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

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 2016 rhalil@bruyere.org

Objectives Review all pharmacology in an abnormally short amount of time in preparation for LMCC Apply knowledge of pharmacology to rationalize the application of therapeutics 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 pharmaco-kinetics and dynamics of these agents can affect their use Highlight clinical pearls in the proper use of these agents in practice.

Adding Pharmacology to your Knowledge Base (Pharmacology Informs Therapeutics) Dr Roland Halil, BSc(Hon), BScPharm, ACPR, PharmD Pharmacist, Bruyere Academic FHT Assistant Professor, Dept Family Medicine, U of Ottawa March 2016

Objectives To promote an efficient process for incorporating pharmacology into your body of knowledge To promote the creation of a “personal formulary” during your residency.

Pharmacology = Mechanism of Action + Pharmacokinetics + Pharmacodynamics Therapeutics = Pharmacology + Pathophysiology

Pharmacology Impossible to know during clerkship – Every drug in every specialty? Get real. Possible to know during residency! – Build your Personal Formulary Drugs that will be bread & butter during your career. – How?

Personal Formulary Pharmacology Pick one drug per class to become the workhorse in your personal formulary. – Need help? Ask a Pharmacist: What is your favourite member of any drug class? Why? Knows the in’s and out’s of that drug: – Learn its Pharmacology (Pharmacology = M.O.A. + PK + PD) + – Dosing range, Cost / Drug coverage status, Dosage forms available

Learning Pharmacology Open your Drug Database Software (Eg. LexiComp, Micromedex, eCPS, etc) Review Mechanism of Action Review Pharmaco-Kinetics Clearance: Renal or Hepatic? Hepatic: CYP-450 or not? Review Pharmaco-Dynamics (ie. Top 3 Side Effects) Rare & Severe Common & Bothersome Total: 3 minutes

Pharmacology Learn the drugs that will be part of your personal formulary. – Build your formulary wisely. Brief & regular review will help you own it! – Patients are treated more optimally – Fewer side effects – Less risk of litigation – Better use of health care dollars – Better likelihood of compliance

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

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 2016

Objectives To promote an efficient process for selecting optimal drug therapy for patients To promote a process for applying population- level EBM 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) 1.Efficacy 2.Toxicity 3.Cost 4.Convenience

A Method of Prioritization Scarce resources: – Your time – Our money Resource allocation is central to decision- making in any health care system. K C Calman. The ethics of allocation of scarce health care resources: a view from the centre. J Med Ethics. 1994 Jun; 20(2): 71–74. PMCID: PMC1376429 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1376429/http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1376429/ ETHICS IN MEDICINE University of Washington School of Medicine https://depts.washington.edu/bioethx/topics/resall.html Accessed Mar 7/16.https://depts.washington.edu/bioethx/topics/resall.html

Step 1: Efficacy How good is good? aka “Take this drug, it doesn’t do anything, but it’s totally safe”

Efficacy “Do you want the drug that prevents death from stroke and lowers your cholesterol…or the one that lowers your cholesterol?” 1.Type of intervention: What will reduce: 1.Mortality 2.Morbidity 3.Surrogate markers 4.Symptoms Disease management Palliative Care

2. Quality of evidence? (Hierarchy of evidence) Robert Yokl. Good Evidence: The Missing Link. Apr 08, 2013. http://valueanalysismag.com/good-evidence-the-missing-link/http://valueanalysismag.com/good-evidence-the-missing-link/ “Take this drug, it’ll reduce the risk of death, because my grandma said so” Efficacy

3. Quantity of evidence? (ie. effect size) a)Absolute is more important than relative – Eg. 2%  1% = 1% absolute risk reduction (i.e. 50% relative risk reduction) b)Number-needed to treat (NNT) – The inverse of the ARR. (NNT = 100) (=1/0.01) – Useful for the shepherd (population health) c)Converse is more clinically informative than inverse – Eg. Without treatment, 98% will be unaffected – With treatment, 99% will be unaffected – Useful for the flock (individual health) Number Needed to Treat http://www.med.uottawa.ca/sim/data/Number_Needed_to_Treat_e.htm Accessed Nov 2/14http://www.med.uottawa.ca/sim/data/Number_Needed_to_Treat_e.htm Efficacy “Take this drug, it’ll reduce mortality, as per 5 well designed RCTs, by 0.001%.”

Efficacy 4.Time to benefit? – The fourth dimension Type Quality Quantity “Take this drug, it’ll reduce mortality by 50% as per many RCTs, but you need to be on it for 20 years to see a benefit.”

Efficacy Four Priorities The key is the prioritization of: Benefit before harm Efficacy endpoints, – Mortality before symptoms Evidence quality and Evidence quantity – Big before small Time to benefit – Acute before chronic

Efficacy If there is no efficacy, why waste your time on the potential toxicity, cost and inconvenience of a drug? If there is efficacy, it is usually proven in populations. Balance this against the potential toxicity to the individual.

Primum non nocere When EBM is strong: – Efficacy easily outweighs Toxicity – Only very specific contraindications to pursuing therapy When EBM is weak – It is easy for Toxicity to outweigh Efficacy – First, do no harm

Step 2: Toxicity How bad is bad? aka “Take this drug, it’s free! …and most people won’t die”

Toxicity Same 4 Priorities Prioritization of: A.Toxicity endpoints, i.What will kill me? ii.…Maim me? iii.…Make me feel lousy? (bothersome side effects) B.Evidence quality and C.Evidence quantity – % risk D.Time to harm

Toxicity Common Not legal Rare Who cares BothersomeSevere Likelihood Severity

Toxicity Time: The 4 th parameter Most drugs are approved based on their efficacy against nothing – (ie. placebo, not the current gold-standard) Studies are usually powered for efficacy, not toxicity – (eg. Phase III study) Tox data is accumulated over time – (eg. Phase IV, post-marketing surveillance study) – Slower than accumulation of efficacy data Time lag!

Toxicity Age Before Beauty Newer agents = Less Safety Data Older agents = More Safety Data Prexige Arcoxia Vioxx Bextra Zelnorm Prepulsid Meridia Baycol Actos Avandia

Efficacy: a population-based parameter Toxicity: an individual risk Robust EBM Eg. ACE-inh post MI – Clear mortality benefit in secondary prevention as per many RCTs – Patient A: K+ = 4.0 mmol/L – Patient B: K+ = 6.0 mmol/L Will both get an ACEinh? Weak EBM Eg. Anti-seizure meds for migraine prophylaxis – Questionable reduction in severity & frequency – Risk of: Hepatitis blood dyscrasias strong drug interactions etc.

Step 3: Cost Who pays the piper? aka “Take this life-saving therapy; it has no risks, but it’ll cost you $1 million and you’ll need blood tests twice daily”

Cost ($) – Ask… Patient cost vs Societal cost Rx cost? – Out of pocket Provincial plan? – Tax dollars Private plan? – Insurance premiums

Efficacy: equivalent Toxicity: equivalent Cost: all cheap, generic – Except: trandolapril & perindopril Convenience: all once daily – Except: captopril TID ACE INHIBITOR (ACEI) / ANGIOTENSIN II RECEPTOR BLOCKER (ARB): Jul 2015 Comparison Chart http://www.rxfiles.ca.proxy.bib.uottawa.ca/rxfiles/uploads/document s/members/CHT-HTN-ace-arb.pdf Accessed Mar 8/16 http://www.rxfiles.ca.proxy.bib.uottawa.ca/rxfiles/uploads/document s/members/CHT-HTN-ace-arb.pdf A simple example: Cost Choosing an ACEinh

Step 4: Convenience (How much work is this?)

Convenience How much work is this drug? 1.How often to take? – QD vs QID 2.Special restrictions? – eg. Bisphosphonates – PO vs SC/IV – Home vs Office vs Hospital therapy 3.Many potential interactions? – eg. Rifampin 4.Special monitoring requirements? – eg. Amiodarone

Your agenda Patient agenda Knowledge translation

A Process for Rational Prescribing Summary 1.Prioritize Efficacy – Improve mortality, morbidity, surrogate markers, sxs 2.Prioritize Toxicity – Minimize mortality, morbidity, bothersome sxs 3.Minimize Costs 4.Maximize Convenience – Else they affect compliance!

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 2016

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

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

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

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’…

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.

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.

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

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.

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

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.

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 [-]: Group A & B streps give Penicillin

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

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.

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.

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) (β-Lact[-]) Neonates, v. elderly, obstetrics S. pneumonia etc. Enterococcus (Formerly thought to be ‘Strep D’) E. faecalis E. faecium A “mean” hospital organism 

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

2.5 - Gram [-] Bacilli “Easy” to Kill Proteus mirabilis Escherichia coli Klebsiella pneumonia Salmonella Shigella PEcKSS bugs “Hard” to Kill Serratia Pseudomonas Acinetobacter Citrobacter Enterobacter SPACE bugs ?“Moderate” To Kill Haemophilus influenza – (Moraxella catarrhalis) (actually a Gm[-] coccus) HiM bugs

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 ;

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

Map the Bugs - Summary Conjunctivitis: viral Sinusitis: viral Oral abscess: oral anaerobes Pharyngitis: viral (Group A Strep) Bronchitis: viral Skin abscess: anaerobes, staph, strep N.B. Boils = Staph H.pylori: Cdiff / Bfrag: Otitis media: S.pneumo, Hi,M AECOPD: S.pneumo, Hi,M C.A.P: S.pneumo, atypicals – CAP+comorb./risk factors, or NHAP: also HiM bugs Cellulitis: MSSA, GAS, GBS UTI (Cystitis): PEcK Pyelonephritis: PEcK Traveller’s Diarrhea : (80% bacterial): EcSS, (camphlyobacter)

Part 2 - Map the Drugs (Save your Ammo)

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

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

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

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

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

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.

