 60% prandial)

152 Insulins Long = Basal – NPH, (N) – Glargine (Lantus) – Detemir (Levemir) Short = Prandial – Short Regular (R) Toronto – Rapid Lispro (Humalog) Aspart (NovoRapid) Glulisine (Apidra) Premixed 30/70 (and 10/90, 20/80, 40/60, 50/50) (Reg + NPH) Humalog Mix-25, NovoMix-30 (Rapid + NPH)

153 Pre-mixed Insulins NovoMix-30 = Humalog Mix25 (equivalent) Efficacy – All ~ 30% short / 70% long Toxicity – Hypoglycemia (less with Rapid vs Regular insulin) Cost: ~$53 (Rapids) ~$40 (Regular 30/70) Convenience ~ Rapids can be injected with meal

154 Starting Pre-mixed Insulins Fancy Way: – Estimate total starting daily dose (0.3-0.6 units/kg) – Divide daily dose: 2/3 before breakfast; 1/3 before supper Primary Care Method: – From scratch: Start 5-10u QD-BID and titrate – From other insulins: Calculate approximate amount of basal and prandial units and divide 2/3 rd - 1/3 rd AM and PM

155 Pearls Insulin is 2 nd line after metformin – No need to save it for last! Better than adding a 3 rd PO drug – Better efficacy, lower toxicity, better studied Improve buy-in from patient: – “Natural” supplement – Only BID glucochecking at alternating times required: FBS AM + PPG AM, then FBS AM + FBS noon, then FBS AM + PPG noon, then FBS AM + FBS PM, then FBS AM + PPG PM, then FBS AM + FBS HS repeat

156 Pearls (cont’d) D/C secretagogues after starting insulin to reduce risk of hypo’s. – Eg. Sulfonylureas, meglitinides – Black box warning against combo with glitizones! (Actos, Avandia)

157 Comments, Questions & Requests? rhalil@bruyere.org Monday & Fridays: – 613-230-7788 ext 238 Tuesday, Wednesday, Thursday: – 613-241-3344 ext 327 Twitter: @Roland Halil, PharmD

158 Anti-Dyslipidemic Drugs (So simple it hurts) Dr Roland Halil, BSc(Hon), BScPharm, ACPR, PharmD Pharmacist, Bruyere Academic FHT Assistant Professor, Dept Family Medicine, U of Ottawa March 2013

159 Objectives List the 4 steps in rationalizing drug therapy choices using evidence based medicine. List the important parameters in choosing anti-dyslipidemia drugs in a clinical setting. Identify clinically important differences in the efficacy, toxicity, cost and convenience of different anti-dyslipidemics. Recognize the inherent weaknesses of current guidelines.

160 Rational Prescribing Process FOUR steps to Rational Prescribing: 1.EFFICACY 2.TOXICITY 3.COST 4.CONVENIENCE

161 Choosing Anti-dyslipidemics First, define your options: 1.Statins (HMG-CoA Reductase inhibitors) Prava-, Fluva-, Simva-, Atorva-, Rosuva-statin 2.Fibrates (The exact mechanism of action of gemfibrozil is unknown; Theories re: the VLDL effect; it can inhibit lipolysis and decrease subsequent hepatic fatty acid uptake as well as inhibit hepatic secretion of VLDL; together these actions decrease serum VLDL levels; increases HDL-cholesterol; the mechanism behind HDL elevation is currently unknown) Feno-, Beza-, Clo-fibrate, & Gemfibrozil 3.Ezetimibe (Inhibits absorption of cholesterol at the brush border of the small intestine via the sterol transporter, Niemann-Pick C1-Like1 (NPC1L1)). 4.Niacin 5.Cholestyramine (Bile acid sequestrant)

162 Efficacy – Endpoints? Hard Endpoints – Reduction in mortality Fatal MI, Fatal stroke – Reduction in morbidity Non-fatal MI, non-fatal stroke, reduction in hospitalization Soft Endpoints – Reduction in plaque size – Reduction in lipid panel values – etc

163 Efficacy Only statins have any proven reduction in hard endpoints.

164 The End.

165 Who cares about lipid panel numbers going up and down if they don’t affect morbidity or mortality? So….why bother with the Toxicity, Cost or Inconvenience of any others?

166 Can J Cardiol Vol 25 No 10 October 2009

167 Cdn Dyslipidemia Guidelines 2009 Can J Cardiol Vol 25 No 10 October 2009

168 Cdn Dyslipidemia Guidelines 2009 Can J Cardiol Vol 25 No 10 October 2009

169 Pharmacotherapy “The majority of patients will be able to achieve target LDL-C levels on statin monotherapy.” “Clinical outcome data on the incremental benefit of combination therapy with statin plus ezetimibe, niacin or fibrate, versus statin monotherapy are lacking, although clinical trials are underway to examine this issue.” Can J Cardiol Vol 25 No 10 October 2009

170 Correlation versus Causation

171 Why statins? Lipid lowering effects vs Pleiotrophic effects – Plaque stabilizing – Anti-inflammatory – Improved endothelial cell function – Inhibition of thrombogenic response Liao JK, Laufs U. Pleiotropic effects of statins. Annu Rev Pharmacol Toxicol. 2005;45:89-118. see: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2694580/?tool=pubmed Accessed Apr 25/12.http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2694580/?tool=pubmed

172 So? So…. If equivalent LDL lowering with non-statin drugs have no effect on morbidity or mortality then LDL may only be a surrogate marker of the pleiotrophic effects of statins.

