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.)

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.

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

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

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

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.

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

1. Efficacy – Ask About… Which HARD Outcomes Which SURROGATE 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?

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.

2. Toxicity – Ask About… Age? Newer agents = Less Safety Data Bothersome Severe Common Not legal Rare Who cares Age? Newer agents = Less Safety Data Older agents = More Safety Data

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

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?

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

Efficacy HARD Outcomes SURROGATE 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

Toxicity Metformin Januvia® ?Unknown - too new 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?

Cost & Convenience Metformin Januvia® 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

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

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

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

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

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

Map the Bugs Aerobes Anaerobes 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Gram Positive Gram Negative Gram Positive Gram Negative Cocci Bacilli Cocci Bacilli Cocci Bacilli Cocci Bacilli 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

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’…

Map the Bugs Aerobes Anaerobes Above & Below diaphragm 9 Gram Positive Gram Negative Cocci Bacilli 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 Anaerobes Above & Below diaphragm B.Frag C.Diff 9 .

Map the Bugs Aerobes Anaerobes Below diaphragm 9 1 2 3 4 5 6 7 8 Gram Positive Gram Negative Cocci Bacilli 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 Anaerobes Below diaphragm B.Frag C.Diff 9 .

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

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

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

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

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

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

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

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

1 - Gram [+] Cocci Staphylococcus S. aureus S. epidermidis 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

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

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;

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

Part 2 - Map the Drugs (Save your Ammo)

Map the Drugs Arms race! Older drugs tend to be simpler drugs 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

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

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

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

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 Cefadroxil (po) 500mg BID or 1g BID – good alternative to KEFLEX 250mg QID or 500mg QID - Same spectrum of activity, only BID, cheap and covered by ODB too.

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.

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

Fluoroquinolones 2nd generation 3rd generation 4th 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. Not good enough for pyelonephritis or systemic infection

Fluoroquinolones The “Respiratory FQs” Levofloxacin Moxifloxacin Concentrate in alveolar macrophages Greater than serum concn Levofloxacin the more active L-enantiomer of Ofloxacin Renal clearance Moxifloxacin Hepatic clearance Enhanced coverage of: Strep pneumo Oral Anaerobes 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

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

Macrolides Coverage of: Clarithromycin Azithromycin Erythromycin 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)

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

Aminoglycosides Gentamicin Tobramycin Amikacin Reserved for Pseudomonas aeruginosa 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

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] Peak Log [Conc] MIC MIC Time (h) Time (h)

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 Peak Peak Log [Conc] Log [Conc] MIC MIC Time (h) Time (h)

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.

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

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

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

Part 3 – Map the Battlefield

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

Map the Battlefield

Map the Battlefield Otitis media: S.pneumo, Hi,M (Amox +/- Clav, Cef2, Septra) Conjunctivitis: viral – no tx Sinusitis: viral – no tx AECOPD: S.pneumo, Hi,M (Amox +/- Clav, Cef2, Septra) Oral anaerobes: abscess drainage – no tx (Amox 2g – pre dental sx?) 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)) Pharyngitis: viral – no tx (Group A Strep – Pen VK) Bronchitis: viral – no tx Skin abscess: drainage – no tx Cellulitis: MSSA, S.pneumo – (Clox, Cef1, Clinda) H.pylori: triple po tx PPI + (Clarithro +/- Amox +/- Metro) Pyelonephritis: PEcK – (Septra, Amox/Clav, FQ (not Norflox) UTI (Cystitis): PEcK – (Septra, Macrobid, Amox, Norflox) Cdiff / Bfrag: Metro / po Vanco Traveller’s Diarrhea: (80% bacterial): EcSS, (camphlyobacter) - Septra, FQ, (Azithro)

(Group A Strep, oral anaerobes, Neisseria) Map the Battlefield Penicillin (Group A Strep, oral anaerobes, Neisseria) Amoxicillin / Ampicillin Cloxacillin (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)

Beta-Lactams - Cephalosporins MSSA and Strep & PEcKSS (same as Amox) N.B. never Enterococcus! 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 Cefipime (iv) To boost: for PEcKSS-HiM (same as Amox/Clav) Increasing Gram[-] coverage SPACE bugs: The Big Guns Cefadroxil (po) 500mg BID or 1g BID – good alternative to KEFLEX 250mg QID or 500mg QID - Same spectrum of activity, only BID, cheap and covered by ODB too.

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

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

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.

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)

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

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

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.