Fluoroquinolones 2 nd generation – Ofloxacin – Ciprofloxacin – Norfloxacin 3 rd generation – Levofloxacin 4 th generation – Moxifloxacin Covers: Gm[-]’s – PEcKSS-HiM & SPACE bugs – 3 rd and 4 th gen. FQs cover strep pneumo. well too 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” – 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

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)

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

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

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

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

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 )

Part 3 – Map the Battlefield

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.

Map the Battlefield

Map the Bugs - Summary Conjunctivitis: viral Sinusitis: viral Oral abscess: oral anaerobes Pharyngitis: viral (Group A Strep) Bronchitis: viral Skin abscess: anaerobes, staph, strep (GAS, GBS) N.B. boils = staph H.pylori: Cdiff / Bfrag: Otitis media: S.pneumo, Hi,M AECOPD: S.pneumo, Hi,M C.A.P: S.pneumo, atypicals – CAP+comorb./risk factors, or NHAP: also HiM bugs Cellulitis: MSSA, GAS, GBS UTI (Cystitis): PEcK Pyelonephritis: PEcK Traveller’s Diarrhea : (80% bacterial): EcSS, (campylobacter)

Map the Battlefield Conjunctivitis: viral – no tx Sinusitis: viral – no tx Oral anaerobes: abscess drainage +/- tx (Amox 2g – pre dental sx?) Pharyngitis: viral – no tx (Group A Strep – Pen VK) Bronchitis: viral – no tx Skin abscess: drainage +/- 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, GAS, GBS - (Clox, Cef1, & Clinda (more resistant) UTI (Cystitis): PEcK – (Septra, Macrobid, Amox+/-Clav, Norflox) Pyelonephritis: PEcK – (Septra, Amox-Clav, FQ (not Norflox) Traveller’s Diarrhea : (80% bacterial): EcSS, (campylobacter) - Septra, FQ, (Azithro)

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)

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

SPACE bugs The Big Guns: – 3 rd and 4 th 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 b-lact[-] Gm[+] cocci (GAS, GBS), oral anaerobes, Neisseria (meningitidis) ?What to do for Strep pneumo /Enterococcus? – 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? (analogous with Amox/Clav and Cef2)

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.

Case 1 Mr. PT 68 y.o. smoker with AE-COPD – Vitals stable; ambulatory; fever, productive cough, phlegm is green – PMHx: HTN, COPD – Allergies: penicillin – Meds: Tiotropium 18mcg qd, Ramipril 10mg qd – Expected pathogens? – Rx options? – Management of allergy status? Rx: ________ ?

Allergy status 1.Severe diarrhea, pain 2.Rash at age of 5 y.o. 3.Rash 2 weeks post Rx – involved hives (raised, intensely itchy spots that come and go over hours), with wheezing & swelling of the skin & throat 4.Major rash 3 yrs ago – flat, blotchy, spread over days but did not change by the hour 5.Anaphylaxis 1.. 2.. 3.. 1.. 2..

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 2016

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

Hypertension Vascular Disease CAD / ACS CHFPVDCKDCVA

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

Essential Hypertension AABCD ACEinhARB (B-bl) beta- blockers DHP-CCB (dihydropyridine) Thiazide Diuretic "-pril""-sartan""-olol""-dipine" enalaprilvalsartanbisoprololnifedipine hydrochlorothiazide lisinoprilirbesartanmetoprololamlodipinechlorthalidone ramiprilcandesartanpropranololfelodipineindapamide 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 Reduces sympathetic outflow & heart rate & renal AT2 production Relaxes peripheral smooth muscle Reduction in systemic vascular resistance (not diuresis) 1st line 1st line (if < 60y.o.) 1st line

Essential Hypertension Efficacy 1st line (< 60yo) 1st line Hypotension hyperK+ Bradycardia Orthostatic hypotension hypoK+, hypoNa+ Acute renal failure (ARF) ARF Bronchoconstric tion in brittle asthmatics (esp high dose, esp non-cardio- selective) EdemaARF Monitor BP, SCr, K+ BP, HR, RR BP, OH, edema BP, SCr, K+, Na+ Cost cheap, generic (except Coversyl & Mavik), ODB covered still expensive, new generics, ODB covered Cheap & generic, ODB covered expensive, generics, ODB covered VERY cheap, generic, ODB covered Convenience (eg.) QD Ramipril 2.5mg - 10mg QD Losartan 25mg - 100mg QD Bisoprolol 2.5mg - 10mg QD Amlodipine 2.5mg - 10mg QAM Chlorthalidone 25mg Toxicity A (ACEinh) A (ARB) BCD

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! Efficacy is population based Toxicities are individual. Additive versus synergistic BP lowering –Can choose between groups A or B plus C or D (synergistic) Rarely clinically relevant N.B. Choice will also be guided by various comorbidites

Hypertension with Comorbidities A (ACEinh) A (ARB) BCD HTN MI CHF DM2 CVA PVD Angina (ALLHAT) (HOPE) (VALIANT) (CAPRICORN, BHAT) (CONSENSUS, SOLVD, ATLAS) (MERIT-HF, CIBIS II, COPERNICUS) (HOPE) (IDNT, IRMA-2, RENAAL) (HOPE, PROGRESS) (LIFE, SCOPE, MOSES) (ALLHAT, PROGRESS) (HOPE)

RAASystem

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 (> 60 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 – 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;

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

Dyslipidemia (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 2016

Objectives 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.

Dyslipidemia Never forget your 4 Steps of Rational Prescribing! It will save you a LOT of time. Efficacy Toxicity Cost Convenience

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)

Dyslipidemia Statins Fibrates Niacin Ezetimibe Cholestyramine 1.Efficacy: 1.Mortality Benefit 2.Morbidity Benefit (reduction in non-fatal MI, CVA, hospitalizations etc) 3.Reduction in Surrogate Markers Eg. LDL

Bottom Line: Statins. Only * statins have clear reduction in mortality. High Risk Framingham patients: – Primary prevention – morbidity reduction – Secondary prevention – mortality reduction Moderate Risk Framingham patients: – Tiny absolute risk reduction – Not usually clinically relevant (*) Some evidence with Gemfibrozil (VA-HIT, HHS trials) but ++ GI side effects

The End.

Exceptions Gemfibrozil – Two trials that show reduction in CVD events Helsinki Heart Study (HHS) Veterans Administration HDL Intervention Trial (VA-HIT) – Performed before widespread adoption of ACEinh, statins, etc – Never combine it with statins Serious risk of rhabdomyolysis N.B. Fenofibrate – No effect on CVD events Fibrates for high TGs – risk of pancreatitis – ?inferior to statins in outcomes? – See: David Preiss, et al. Lipid-Modifying Therapies and Risk of Pancreatitis: A Meta-analysis. JAMA. 2012;308(8):804-811. (see: http://jama.jamanetwork.com/article.aspx?articleid=1352090 ) http://jama.jamanetwork.com/article.aspx?articleid=1352090 Fibrates for high TGs – treatment of gout risk factors

What about Ezetimibe? Many negative trials for efficacy – ENHANCE – SEAS – ARBITER-HALTS 6 – SHARP – AIM-HIGH, etc. Lots of evidence of no benefit No evidence for benefit 1) Table summary of clinical trials for ezetimibe. http://www.trialresultscenter.org/DR-ezetimibe%20clinical%20trials.htm Accessed Feb 23/16http://www.trialresultscenter.org/DR-ezetimibe%20clinical%20trials.htm 2) Doggrell SA. Expert Opin Pharmacother. 2012 Jul;13(10):1469-80. http://www.ncbi.nlm.nih.gov/pubmed/22725704 Accessed Feb 23/16http://www.ncbi.nlm.nih.gov/pubmed/22725704 3) Battaggia A et al. Clinical efficacy and safety of Ezetimibe on major cardiovascular endpoints: systematic review and meta-analysis of randomized controlled trials. PLoS One. 2015 Apr 27;10(4):e0124587 http://www.ncbi.nlm.nih.gov/pubmed/25915909 Accessed Mar 7/16http://www.ncbi.nlm.nih.gov/pubmed/25915909

What about Ezetimibe? The IMPROVE-IT trial – Type: Reduction in cardiac mortality & morbidity – Quality: Well designed RCT – Quantity: 2% ARR… [34.7% down to 32.7%] – i.e. 65.3% improved to 67.3% – Time: 7 years to benefit… $185 million spent in 2013 (up 6.4% from 2012) 1) Rxfiles. IMPROVE-IT trial summary. http://www.rxfiles.ca/rxfiles/uploads/documents/Lipid-IMPROVE-IT-Trial-Summary- QandA.pdf Accessed Feb 23/16http://www.rxfiles.ca/rxfiles/uploads/documents/Lipid-IMPROVE-IT-Trial-Summary- QandA.pdf 2) IMS Health Pharmafocus 2018; Table 7. https://www.ic.gc.ca/eic/site/lsg-pdsv.nsf/eng/h_hn01703.html Accessed Feb 23/16https://www.ic.gc.ca/eic/site/lsg-pdsv.nsf/eng/h_hn01703.html

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

Correlation versus Causation

Bottom Line Priority #1 = any statin at any dose is Prioirty #2 = highest dose of the highest potency statin you can tolerate. – Push the dose too hard = Side effects = Noncompliance Doubling the statin dose only lowers LDL by 6% The LDL target is just your guide – A marker of the statin’s pleiotrophic effects – (Or a compliance check)

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 If a patient is already on it, don’t stop, but don’t bother checking LDL either.