173 Bottom Line Being on any statin at any dose is the most important thing. Being on the highest dose of statin that a patient can tolerate is secondary. – Doubling the statin dose only lowers LDL by 6% – Pushing the statin dose to levels that result in side effects is just not worth it. Non-compliance will result. The LDL target is just your guide.

174 Exceptions Gemfibrozil – Two trials that show reduction in CVD events Helsinki Heart Study (HHS) Veterans Administration HDL Intervention Trial (VA-HIT) – Never combine it with statins Serious risk of rhabdomyolysis N.B. Fenofibrate – No effect on CVD events Fibrates for high TGs – reduce risk of pancreatitis Fibrates for high TGs – treatment of gout

175 Statin + Fibrate (ACCORD-Lipid Trial) No difference in vascular (hard) outcomes. – Almost a difference in lipids values (ie. soft outcomes) – ?Possible vascular harm in women? [9.1% vs 6.6%] Rxfiles.ca ACCORD Lipid & BP Trial Overview Sept 2010. Accessed Apr 26/12.

176 Statin + Ezetimibe (Lipid-ENHANCE Trial) No hard endpoints reported. Even intima-media thickness non-significant – IMPROVE-IT Trial still ongoing (expected 2013) – “Dr Steven Nissen (Cleveland Clinic, OH) questioned whether the trial would be completed because more than 5000 hard clinical end points are needed for the study to reach statistical significance, an unusually high number given that past studies required a few hundred events.” (see: http://www.theheart.org/article/1064755.do )http://www.theheart.org/article/1064755.do Rxfiles.ca. ENHANCE Trial Summary, June 2008. Accessed Apr 26/12.

177 “ …stopped early for futility.” – 3414 patients Earlier Statin + Niacin studies had only showed reduction in soft endpoints. – Eg. Regression of carotid atherosclerosis Statin + Niacin (AIM-HIGH Trial) Michael O'Riordan. AIM-HIGH fell short, leaving experts looking for reasons in new review. Heart.org APR 19, 2012. Accessed Apr 25/12 Rxfiles.ca. AIM-HIGH Trial Summary, Dec 2011. Accessed Apr 29/12.

178 Treatment Populations Who gets statins? – Secondary prevention – Primary prevention? – Moderate risk?? – Put it in the water???

179 Secondary Prevention Clear efficacy Reduction of mortality Reduction of morbidity Benefit in as little as one year – (usually 4-5 years)

180 Primary Prevention Clear efficacy in High Risk Framingham Reduction in morbidity No effect on mortality

181 Primary Prevention (never had an MI or Stroke) High risk Framingham patients with history of: – Diabetes – CKD – CHF – Angina – PVD – CABG or PCI – Metabolic syndrome – Score > 20%

182 Moderate Risk Likely not worthwhile… BUT, the JUPITER trial = reduction in hard endpoints! – Patients with low/normal cholesterol and high CRP – Relative Risk Reduction ~ 50%! – But the Absolute Risk Reduction was tiny! – hsCRP can differentiate between higher- and lower- risk Moderate Category Framingham patients Ridker PM, et al. the JUPITER Study Group. Rosuvastatin to Prevent Vascular Events in Men and Women with Elevated C-Reactive Protein. N Engl J Med. 2008 Nov 9.

183 JUPITER trial N Engl J Med 2008;359:2195-207. Rosuvastatin: 22/8901 (0.28%) of non-fatal MI Placebo: 62/8901 (0.70%) of non-fatal MI

184 Relative vs Absolute Risk

185 Time to Benefit How old is too old to start therapy? – Upper ages of trials ~ 80-83 yrs old. – …Add time to divergence of survival curves ~ 4 to 6 years… plus ?Prognosis Older than 85y.o, don’t start? – Already on it, don’t stop, but don’t bother checking LDL either.

186 Pharmacotherapy “The majority of patients will be able to achieve target LDL-C levels on statin monotherapy.” “Clinical outcome data on the incremental benefit of combination therapy with statin plus ezetimibe, niacin or fibrate, versus statin monotherapy are lacking, although clinical trials are underway to examine this issue.” Can J Cardiol Vol 25 No 10 October 2009

187 “…Trials (were) Underway…” Statin + Niacin trials: AIM-HIGH trial – Stopped early. No benefit from niacin in HDL raising. See: http://www.theheart.org/article/1231453.dohttp://www.theheart.org/article/1231453.do – Known risk of hepatotoxicty with Niacin and significant flushing. HPS2-THRIVE trial (statin + ER Niacin/Laropiprant) – No benefit (n = 25673) See: http://www.theheart.org/article/1515533.dohttp://www.theheart.org/article/1515533.do

188 Toxicity Statin – Rare/Severe: Myopathy, even Myositis/Rhabdomyolysis Hepatotoxicty Memory impairment ?Diabetes?? – discuss – Common/Bothersome: Myalgias Fibrates – Same as above Ezetimibe – Same as above Niacin – +++ flushing – Hepatotoxicity (esp with long acting form – Niaspan)

189 Cost All statins covered under ODB All statins are generic

190 Convenience Older statins require QHS dosing – Cholesterol synthesis mostly occurs late at night New statins last long enough to be dosed daily at any time Lacking grapefruit juice interaction: – Rosuvastatin, fluvastatin, pravastatin (non 3A4 P450 metabolism)

191 Comments, Questions & Requests? rhalil@bruyere.org Monday & Fridays: – 613-230-7788 ext 238 Tuesday, Wednesday, Thursday: – 613-241-3344 ext 327 Twitter: @Roland Halil, PharmD


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