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

Adapted from: Marc Riachi, RPh TB drugs Adapted from: Marc Riachi, RPh

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

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

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.

Treatment – Latent TB RIF – GI toxicities, major drug interactions! INH – monitor LFTs Hepatitis (rare < 20y.o.; >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.

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 2nd line agents Ref: Marc Riachi, RPh

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

Adapted from: Marc Riachi, RPh Anti-fungals Adapted from: Marc Riachi, RPh

Drug info PZA (may inhibit mycobacterial metabolism): 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): Hepatotoxicity (↑ with alcohol)  monitor LFTs 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

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

Which agents to use? Onychomycosis: Fungal skin: 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

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

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

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

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

Rational Prescribing Rational prescribing requires a process for selecting therapy: (in order) Efficacy Toxicity Cost Convenience

Reduced sympathetic outflow, and heart rate B C D ARB ACEinh B-blockers CCB (DHP-type) Diuretics (Thiazide type) Angiotension Receptor Blocker Angiotensin Converting Enzyme Inhibitor Beta-Blocker Calcium Channel Blocker (dihydropyridine type) -sartan -pril -olol -dipine Losartan Valsartan Candesartan Etc Ramipril Enalapril Perindopril Bisoprolol Metoprolol Atenolol Amlodipine Nifedipine Felodipine Chlorthalidone Hydrochlorothiazide Indapamide 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: 1st line 1st line 1st line (< 65y.o.)

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

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

Comorbidities ARB ACEinh B C D Indication HTN (ALLHAT) MI (HOPE trial)   (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 Afib (Diltiazem)

Second Line Therapy What if you have used all available 1st line options? 2nd 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.

Second Line Therapy Alpha blockers Spironolactone Hydralazine Nitrates Eg. Terazosin, Prazosin, Doxazosin Toxicity: Risk of orthostatic hypotension Cost: cheap, generic Convenience: only QD Good 1st choice of 2nd 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 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;

Process Start first drug Increase to moderate dose 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 BP mg

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

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

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.

Diagnosis of IFG, IGT Category FPG 2-hour after OGTT And/or IFG 6.1-6.9 N/A IFG (isolated) AND < 7.8 IGT (Isolated) < 6.1 7.8-11.0 IFG and IGT If 5.7-6.0 FPG + risk factor for diabetes/IGT order a 2hPG in a 75-OGTT. If 6.1-6.9 and no risk factor then IFG. Can J Diabetes 2003;27(2);S11

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

Kumamoto Study – HgbA1c & Complications Intensive vs. conventional insulin therapy (n=110) Median A1c - 7.1% vs. 9.4% Retinopathy 16 Nephropathy 16 14 14 12 12 Rate per patient-years Rate per patient-years 10 10 8 8 6 6 7% 7% 4 4 2 2 5 6 7 8 9 10 11 5 6 7 8 9 10 11 HbA1c (%) HbA1c (%)

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 ***Based on the Finnish Diabetes Prevention Study and the Diabetes Prevention Program. Can J Diabetes 2003;27(2);S12

Pharmacological Prevention Studies Study Drug Duration (years) RRR (%) DPP Metformin 850mg BID 2.8 31 STOP-NIDDM Acarbose 100mg TID 3.3 30 DREAM Rosiglitazone 8mg daily 3.0 55 XENDOS Orlistat 120mg TID 4.0 37 DPP Diabetes Prevention Program Metformin was more effective in younger more obese subjects and less effective among older, thinner people. STOP-NIDDM - Study to Prevent Non-Insulin Dependent Diabetes Mellitus TRIPOD Troglitazone in Prevention of Diabetes This glitazone was withdrawn from the market and was never availabe in Canada XENDOS Xenical in the prevention of diabetes in obese swedish subjects Prouded an average weight loss of 5.8 kg DREAM Published Sept 2006. Included patients with IFG or IGT or both.

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

Comparison of antihyperglycemics Pharmacotherapy Comparison of antihyperglycemics

Drug Classes Sensitizers Secretagogues Other

Drug Classes Sensitizers Secretagogues Other 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)

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

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

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

Rational Prescribing FOUR steps to Rational Prescribing: EFFICACY TOXICITY COST CONVENIENCE

EFFICACY – Ask… HARD Outcomes SURROGATE Outcomes Any mortality benefit? Any morbidity benefit? Then, SURROGATE Outcomes Clinically relevant?