Toxicity Statin – Rare/Severe: Myopathy, even Myositis/Rhabdomyolysis Hepatotoxicty Memory impairment ?Diabetes?? – discuss – Common/Bothersome: Myalgias Fibrates – Same as statins (Additive) Ezetimibe – Same as statins (Additive) 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 – Shorter half-life vs newer, more potent statins – 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)

Coronary Artery Disease & Acute Coronary Syndromes Dr Roland Halil, BSc(Hon), BScPharm, ACPR, PharmD Pharmacist, Bruyere Academic FHT Assistant Professor, Dept Family Medicine, U of Ottawa March 2016

CAD / ACS All on a spectrum of ischemic damage: Stable Angina Unstable Angina NSTEMI STEMI Basic Principles: 1.BP control 2.Plaque stabilization 3.Clot prevention

CAD / ACS 1)BP control Mortality benefit with: – ACEinh or ARB plus – Beta-blocker (see: HTN section) 2) Plaque Control Mortality benefit with: – Statin (see: Dyslipidemia section) N.B. HTN accelerates atherosclerosis!

CAD / ACS 3) Clot Prevention Anti-Thrombotics – lots! From: http://en.wikipedia.org/wiki/Direct_thrombin_inhibitorhttp://en.wikipedia.org/wiki/Direct_thrombin_inhibitor

Antiplatelets Options Primary prevention ACS – ASA – Clopidogrel Primary prevention CVA – ASA – Clopidogrel Secondary prevention ACS –ASA + –Clopidogrel –Prasugrel –Ticagrelor Secondary prevention CVA –ASA (Aspirin®) –Clopidogrel (Plavix®) –ASA + Dipyridamole MR (Aggrenox®)

Mechanisms of Action ASA Irreversible inh of COX-1 – (thromboxane reduction) – Platelet lifespan: 7-10 days Dipyridamole MR inhibits the uptake of adenosine & breakdown of cGMP Ticagrelor Reversible inhibition of ADP platelet receptor subtype P2Y 12 Thienopyridines Clopidogrel – Prodrug activated by P450-2C19 – N.B. 2% - 14% of population are poor metabolizers Prasugrel – Prodrug activated by ester bond hydrolysis via: Irreversible inhibition of ADP platelet receptor subtype P2Y 12

How to Choose? (if only there was a process…) 1.Efficacy 2.Toxicity 3.Cost 4.Convenience

Primary Prevention – ACS & CVA 1) Efficacy (all ~ equivalent) – ASA (+/- evidence) 75mg = 325mg daily “For older patients with risk factors” CHEST’12: >50yrs consider risk vs benefit CCS’11: not recommended AHA’14: if 10yr CAD risk ≥10% USPSTF’09: men 45‐79 yrs if low bleed risk Diabetes: CDA’13: not rec ; age & ≥1 risk factor, ADA’16: 1RF & men>50yr, women>60yr; ~ 10yr risk >10%. smoking,  BP,  lipids, history of young parenteral MI, albuminuria – Clopidogrel Little direct evidence Only for ASA allergic or intolerant 2) Toxicity (bleeding ~ same) ASA – NNH 125; major bleeds (WHS trial) – Bleed: Any GI bleed 2.7% (severe 0.7%) – Dyspepsia ~ 5% Clopidogrel – Bleed: Any GI bleed 2% (severe 0.5%) – Rash: 6% – TTP : >20/3 million – Neutropenia : <1% From: www.Rxfiles.ca ORAL ANTIPLATELET & ANTITHROMBOTIC AGENTS Comparison Table; Jan 2016www.Rxfiles.ca

Primary Prevention – ACS & CVA 3) Cost – ASA Pennies! ($4/mo) 81mg costs > 325mg – Can cut 325mg in 1/4 th – Clopidogrel ~ $26/mo 4) Convenience – ASA 75-325mg once daily – Clopidogrel 75mg once daily From: www.Rxfiles.ca ORAL ANTIPLATELET & ANTITHROMBOTIC AGENTS Comparison Table; Jan 2016www.Rxfiles.ca

Bottom Line: 1 o Prevention ACS & CVA ASA. – Most evidence, well tolerated, cheap cheap!, QD Ongoing efficacy studies for primary prevention (eg. ASPREE) – http://www.ahrq.gov/professionals/clinicians-providers/resources/aspprovider.html http://www.ahrq.gov/professionals/clinicians-providers/resources/aspprovider.html – Consider bleed risks, even with “baby” ASA (81mg) RISK FACTORS FOR BLEEDING: – Age >75 yrs, DM, elevated INR warfarin, female, ↓ hematocrit, HF/MI, ↑HR, length of antithrombotic tx, liver dx, ↑↓ systolic BP, medications (e.g. anticoagulants, antiplatelets, NSAIDs), previous GI bleed or stroke noncardioembolic, ↑Scr, ↓ wt. – Clopidogrel only if ASA allergic / severe intolerance – Ignore ticlopidine: Little evidence, serious toxicities, BID dosing plus regular blood work! – No evidence for Aggrenox® in primary prevention From: www.Rxfiles.ca ORAL ANTIPLATELET & ANTITHROMBOTIC AGENTS Comparison Table; Jan 2015www.Rxfiles.ca

Secondary Prevention – ACS Efficacy AgentMonotherapyCombo w/ ASA ASA Excellent evidence for: NSTEMI, STEMI, CABG, PCI (low NNTs) -- Clopidogrel ~ equivalent to ASA (small absolute improvement per CAPRIE trial) Clopidogrel + ASA > ASA x3-12 mo (CURE trial) (ACS, PCI various durations) Prasugrel untested Prasugrel + ASA > Clop + ASA (ACS + PCI) x12 mo (TRITON-TIMI 38 trial) Ticagrelor untested Ticagrelor + ASA > Clop + ASA (ACS + PCI +/- CABG) x12mo (PLATO trial) From: www.Rxfiles.ca ORAL ANTIPLATELET & ANTITHROMBOTIC AGENTS Comparison Table; Jan 2016www.Rxfiles.ca From: Antiplatelet treatment http://cks.nice.org.uk/antiplatelet-treatment#!management Accessed Apr 4/13http://cks.nice.org.uk/antiplatelet-treatment#!management From: http://www.nice.org.uk/nicemedia/live/13588/56819/56819.pdf Accessed Apr 4/13.http://www.nice.org.uk/nicemedia/live/13588/56819/56819.pdf

Secondary Prevention – ACS Toxicity AgentMonotherapyC ombo w/ ASA ASA w/ ASA: rate of hemorrhagic events = 5.58 (95% CI, 5.39-5.77) / 1000 pt-yrs VS. w/o ASA: 3.60 (95% CI, 3.48-3.72) Incidence rate ratio: 1.55; (95% CI, 1.48-1.63 ) -- Clopidogrel ~ equivalent in absolute sense Slightly less GI bleed & GI events except diarrhea; More Rash More major bleeding vs ASA alone Prasugrel untested More fatal & life- threatening bleeds vs Clopid + ASA Ticagrelor untested More major & minor bleeds vs C + ASA More dyspnea & increased urate

Secondary Prevention – ACS Toxicity AgentMonotherapyC ombo w/ ASA ASA w/ ASA: rate of hemorrhagic events = 5.58 (95% CI, 5.39-5.77) / 1000 pt-yrs VS. w/o ASA: 3.60 (95% CI, 3.48-3.72) Incidence rate ratio: 1.55; (95% CI, 1.48-1.63 ) -- Clopidogrel Less GI bleeding: Clopidogrel < ASA (1.99% vs 2.66% p < 0.002) (Less severe GI bleed - 0.49 vs 0.71%; p < 0.05) Less GI events - clopidogrel < ASA (27.1 vs 29.8%; p < 0.001) More Diarrhea clopidogrel > ASA (4.46 vs 3.36%; p < 0.001) More Rash – clopidogrel > ASA (6.0% vs 4.6% p < 0.001) No difference in: Early D/C, Neutropenia, Thrombocytopenia & Intracranial bleed. (per CAPRIE) Major bleeding – clop + ASA > ASA (3.7% vs. 2.7%; RR = 1.38; P=0.001), Life-threatening bleeding - no diff (2.1 percent vs. 1.8 percent, P=0.13) Hemorrhagic strokes – no diff (per CURE trial) Prasugrel untested More fatal and life- threatening bleeds vs clopid + ASA Ticagrelor untested More major and minor bleeds vs clopid + ASA More dyspnea, & incr UA

Secondary Prevention – ACS 3) Cost – ASA Pennies! (only 325mg covered) – Clopidogrel ~ $26/mo LU code for ACS – Prasugrel ~ $100/mo; covered w/ LU code – Ticagrelor ~ $109/mo; covered w/ LU code 4) Convenience – ASA 75-325mg once daily – Clopidogrel 75mg once daily – Prasugrel 10mg once daily – Tigagrelor 90mg BID From: www.Rxfiles.ca ORAL ANTIPLATELET & ANTITHROMBOTIC AGENTS Comparison Table; Jan 2016www.Rxfiles.ca

Bottom Line: 2 o Prevention ACS ASA + Clopidogrel x 3- 12 mo, then ASA alone – Clopidogrel alone if ASA allergy – Prasugrel only in cardiac centres post ACS + PCI & if no excess bleed risks Always assess risk of clotting vs risk of bleeding!

Secondary Prevention – CVA Efficacy AgentMonotherapyCombo w/ ASA ASA ASA ~23% RRR > placebo NNT ~ 50-100 x1 year to prevent any vascular event. (50-325mg) (CAST, IST, SALT, Dutch-TIA trials) -- Clopidogrel Equivalent to ASA (extremely small absolute improvement per CAPRIE trial) Possible improvement for 1 st 21 days post CVA (CHANCE trial) No benefit long term (CHARISMA, MATCH trials) Aggrenox ® Superior to ASA (ESPRIT & ESPS2 trials), but Equivalent to Clopidogrel (PRoFESS trial) whaaa…?? -- From: www.Rxfiles.ca ORAL ANTIPLATELET & ANTITHROMBOTIC AGENTS Comparison Table; Feb 2016www.Rxfiles.ca From: Antiplatelet treatment http://cks.nice.org.uk/antiplatelet-treatment#!management Accessed Apr 4/13http://cks.nice.org.uk/antiplatelet-treatment#!management From: http://www.nice.org.uk/nicemedia/live/13588/56819/56819.pdf Accessed Apr 4/13.http://www.nice.org.uk/nicemedia/live/13588/56819/56819.pdf

Secondary Prevention – CVA Toxicity AgentMonotherapyC ombo w/ ASA ASA Low, but look at additive bleeding risk factors: ( Age >75 yrs, DM, elevated INR warfarin, female, ↓ hematocrit, HF/MI, ↑HR, length of antithrombotic tx, liver dx, ↑↓ systolic BP, medications (e.g. anticoagulants, antiplatelets, NSAIDs), previous GI bleed or stroke noncardioembolic, ↑Scr, ↓ wt. ) -- Clopidogrel ~ equivalent in absolute sense Slightly less GI bleed & GI events except diarrhea; More Rash More bleeding vs ASA alone (CHARISMA & MATCH trials) Aggrenox ® More headache, diarrhea, GI upset, dizziness, & early D/C vs ASA or Clopidogrel More intracranial bleed vs Clopidogrel --

Secondary Prevention – CVA 3) Cost – ASA Pennies! ($4/mo) – Clopidogrel ~ $26/mo LU code for ASA intolerance only – Aggrenox® ~ $66/mo LU code for CVA 4) Convenience – ASA 75-325mg once daily – Clopidogrel 75mg once daily – Aggrenox® 200/25mg BID po From: www.Rxfiles.ca ORAL ANTIPLATELET & ANTITHROMBOTIC AGENTS Comparison Table; Jan 2016www.Rxfiles.ca

Bottom Line 2 o Prevention CVA ASA or Clopidogrel or Aggrenox® – Any will do, until tie breaker trial between these agents. – Aggrenox® might be more efficacious, but with more side effects and less convenience.

Summary – CAD / ACS N.B. Remember which modifiable risk factors need management – Remember which medications offer a mortality benefit in treated those risk factors; Use them 1 st ! BP control with ACEinh (or ARB) + b-blocker – (For stroke: ACEinh (or ARB) + Thiazide) Plaque stabilization with statin Clot prevention with ASA (+/- Clopidogrel)

(Congestive) Heart Failure (CHF) Dr Roland Halil, BSc(Hon), BScPharm, ACPR, PharmD Pharmacist, Bruyere Academic FHT Assistant Professor, Dept Family Medicine, U of Ottawa March 2016

Heart Failure Several types: – Left vs Right sided – Systolic vs Diastolic – Preserved ejection fraction vs not Basic Principles: 1.BP control 2.Plaque stabilization 3.Clot prevention

CHF – Systolic, Poor LVEF 1)BP control Mortality benefit with: – ACEinh or ARB plus – Beta-blocker (see: HTN section) 2) Plaque Control Mortality benefit with: – Statin (see: Dyslipidemia section)

CHF – Systolic, Poor LVEF 3) Clot Prevention Mortality Benefit with: – ASA 81mg qd – If ASA allergic: Clopidogrel 75mg qd (see: Primary prevention of ACS & CVA section) Other forms of CHF less well studied. Benefits of these interventions are not as clear – But offered anyway. – Pay closer attention to benefit/risk ratio since benefit is smaller / unknown

CHF – other interventions Spironolactone – Mortality benefit in NYHA Class III & IV – N.B. Increased harm in NYHA Class I or II Risk of hyperK+ ! Furosemide – Reduction in CHF symptoms – No morbidity nor mortality benefit (chronically). Digoxin – Morbidity benefit – (See DIG trial, PROVED trial) – Reduction in hospitalizations due to CHF Not seen with preserved ejection fraction – Reduction in sxs of CHF For patients in sinus rhythm with moderate- severe persistent sxs despite optimized CHF Rx Rxfiles.ca HEART FAILURE: Drug & Dosage Considerations. Jan 2016

CKD & PVD Dr Roland Halil, BSc(Hon), BScPharm, ACPR, PharmD Pharmacist, Bruyere Academic FHT Assistant Professor, Dept Family Medicine, U of Ottawa March 2016

Chronic Kidney Disease (CKD) Vascular damage to renal beds – Is BP control required? If so, what is the best agent? ACEinh or ARB first! – Is prevention of atherosclerosis required? If so, what is the best agent? Statin at any dose tolerated – Is CKD a vascular risk? If so, are anti-platelets required? ASA (low dose, every day)

Peripheral Vascular Disease (PVD) Vascular damage to peripheral beds – Is BP control required? If so, what is the best agent? – Is prevention of atherosclerosis required? If so, what is the best agent? – Is PVD a vascular risk? If so, are anti-platelets required? (Same)

Overall Summary Vascular problems throughout the body require similar approaches to management. Understanding the pathophysiology and pharmacology of preferred agents will inform your therapeutics. – ACEinh Anti-inflammatory and modulation of RAAS – Statin Anti-inflammatory and other pleiotrophic effects – ASA Anti-inflammatory and anti-platelet – Beta-blocker (If cardiac involvement) – to reduce MVO 2

Hypoglycemic Drugs Dr Roland Halil, BSc(Hon), BScPharm, ACPR, PharmD Pharmacist, Bruyere Academic FHT Assistant Professor, Dept Family Medicine, U of Ottawa March 2016

Objectives List the classes of 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 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

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

Kumamoto Study – HbA1c & 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 Shichiri M et al. Long-term results of the Kumamoto Study on optimal diabetes control in type 2 diabetic patients. Diabetes Care. 2000 Apr;23 Suppl 2:B21-9. from: http://www.ncbi.nlm.nih.gov/pubmed/10860187http://www.ncbi.nlm.nih.gov/pubmed/10860187

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

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

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

Pharmacotherapy Comparison of antihyperglycemics

Drug Classes SensitizersSecretagogues Other

Drug Classes Sensitizers Metformin Glitazones – Rosiglitazone (AVANDIA) – Pioglitazone (ACTOS) Secretagogues Sulfonylureas – Eg. Glyburide, Gliclazide Meglitinides – Eg Repaglinide (GLUCONORM) Other Alpha glucosidase inhibitors (Acarbose) SGLT2 inhibitors (Cana-, Dapa-, Empagliflozin ) DPP4 inhibitors (Gliptins) Incretin (GLP1) Analogues Sitagliptin, Linagliptin * Liraglutide (VICTOZA) (sc inj) Saxagliptin, Alogliptin * Exenatide (BYETTA) (sc inj)

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

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)

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 SGLT2 inhibitors (Canagliflozin)(Dapagliflozin) – Inhibits sodium-glucose cotransporter 2 (SGLT2) in the proximal renal tubules, reducing reabsorption of filtered glucose from the tubular lumen and lowering the renal threshold for glucose (RTG). SGLT2 is the main site of filtered glucose reabsorption; reduction of filtered glucose reabsorption and lowering of RTG result in increased urinary excretion of glucose, thereby reducing plasma glucose concentrations. DPP4 inhibitors (Gliptins) – (Sitagliptin, Lingliptin, Saxagliptin, Alogliptin) 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 (GLP1) Analogues – (Liraglutide (Victoza®), Exenatide (Byetta®)) (sc inj) mimic endogenous incretin hormones

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

EFFICACY 1.HARD Outcomes – Mortality benefit – Metformin – Metformin – UKPDS-34 trial – ?Empagliflozin – EMPA-REG OUTCOME trial – Morbidity – Reduction in microvascular complications (nephropathy, retinopathy, neuropathy) 2.SURROGATE Outcomes a)Hgb-A1c reduction Blood glucose level reduction – Fasting or Prandial b)Insulin Sparing Effects

EFFICACY A) Surrogate Outcome - Hgb-A1c – ~ 1% to 2% Metformin (1% - 2%) Sulfonylureas (1% - 2%) Repaglinide (1% - 1.5%) Glitazones (TZDs) (0.4% - 1.5%) Canagliflozin (0.8 – 1%) – ~ 0.5% to 0.9% Acarbose DPP4 inhibitors (‘Gliptins) Dapagliflozin, Empagliflozin Nateglinide Nathan DM, et al. Diabetes Care 2008 (Dec);31:1-11.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) – SGLT2 inh (Canagliflozin, Dapagliflozin) = Weight neutral or weight negative = Reduction of hyperinsulinemia

TOXICITY – Ask… 1.Serious / Fatal Side Effects 2.Bothersome / Common s.e. 3.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 SGLT2 inhibitors (Canagliflozin) (Dapagliflozin) – ?DKA “March 2013 to June 6, 2014, 20 cases of acidosis — diabetic ketoacidosis, ketoacidosis or ketosis — were recorded in the FDA Adverse Event Reporting System in patients treated with SGLT2 inhibitors. All patients required emergency room visits or hospitalization to treat the ketoacidosis.” http://www.fda.gov/Drugs/DrugSafety/ucm446845. htm http://www.fda.gov/Drugs/DrugSafety/ucm446845. htm – Bone fracture as soon as 12 weeks (Canagliflozin) see: herehere – Unknown – too new Incretin Analogues – (Liraglutide, Exenatide (sc inj)) & DPP4 inhibitors (‘gliptins) – ?Heart failure http://www.medscape.com/viewarticle/839315 – ?Pancreatitis http://www.ncbi.nlm.nih.gov/pubmed/24352344 – Unknown - too new