EFFICACY HARD Outcomes SURROGATE Outcomes Mortality benefit Morbidity Metformin – UKPDS-34 trial Morbidity SURROGATE Outcomes Hgb-A1c Blood glucose levels Fasting or Prandial Insulin Sparing Effects

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?)

EFFICACY A) Surrogate Outcome - Hgb-A1c ~ 1% to 2% ~ 0.5% to 0.8% 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.

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

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

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

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.

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) 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.

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

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

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)

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

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

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)

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

Convenience PO vs IV? QD vs QID?

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

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

Individualization of Drug Therapy www.rxfiles.ca Patient Factor Consider→ Possibly preferred drugs Renal Failure Repaglinide (Gluconorm) Also: gliclazide, insulin Hepatic Disease Insulin, repaglinide, acarbose Caution: glyburide, metformin, glitazones Hyoglycemia Metformin, Acarbose Also, repaglinide, nateglinide, gliclazide, glimepiride; Obese Irregular Mealtimes Repaglinide (may be preferred over SU) PPBG >10mmol/L and FBG minimally ↑’d Repaglinide or Acarbose Insulin lispro (Humalog) if PPBG very high

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

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

**Animal-source insulin- demand has decreased now that human insulin is available. There are some patients who cannot control their diabetes on human insulin. **Beef insulin also available through Health Canada’s Special Access Programme. Humalog 388 For the treatment of patients with Type 1 diabetes mellitus.   LU Authorization Period: Indefinite. 389 For the treatment of patients with Type 2 diabetes mellitus using insulin in an intensive regimen with 3 or more injections per day or an insulin pump.   LU Authorization Period: Indefinite. 390 For the treatment of patients with Type 2 diabetes mellitus who are either experiencing recurrent hypoglycemia OR are unable to achieve adequate post-prandial glucose control while on a less intensive regimen of regular insulin (1-2 injections per day). NovoRapid Humulin R, NPH vial $15, 3X5 cartridges 32$ Humalog, Novorapid vial 23$, 3X5 cartidges $46 New Drugs/Drug News vol 24 (3): May/June 2006

Insulins - Simplified Long = Basal Short = Prandial Premixed 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) Humalog Mix-25, NovoMix-30 Which to choose?

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! ?Any hypo’s?- fix ‘em! then, FBS AM FBS Noon FBS PM FBS HS 2h PPG AM 2h PPG Noon 2h PPG PM

Humalog Mix-25, NovoMix-30 (Rapid + NPH) 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) Now, which to choose?

Rational Prescribing FOUR steps to Rational Prescribing: EFFICACY TOXICITY COST CONVENIENCE

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

Long – Basal Insulins Toxicity: All: NPH: Lantus / Levemir: 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

Long – Basal Insulins Cost: Convenience: 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

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.

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.

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

Humalog Mix-25, NovoMix-30 (Rapid + NPH) 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)

Short – Prandial Insulins Efficacy Equivalent reduction in morbidity, HgbA1c

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

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

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.

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 ~ 2/3rds split (40% basal / 60% prandial)

Humalog Mix-25, NovoMix-30 (Rapid + NPH) 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)

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

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 2/3rd - 1/3rd AM and PM

Pearls Insulin is 2nd line after metformin No need to save it for last! Better than adding a 3rd 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

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)

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

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

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.

Rational Prescribing Process FOUR steps to Rational Prescribing: EFFICACY TOXICITY COST CONVENIENCE

Choosing Anti-dyslipidemics First, define your options: Statins (HMG-CoA Reductase inhibitors) Prava-, Fluva-, Simva-, Atorva-, Rosuva-statin 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 Ezetimibe (Inhibits absorption of cholesterol at the brush border of the small intestine via the sterol transporter, Niemann-Pick C1-Like1 (NPC1L1)). Niacin Cholestyramine (Bile acid sequestrant)

Efficacy – Endpoints? Hard Endpoints Soft 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

Efficacy Only statins have any proven reduction in hard endpoints.

The End.

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?

Can J Cardiol Vol 25 No 10 October 2009

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

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

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

Correlation versus Causation Example of sun rise and sun set and flag going up and down the flag pole – can’t make the sun set by taking down the flag….

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.

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.

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.

Exceptions Gemfibrozil N.B. Fenofibrate 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

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.

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 ) Rxfiles.ca. ENHANCE Trial Summary, June 2008. Accessed Apr 26/12.

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

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

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

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

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%

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.

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

Relative vs Absolute Risk

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.

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

“…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.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.do

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

Cost All statins covered under ODB All statins are generic

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)

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