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) – 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. 1) Salpeter SR, et al. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. Cochrane Database of Systematic Reviews 2010, Issue 4. Art. No.: CD002967. http://www.cochrane.org/CD002967/ENDOC_risk-of-fatal-and-nonfatal-lactic-acidosis-with-metformin-use-in-type-2- diabetes-mellitus Accessed Sept 24, 2015http://www.cochrane.org/CD002967/ENDOC_risk-of-fatal-and-nonfatal-lactic-acidosis-with-metformin-use-in-type-2- diabetes-mellitus 2) Nasri, H. et al. Metformin: Current knowledge. J Res Med Sci. 2014 Jul; 19(7): 658–664. PMCID: PMC4214027 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4214027/ Accessed Sept 24, 2015 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4214027/ 3) A A Tahrani, et al. Metformin, heart failure, and lactic acidosis: is metformin absolutely contraindicated? BMJ. 2007 Sep 8; 335(7618): 508–512. PMCID: PMC1971167. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1971167/ Accessed Sept 24, 2015http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1971167/ 4) Lalau JD. Lactic acidosis induced by metformin: incidence, management and prevention. Drug Saf. 2010 Sep 1;33(9):727-40. PMID: 20701406

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

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: – Edema 4) Meglitinides: – Hypoglycemia 5) Acarbose: – GI upset / diarrhea / bloating 6)Gliptins: – GI upset, edema, ?infection 7) Incretin analogues – N/V/D, ?infection 8) SGLT2 inhibitors – HyperK+, ARF (AKI) – UTI (includes bacteriuria [asymptomatic], cystitis: 9%; females: 4%-18%; males: 4%), – Genitourinary fungal infection (4%; females: 5% to 11% [includes bacterial vaginosis, cervicitis, vulvitis, vulvovaginal candidiasis, vulvovaginal infection, vulvovaginitis]; – males: 2% to 3% [includes balanitis, balanoposthitis, genitourinary fungal infection, penile infection, scrotal abscess])

Cost From Rxfiles May 2013 – Unchanged for 2016 – Cost per 100 days therapy (in Sask.) Alternatively, check ODB e-formulary – N.B. Not true pt costs – Comparative costs http://www.rxfiles.ca/rxfiles/uploads/documents/members/cht-diabetes.pdf

Convenience Gliptin’s - QD Glitazones - QD SGLT2 inh- QD Sulfonylureas– QD to BID Metformin - QD to TID Meglitinides – QD to TID with meals Acarbose – QD to TID

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

Individualization of Drug Therapy Patient FactorConsider→ Possibly preferred drugs Renal FailureRepaglinide (not SU), Acarbose, ‘Gliptins Also: insulin (easier to fine tune) Hepatic DiseaseInsulin, repaglinide (fast in/out), acarbose, Caution: glyburide, ?metformin, glitazones HyoglycemiaMetformin, Acarbose, (DPP4 inh),(SGLT2 inh) Also, repaglinide (fast in/out), gliclazide (no active metabolites vs glyburide) ObeseMetformin, Acarbose Irregular MealtimesRepaglinide (may be preferred over SU) www.rxfiles.ca

Insulins Dr Roland Halil, BSc(Hon), BScPharm, ACPR, PharmD Pharmacist, Bruyere Academic FHT Assistant Professor, Dept Family Medicine, U of Ottawa March 2016

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

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

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

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)

Rational Prescribing FOUR steps to Rational Prescribing: 1.EFFICACY 2.TOXICITY 3.COST 4.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 (esp w/ CKD)

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

Long – Basal Insulins Cost: – All: covered under ODB N.B. No Rx required for any insulins – all “Schedule 2” – NPH: ~ $45 – Lantus: ~ $110 – Levemir: ~ $115 Convenience: – All sc injections, via penfills – All QD – BID – All stable at room temp x 30 days

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 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)

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 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 (all Schedule 2 drugs) Regular (R) / Toronto ~ $45 NovoRapid (aspart) ~ $56 Humalog (lispro) ~ $58 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 ~ 2/3 rds split (40% basal / 60% prandial)

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 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: ~$63 (Rapids) ~$47 (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 2/3 rd - 1/3 rd AM and PM

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 breakfast, then FBS AM + FBS lunch, then FBS AM + PPG lunch, then FBS AM + FBS supper, then FBS AM + PPG supper, 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)

GI Meds Dr Roland Halil, BSc(Hon), BScPharm, ACPR, PharmD Pharmacist, Bruyere Academic FHT Assistant Professor, Dept Family Medicine, U of Ottawa March 2016

Objectives Describe the utility of step up or step down approach to therapy in the treatment of GI problems List classes of medications used in common GI complaints and understand differences in their pharmacology Choose therapy using a process for rational prescribing

Dyspepsia, GERD, PUD: Options Buffer antacids – MOA: raise gastric pH Immediate effect, short lived – Efficacy: relieves mild GERD sxs in ~20% of patients – Calcium carbonate: Eg. TUMS, Rolaids most potent, chew 2-3 tabs prn, Tox: constipation – Sodium bicarb Eg. Alka-Seltzer Tox: flatulence, belching. C.I. in CHF, edema, renal dysfunction – Magnesium/Aluminum hydroxide Eg. Gelusil, Maalox liquid Tox: diarrhea. C.I. in CKD, ARF H2 receptor blocker (H2RA) – Eg. Ranitidine, Famotidine, Nizatidine, Cimetidine – MOA: competitively inhibit histamine H2 receptors on parietal cells thereby decrease gastric acid secretion – Efficacy: all equivalent useful in treatment/prevention of mild GERD Not effective enough for NSAID prophylaxis of PUD – Toxicity: well tolerated Cimetidine: ++ interactions – Cost: Cheap, generic, OTC – Convenience: BID dosing Eg. Ranitidine 75-150mg QD-BID

Dyspepsia, GERD, PUD: Options Proton Pump Inhibitors (PPI) – Eg. Omeprazole 20mg, (esomeprazole 20mg), rabeprazole 20mg, pantoprazole 40mg, lansoprazole 30mg, (dexlansoprazole 30mg) – MOA: suppresses gastric basal and stimulated acid secretion by inhibiting the parietal cell H+/K+ ATP pump Efficacy: (all equivalent) – Superior to H2RAs for dyspepsia, GERD, & PUD (esp meal-induced acid secretion) – QD vs BID dosing – no difference BID for severe, persistent sxs Toxicity: – Rebound hypersecretion – taper! – Reduced calcium absorption – hip# – ?Elevated risk of VIT B12 deficiency – ?Elevated risk of C-Diff infection? – ?Elevated risk of pneumonia? Cost: generic, ODB and OTC – Tecta (pantoprazole magnesium) and Pariet (rabeprazole) – ODB coverage, no LU code required Convenience: all QD or BID – Eg. Pantoprazole magnesium (Tecta®) 40mg once daily

Dyspepsia & GERD Step-up Therapy: – Find minimally effective, safest dose Vs Step-down Therapy: – Immediate relief first, then reduce Hiatus Hernia with symptoms: PPI QD-BID for prevention of Barrett’s esophagus

Peptic Ulcer Disease H.pylori-Induced 90% of DU, 70% of GU Once diagnosed, treat with at least triple therapy – Single and dual therapy are not effective enough – 14 day tx more effective than 7-10 day tx NSAID-Induced Cause most H.pylori- negative PUD Assess risk factors! – Previous Hx (OR=13.5x) – High dose NSAID (OR=7x) – Anticoagulants (OR=6.4x) – Age > 70y.o. (OR=5.6x) – SSRI use (OR=4.8x) – Age > 60y.o. (OR=3.1x) – Steroids (OR=2.2x) Rxfiles Comparison Charts. p40 Aug 2012. Accessed Mar 2013

Helicobacter pylori 1-2-3: “one week, twice daily, 3 drugs” – 14d versus 7-10d Rx: Superior efficacy, but elevated toxicity & cost Triple therapy (all BID): – PPI + Clarithromycin + Amoxicillin – PPI + Clarithromcyin + Metronidazole – N.B. PPI + Amox + Metro – inferior regimen Quadruple therapy: (also 1 st line) – PPI BID plus Metronidazole + Tetracyline + Bismuth subsalicylate (PeptoBismol®) all QID

NSAID-induced Peptic Ulcer Disease PPI superior to H2RA or Misoprostol (PG analog) PPI QD = PPI BID – BID only for symptomatic control Misoprostol 200mcg TID-QID – Effective, but intolerable! (mucho diarrhea) – Arthrotec® usually only BID dosing, so, under-dosed. GU: PPI QD x 8 weeks DU: PPI QD x 4 weeks

Laxatives 1.Stool Softeners – Eg. Docusate sodium – Not a laxative: “All mush, no push” 2.Bulk laxatives: – Water absorption; peristalsis – Eg. Psyllium, fibre, calcium polycarbophil (Prodiem®) 3.Osmotic laxatives – Osmotic + colonic acidification – Eg. Milk of magnesia, mag citrate, sorbitol, lactulose, PEG solution, sodium phosphate, glycerin suppositories 4.Stimulant laxatives – Direct effect on mucosa – Bisacodyl, sennosides Increasing potency = – Increasing efficacy and – Increasing side effects – Cramps, pain, diarrhea Narcotic induced constipation requires at least an osmotic laxative, (usually stimulant laxative)

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

Analgesics Dr Roland Halil, BSc(Hon), BScPharm, ACPR, PharmD Pharmacist, Bruyere Academic FHT Assistant Professor, Dept Family Medicine, U of Ottawa March 2016

Objectives Compare and contrast somatic and neuropathic pain List the relative efficacy and toxicities of analgesics Develop a step-wise approach to treating chronic, non-malignant pain

Pain: Somatic vs Neuropathic Somatic WHO Pain Ladder: 1.Acetaminophen 2.NSAID 3.Acetaminophen or NSAID + “weak” opioid (eg. Codeine) Eg. Tylenol #2, Tyl#3, 222’s, 4.Pure “strong” opioid Hydromorphone Oxycodone Morphine Codeine Neuropathic TCA – Nortriptyline – Amitriptyline Gabapentin Pregabalin Anti-epileptics – CBZ – VPA – Phenytoin

Acetaminophen MOA: unknown – (NAPQI metabolite may interfere w/ TRPA1 mediated pain transmission in the spine) Efficacy – Equivalent analgesia and antipyresis to NSAIDs Eg. OA, non-inflammatory pain Toxicity – Much less GI upset vs NSAIDs, no PUD, no ARF – Liver toxicity in overdose – N.B. combo OTC products! Cost – Cheap! Convenience – Q4h dosing, same as NSAIDs

Choosing NSAIDs As ever, work through the 4 steps: 1.EFFICACY: What are the endpoints of interest? 1.Analgesia 2.Anti-inflammation 3.Antipyresis All NSAIDs are generally considered equivalent for each endpoint. Few useful comparative trials published

Efficacy - Analgesia Efficacy vs placebo – Clearly beneficial – Lots of evidence (RCTs, meta-analyses etc) Efficacy vs other NSAIDs – Indirect evidence of differences in analgesia. Single dose studies only Acute pain only Limited number of indications & comparators – Ass-u-me-s we are able to extrapolate data See Oxford League Table (Table 1) – here: http://www.clinmedres.org/content/5/1/19.longhttp://www.clinmedres.org/content/5/1/19.long – N.B. ONLY compares EFFICACY Ong CKS et al. An Evidence-Based Update on Nonsteroidal Anti-Inflammatory Drugs. ClinMedRes 2007;5(1):19-34 see: http://www.clinmedres.org/content/5/1/19.long Accessed Oct 31, /11http://www.clinmedres.org/content/5/1/19.long

Oxford League Table Ong CKS et al. An Evidence-Based Update on Nonsteroidal Anti-Inflammatory Drugs. ClinMedRes 2007;5(1):19-34 see: http://www.clinmedres.org/content/5/1/19.long Accessed Oct 31, /11http://www.clinmedres.org/content/5/1/19.long

Toxicity – 1) Renal Additive pharmacodynamic effects on renal vasculature – ACEinh – ARBs – Aliskiren – Diuretics – NSAIDs NSAIDs equivalent Direct nephrotoxicity – Antibiotics – Aminoglycosides, Sulfonamides, Amphotericin B, Foscarnet, Fluoroquinolones, Rifampin, Tetracycline, Acyclovir (only IV), Pentamidine, Vancomycin – Immunosuppressants – Cisplatin, Methotrexate, Mitomycin, Cyclosporine, Ifosphamide – Heavy Metal Poisoning – Mercury, Lead, Arsenic, Bismuth – Lithium

Toxicity – Renal Triple Whammy! Katarzyna K Loboz and Gillian M Shenfield. Drug combinations and impaired renal function – the ‘triple whammy’. Br J Clin Pharmacol. 2005 February; 59(2): 239–243. see: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1884747/ Accessed Oct 31/11http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1884747/ 3) ACEinh / ARBs vasodilate efferent arterioles (blockade of ATii effects) 2) NSAIDs vasoconstrict afferent arterioles (inh of PG synthesis) 1) Diuretics reduce forward flow into kidney Result: Reduced GFR & Acute Renal Failure!

Toxicity – 2) Gastrointestinal Mechanism Direct (local) – Contact with GI mucosa – Acidic – Toxic to epithelia – Reduction of mucus and bicarb secretion – Enterohepatic circulation of some NSAIDs (repeated exposure) Indirect (systemic) – Inhibition of PG synthesis JOHN L. WALLACE Physiol Rev 88: 1547–1565, 2008 Accessed Nov 11/11 http://physrev.physiology.org/content/88/4/1547.full.pdf+htmlhttp://physrev.physiology.org/content/88/4/1547.full.pdf+html

Toxicity – Gastrointestinal Relative

Toxicity - Gastrointestinal In general: – LOW Risk: Ibuprofen – INTERMEDIATE Risk: Naproxen, Diclofenac – HIGH Risk: Ketorolac, Piroxicam

Toxicity - Gastrointestinal Risk Factors: – Age > 60 – Hx of PUD – GI cancer – GERD – esophageal varices – liver disease – recent MI or CVA Drugs: – Antiplatelets – Anticoagulants – Corticosteroids – Alcohol – ASA 81mg too! N.B. There is no correlation between symptoms of dyspepsia and GI mucosal damage as seen on endoscope.

Toxicity - Gastrointestinal GI ULCER Risk: ~annual risk 1-4% Elevated odds ratio (OR) with: (Consider adding PPI) – Hx of ulcer complication OR =13.5 – Multiple NSAID OR = 9 – High dose NSAID OR = 7 – Concomitant anticoagulant OR = 6.4 – Age≥70 OR = 5.6 – SSRI useOR = 4.8 – Age ≥60 OR = 3.1 – Concomitant steroidOR = 2.2 – Hx heart dx OR = 1.8 Rxfiles. NSAID comparison chart. p98 Jan 2015 – Access Mar 10/15 www.Rxfiles.cawww.Rxfiles.ca

Toxicity – GI – COX-2 inhibitors The sole COX-2 inhibitor on the market is Celecoxib (Celebrex®). SUCCESS-I trial – RCT showed celecoxib was ?“safer”. – celecoxib 100 mg bid (n=4393) – celecoxib 200 mg bid (n=4407) – naproxen 500 mg bid (n=905) – diclofenac 50 mg bid (n=3489) Singh G, Fort JG, Goldstein JL, et al. Celecoxib versus naproxen and diclofenac in osteoarthritis patients: SUCCESS-I study. Am J Med 2006; 119:255-266

Landmark CLASS trial (Celebrex® / Celecoxib) “… an interim report of the first 6 months of data from 2 trials that lasted 12 and 16 months.” – “… at …16 months there was no difference in GI adverse effects between celecoxib and traditional NSAID groups.” Discovered because crucial info was posted on FDA website – Not included in Canadian disclosures. 1) Lexhin, J et al. CMAJ NOV. 23, 2004; 171 (11) 2) Silverstein FE, et al. Celecoxib Long-term Arthritis Safety Study. JAMA 2000;284(10):1247-55 12 mo 16 mo 6 mo

Toxicity – 3) Cardiac COX-2 selectivity seems to increase cardiac risk – Dose and duration dependent Ratio of COX-2 : COX-1 inhibition: – Rofecoxib 80 : 1 – Celecoxib 9 : 1 – Ibuprofen 0.4 : 1 – Naproxen 0.3 : 1

Somatic: NSAID Toxicity: Cardiac Celebrex™ (Celecoxib) “Pfizer announced Dec 17, 2004, just 11 weeks after the Vioxx recall, that the National Cancer Institute suspended a trial after finding patients in the cancer study taking 400 to 800 mg of Celebrex daily had 2-3 times the cardiovascular risk than those taking a placebo.” Celebrex Safety. http://www.adrugrecall.com/celebrex/safety.html Accessed Feb 10/08http://www.adrugrecall.com/celebrex/safety.html

Toxicity - Cardiac (incl. PGI 2 ) (Also involved in renal function, tissue repair and reproduction).

Toxicity - Cardiac Higher cardiac risk might also occur in traditional NSAIDs – ?that are more COX-2 selective? – Diclofenac – Meloxicam – ?Indomethacin Based on observational studies only “Safer” = Naproxen, ?ibuprofen Health Canada. Summary Safety Review - Diclofenac - Risk of Major Heart and Stroke Related Adverse Events. October 6, 2014 - updated October 14, 2014. See: http://www.hc-sc.gc.ca/dhp-mps/medeff/reviews-examens/diclofenac-eng.php Accessed Mar 10/15http://www.hc-sc.gc.ca/dhp-mps/medeff/reviews-examens/diclofenac-eng.php Accessed Mar 10/15 Pawlosky, N. Cardiovascular risk: Are all NSAIDs alike? Can Pharm J (Ott). 2013 Mar; 146(2): 80–83. see: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3676195/ Accessed Mar 10/15 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3676195/

Cost Cheapest = older & generic ($/30 days) – Naproxen $8 - $20 – Ibuprofen $12 – ASA $18 – Meloxicam $20 – Indomethacin $19 – Celecoxib$54 - $100 Rxfiles. NSAID comparison chart. p98 Jan 2015 – Access Mar 10/15 www.Rxfiles.cawww.Rxfiles.ca

Convenience All po – Some IV, some PR Shorter effect (q4-6h) – Ibuprofen – Indomethacin – ASA Longer effect (q8-12h) – Naproxen – Diclofenac

Summary 1.Efficacy – equivalent at equipotent doses 2.Toxicity – Renal – equivalent risk – GI – dose and duration dependent Higher with some NSAIDs (eg. Ketorolac) With more risk factors – add a PPI or Misoprostol – CV - COX-2 inhibitors > NSAIDs AVOID COX-2 inh. Higher risk with Diclofenac (?and Meloxicam?) Safer with Naproxen (?and Ibuprofen?) 3.Cost – cheap & generic! 4.Convenience – Naproxen for BID convenience – Ibuprofen for short half-life (faster onset and offset)(eg. Gout tx) Remember: time to steady state = time to exit system = 3-5 half-lives

Opioids Efficacy: – All equivalent analgesia at equipotent doses – Bioavailability PO:IV = 2:1 Toxicity: (many!) – Constipation: ~ equivalent (no tolerance) (?codeine more than others) – Respiratory depression: ~ equivalent(rapid tolerance) – Sedation: ~ equivalent(rapid tolerance) – Pruritis / Histamine release: (slow tolerance) Morphine > Hydromorphone > Fentanyl Cost: – all have generic forms, short and long acting forms. – Codeine, morphine, hydromorphone, oxycodone, fentanyl all ODB covered +/- LU code Convenience: all po q4h (long acting versions all q12h)

Rxfiles.ca – Opioid Comparison Chart

Opioids Bottom line: all about the same. – Choose one or two and learn them well Hydromorphone 1mg Oxycodone~ 2.5mg Morphine~ 5mg Codeine ~ 60mg N.B. conversion requires calculation that takes into account possible incomplete cross tolerance ~ 5:1 ~ 2:1 ~ 12:1

Neuropathic Agents Efficacy: ~ the same; but additive – Presumed inhibition of fast, neuronal Na+ channels 1.Antidepressants – TCAs: Nortriptyline, Amitriptyline, etc. – SNRIs: Duloxetine, Venlafaxine 2.Anticonvulsants – Gabapentin, Pregabalin, VPA, CBZ, phenytoin, topiramate 3.Topicals – Lidocaine 5%, capscaicin, NSAIDs, compounded agents above etc.

Neuropathic Agents If Efficacy is ~ equivalent; choose based on potential toxicity, cost, and convenience factors Toxicity: – TCA’s: anticholinergic, sedation, QTc prolongation – Gabapentin & Pregabalin: sedation, edema, dizziness – Duloxetine & Venlafaxine : CNS effects, GI effects – Anti-epileptics: hepatitis, GI effects, CBC alterations, drug interactions Cost: – Pregabalin & duloxetine – pricey, (since no generics) Convenience: all ~ qhs or BID

Rxfiles.ca - Neuropathic Agents Rxfiles.ca Table 2: Overview of Drugs Used in Treatment of Chronic Non‐Cancer Pain (CNCP) Feb 2013. pg 67 Accessed Mar 24/13

Drug-Drug Interactions Dr Roland Halil, BSc(Hon), BScPharm, ACPR, PharmD Pharmacist, Bruyere Academic FHT Assistant Professor, Dept Family Medicine, U of Ottawa March 2016

Objectives List the mechanism of various pharmacodynamic and pharmacokinetic drug-drug interactions Define clinically relevant interactions List common red-flag interactions that all practitioners should be aware of in primary care Learn useful resources for finding accurate and timely information regarding drug interactions

Outline Intro Mechanisms – Outline bread & butter examples for each type – Summarize and underscore mains types – Outline rare & severe examples (5HT syndrome, QTc prolongation, prescribing cascades, renal triple whammy) Future support – Tricks for clinical context

Introduction Things will only get worse…. Wide spectrum of cases in Family Practice – Cradle to grave – 2/3 rds of MD office visits result in a prescription Aging population – Multiple disease states – Multiple caregivers – Self Treatment An increasing armamentum of drugs – Rx / OTC / herbal / homeopathic Jaski M.E. et al. Effective Clinical Practice, ACP Internal Medicine Jan/Feb 2000. http://www.acponline.org/journals/ecp/janfeb00/jaski.htm Accessed April 17/12.http://www.acponline.org/journals/ecp/janfeb00/jaski.htm

Drug Interactions Nature – Synergistic – Additive – Antagonistic Consequence – Beneficial Increased therapeutic effect Reduced toxicity – Adverse Reduced therapeutic effect Increased toxicity

Drug Interactions – Mechanism 1.Pharmacokinetic (PK) – What the body does to the drug 1.Absorption 2.Distribution 3.Metabolism 4.Excretion 2.Pharmacodynamic (PD) – What the drug does to the body

PK – 1) Absorption Interactions Important in family practice: – Chelation (binding interactions) Less commonly clinically relevant: – Alteration of gastric pH – Alteration of GI motility 1.Aymard JP et al. Med Toxicol Adverse Drug Exp 1988;3:430-48. 2.Murray J.J. et al. JAMDA 1991;1:p. 3.Lomaestro BM et al. Drug Intell Clin Pharm 1991;25: 1249-58.

PK – 1) Absorption Interactions Chelation 1.Fluoroquinolones or Tetracyclines plus minerals [Minerals = calcium (Ca 2+ ), magnesium (Mg 2+ ), iron (Fe 3+ ), aluminum (Al 3+ )] [Almost all buffering antacids (TUMS, Gaviscon, Milk of Magnesia, Rolaids, etc.), as well as MVITs, iron tabs etc.] – Risk of treatment failure! 2.Bisphosphonates plus minerals – Risk of osteoporotic fracture 3.Phenytoin plus minerals – Potential loss of seizure control Separate administration by 2 hours

PK – 1) Absorption Interactions Alteration of gastric pH – Increased pH Eg. Iron / Ketoconazole / Vit B12 absorption is reduced Administer with OJ or Coca-cola Alteration of GI motility – Decreased motility Eg. Decreased absorption of Levodopa – Increased metabolism at intestinal brush border – Increased motility Eg. Decreased absorption of Digoxin

PK – 2) Distribution Interactions Displacement Reaction – (from protein binding sites) – Rarely significant – Often need: Highly bound drug – (98% bound to 96% bound = 100% increase in free concentration) PLUS, you often need inhibition of metabolism (or elimination) to allow enough time for these effects before redistribution to a new steady state.

PK – 2) Distribution Interactions Eg. Warfarin + Septra – Displacement of warfarin off protein binding sites (plus inhibition of metabolism and Vitamin K synthesis by gut flora) Eg. Phenytoin + Valproic acid – Displacement of phenytoin off binding sites (plus inhibition of metabolism and zero order kinetics (enzyme saturation kinetics) of phenytoin) Hogan M.J. et al. DNS Aug. 30, 1999 http://www.findarticles.com/p/articles/mi_m3374/is_13_21/ai_55693815/pg_4 Accessed Apr 18/12http://www.findarticles.com/p/articles/mi_m3374/is_13_21/ai_55693815/pg_4

PK – 3) Metabolism Interactions Metabolism occurs in many places – Skin, lung, intestine, serum, kidney, liver – Most metabolism occurs in the liver Few interactions with non-oxidative metabolism – (ubiquitous enzymes) – Not everything is P450 P-glycoprotein poorly understood so far – Genetic variability becoming more important Isoniazid, codeine

PK – 3) Metabolism Interactions Cytochrome P450 isoforms – so many! Family - Subfamily - Genotype (eg. 2-C-19) (18) (42) (60) – Substrates, inhibitors, & inducers for each isoform! – 3A4 - most common

Inducers: Ask: Time to effect? – ~ 2 weeks to kick in – ~ 2 weeks to fade out Substrates: – Ask: Consequences of sub-therapeutic doses? Flockhart D.A. P450 Table www.medicine.iupui.edu/flockhart/table.htm Accessed Sept 19/04.www.medicine.iupui.edu/flockhart/table.htm PK – 3) Metabolism Interactions

Inducers of 3A4: – Rifampin / Rifabutin – Efavirenz / Nevirapine – Glucocorticoids – Phenytoin – Carbamazepine – Barbiturates – St. John's Wort – Pioglitazone etc Substrates of 3A4: – Clarithro / Erythromycin – Alpraz / Diaz / Midazolam – CSA / Tacrolimus – Indinavir / Nelfinavir Ritonavir / Saquinavir – Amlodipine / Felodipine Nifedipine / Verap / Dilt – Atorva / Simvastatin – Estrogen – Carbamazepine etc Flockhart D.A. P450 Table www.medicine.iupui.edu/flockhart/table.htm Accessed Sept 19/04.www.medicine.iupui.edu/flockhart/table.htm PK – 3) Metabolism Interactions

PK – 3) Metabolism Interactions Clinical Scenarios 50 y.o. male - PMHx of HTN, MI x3, COPD on: – Ramipril 10mg daily – HCTZ 25mg qAM – Amlodipine 10mg daily – BP control borderline/high – COPD exacerbation Rx: PREDNISONE 25mg qAM for 7 days Issues? » NO! 50 y.o. female – PMHx of DM2, renal transplant on: – Ramipril 10mg daily – Amlodipine 10mg daily – Tacrolimus 10mg BID – Cyclosporine 15mg BID – Endo Rx: ACTOS 30mg qd – N.D.: St John’s Wort i qd Issues? » YES!

Inducers of 1A2: – Nicotine – Smoking cessation… Substrates of 1A2: – Caffeine – Sweaty, anxious, nauseous, sleepless… – Nicotine withdrawal? – No! Caffeine overdose! Flockhart D.A. P450 Table www.medicine.iupui.edu/flockhart/table.htm Accessed Sept 19/04.www.medicine.iupui.edu/flockhart/table.htm PK – 3) Metabolism Interactions Pearl

Inhibitors: Ask: Time to effect? – Immediate effect – Hours/days to fade Substrates: – Ask: Consequences of supra-therapeutic doses? Flockhart D.A. P450 Table www.medicine.iupui.edu/flockhart/table.htm Accessed Sept 19/04.www.medicine.iupui.edu/flockhart/table.htm PK – 3) Metabolism Interactions

Inhibitors of 3A4: – Clarithro / Erythro – Ciprofloxacin – Fluco / Itra / Ketoconazole – Grapefruit juice – Amiodarone – Indinavir / Nelfinavir Ritonavir /Saquinavir Delaviridine – Verapamil / Diltiazem – Cimetidine Substrates of 3A4: – Alpraz / Diaz / Midazolam – CSA / Tacrolimus – Amlodipine / Felodipine Nifedipine / Verap / Dilt – Atorva / Simvastatin – Clarithro / Erythromycin – Indinavir / Nelfinavir Ritonavir / Saquinavir – Estrogen – Carbamazepine etc Flockhart D.A. P450 Table www.medicine.iupui.edu/flockhart/table.htm Accessed Sept 19/04.www.medicine.iupui.edu/flockhart/table.htm PK – 3) Metabolism Interactions

PK – 3) Metabolism Interactions Clinical Scenarios 60 y.o. female – PMHx of HTN on: – Nifedipine XL 60mg qd – BP: 105/60 – Enjoys a fresh grapefruit when in season. Issues? » No! 60 y.o. male – PMHx of NSTEMI, CHF on: – Lipitor 80mg qd – Ramipril 10mg qd – ASA 81mg qd – Bisoprolol 5mg qd – New onset Afib – Cardio Rx: Amiodarone 200mg daily Issues? » Yes, two!

Inhibitor of 2C19: – Omeprazole ?All PPI’s – Time to effect is immediate Substrates of 2C19: – Clopidogrel – Lack of metabolism from pro-drug to active form – Sub-therapeutic effect! Flockhart D.A. P450 Table www.medicine.iupui.edu/flockhart/table.htm Accessed Sept 19/04.www.medicine.iupui.edu/flockhart/table.htm PK – 3) Metabolism Interactions Pearl

PK – 3) Metabolism Summary Inducers – Remember: time to effect ~ 2 weeks Longer treatments will result in more significant interactions Harder to see the temporal correlation – Lower doses of affected substrate need to be clinically relevant Inhibitors – Remember: time to effect is immediate Shorter treatments will result in more significant interactions N.B. Drugs with long half- lives will take longer to show their effect! – Higher doses of affected substrate need to be clinically relevant

Rarely significant, but… – Enterohepatic circulation: Bile acid sequestrants + Warfarin or L-T4 or Estrogen – Alteration in urine pH Ion trapping – Eg. Management of ASA overdose with bicarb – Eg. Methamphetamine overdose with Vit C / NH 4 Cl – Competition for tubular transporters Anion: Probenecid + beta-lactams (osteomyelitis) Cation: Itraconazole /cimetidine + digoxin / quinidine PK – 4) Excretion Interactions

Pharmacodynamic (PD) Interactions Think: Review of Systems – Head to Toe Bottom Line: – The molecular mechanism is irrelevant. – The physiological effect is important. These effects are additive. – (or synergistic or antagonistic)

PD - CNS Eg. CNS depression – Alcohol – Opioids – Benzodiazepines – Antihistamines Diphenydramine, hydroxyzine, etc – Antipsychotics (typical & atypical) – Antidepressants (TCAs, SSRIs etc) – Barbiturates – Etc.

What to do? Monitor more closely for tolerance – Temporal correlations will be helpful Other classic pearls of prescribing: – Avoid the combo if possible Explore alternatives using the 4 steps of rational prescribing – Use the lowest effective dose – Limit duration of treatment – Start low, go slow

PD - CV Bradycardia – Beta blockers – Diltiazem, Verapamil – Digoxin – Amiodarone Hypertension – NSAIDs & COX-2 inh – Corticosteroids – EPO – Estrogens – Cyclosporine – Sympathomimetics phenylephrine caffeine pseudoephedrine

PD Respiratory Depression – Opioids – Barbiturates – Benzodiazepines – Alcohol Constipation Loperamide Opioids Calcium / antacids Anticholinergics Metamucil Etc Diarrhea Laxatives Erythromcyin Antibiotics Magnesium So many more! PD interactions are common and best prevented by understanding the MOA of drugs used in practice.

Prescribing Cascades Very common in primary care Unrecognized side effects of one drug lead to prescribing of another to compensate. – Chain linked pharmacodynamic interactions! – Have seen up to 20 drugs in elderly patients accumulate over the years!

Renal Triple Whammy Commonly overlooked in Primary Care ACEinh (or ARB) + diuretic + NSAID Katarzyna K Loboz et al. Drug combinations and impaired renal function – the ‘triple whammy’. Br J Clin Pharmacol. 2005 February; 59(2): 239–243. see: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1884747/pdf/bcp0059-0239.pdf Accessed Apr 18/12http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1884747/pdf/bcp0059-0239.pdf

Katarzyna K Loboz and Gillian M Shenfield. Drug combinations and impaired renal function – the ‘triple whammy’. Br J Clin Pharmacol. 2005 February; 59(2): 239–243. see: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1884747/ Accessed Oct 31/11http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1884747/ 3) ACEinh / ARBs vasodilate efferent arterioles (blockade of ATii effects) 2) NSAIDs vasoconstrict afferent arterioles (inh of PG synthesis) 1) Diuretics reduce forward flow into kidney Result: Reduced GFR & Acute Renal Failure!

Rarities (that never seem rare enough)

Serotonin Syndrome – Hyperstimulation of 5-HT 1A & 2A receptors Peripherally and centrally – Concentration dependent symptoms Mild - tremors and diarrhea Severe – hyperthermia and rigidity, even death. – Rare in monotherapy Usually with polypharmacy Rastogi, Rahul et al. Case Scenario: Opioid Association with Serotonin Syndrome: Implications to the Practitioners. Anesthesiology: December 2011 - Volume 115 - Issue 6 - p 1291–1298 see: http://journals.lww.com/anesthesiology/Fulltext/2011/12000/Case_Scenario___Opioid_Association_with_Serotonin.24.aspx Accessed Apr 18/12.http://journals.lww.com/anesthesiology/Fulltext/2011/12000/Case_Scenario___Opioid_Association_with_Serotonin.24.aspx

Serotonin Syndrome Important Meds: – SSRIs- SNRIs – TCAs- MAOinh’s – Triptans- St John’s Wort – Opioids (incl. DM syrup)- MDMA (ecstasy) Opioids may affect serotonin levels – Tramadol, fentanyl, methadone, meperidine, dextromethorphan Weak SSRI’s and also increase release of 5HT into the synapse Possibly also morphine, hydromorphone, oxycodone and buprenorphine (which lack SSRI activity) Joel Lamoure. How Common or Significant Is Serotonin Syndrome? Medscape 11/10/2008 http://www.medscape.com/viewarticle/582862 Accessed Apr 18/12.http://www.medscape.com/viewarticle/582862

Serotonin Syndrome Predisposing factors: – Serotonergic Load Consider all potentially offending drugs Gauge the load by dose and frequency of use. – P450-2D6 and -3A4 mutations (polymorphisms) – P450-2D6 and -3A4 inhibitors – Inhibitors of: NE reuptake, GABA, NMDA, and 5HT3

Clinical Scenario 39 year old male on: – Citalopram 10mg qd for depression – Nortriptyline 75mg qhs for neuropathy – Ibuprofen 400mg prn for migraine He is asking about a triptan for his migraines. They were effective back home in Lebanon. – Considerations? (five of them)

QTc Prolongation Also rare, but with serious potential outcomes. – Torsades (TdP), death Hard to predict Long list of meds that prolong the QTc – See: www.crediblemeds.org (free registration)www.crediblemeds.org

Common Culprits Recent cases: – Domperidone, Citalopram, Escitalopram Macrolides – Erythromycin > Clarithromycin > Azithromycin Fluoroquinolones – Ciprofloxacin, Levofloxacin, Moxifloxacin, Norfloxacin Miscellaneous – Clindamycin, Trimethoprim/Sulfamethoxazole Azole Antifungals – Fluconazole, Itraconazole, Ketoconazole Antipsychotics SSRI’s TCAs Etc.

Risk factors for QTc Prolongation – Female - Hypokalemia – Elderly - Hypothyroidism – Myocarditis -Hypomagnesemia – Bradycardia - Hypothermia – Myocardial infarction - Hypocalcemia – Stroke - Hypoglycemia – Long QT Syndrome (congenital form) – Syncope of unknown cause

QTc Prolongation Clinical Scenario 66 y.o. female with PMHx of Long QT Syndrome – Normal EKG 3 months ago – Labs normal New UTI; No C&S yet – Options? – Macrobid, Amox – avoid macrolides, septra, cipro! 66 y.o. male with PMHx of bipolar on: – Quetiapine 400mg qd – Citalopram 20mg qd – Labs normal New pneumonia (CAP) – Options? – Any will do, preferrably Azithro, Clavulin, Doxy

Summary - Resources 1.Learn the basic mechanism of action of the drugs in your personal formulary – Most interactions you’ll see are pharmacodynamic For pharmacokinetic interactions (usu CYP-P450): 2.Get a good EMR – Most have interactions checkers – active while Rx’ing 3.Get a good drug database – (All have superior interaction checkers in them!) Eg. Micromedex or Lexi-Comp 4.Get a good pharmacist – They are well positioned to help manage these cases

Clinical Scenario 1 H.R. - 66y.o. male with hypothyroidism, HTN and OP Meds: – Synthroid 100mcg qAM – Altace 5mg qPM – Triamterene 100mg qAM – Actonel 35mg/wk – Calcium/Vitamin D 1000mg/1000iu qAM Three potential issues!

Clinical Scenario 1 - answer 1) ? Ca 2+ & Synthroid co-administration? 2) ? Ca 2+ & Actonel co-administration? 3) ? Hyperkalemia with ACEi & K + sparing diuretic?

Clinical Scenario 2 J.K. - 29y.o. female from Sudan Meds: – Rifampin 600mg – Isoniazid 300mg – Pyrazinamide 2g – Ethambutol 1.6g – Alesse 21

Clinical Scenario 2 - answer Rifampin induction of P450 3A4 Risk of OCP failure (When? Within 2 weeks) Management: – Barrier method until 2 weeks post RIF – INH 3A4 DI, not significant here

Clinical Scenario 3 T.Y. 83 y.o. female with DM2, HTN, delirium and recent fall Meds: – Altace 5mg- Atenolol 25mg – HCTZ 12.5mg- ASA 81mg – Amitriptyline 25mg- Trazodone 50mg – Insulin NPH & R- Glycopyrrolate 2mg – Haloperidol 1mg- Demerol 50mg

Clinical Scenario 3 - answer Delirium: – Additive anticholinergic fx in elderly Glycopyrrolate, trazodone, amitriptyline, haloperidol Fall: – Additive sedative fx in elderly Haloperidol, demerol, trazodone, amitriptyline – Additive dizziness Atenolol, altace, HCTZ, demerol, trazodone

Summary The more meds patients take, the greater the risk of drug interactions (DI) – The nature and mechanism of DI’s can have beneficial or adverse consequences Pharmacokinetic DI - alter drug levels – Most commonly metabolic DI (P450) We’ll never know them all; get good software! Pharmacodynamic DI - alter responses – Additive, synergistic or antagonistic effects occur regardless of the mechanism – most common DI’s!

Oral Anti-Thrombotics Dr. Roland Halil, BSc(Hon), BScPharm, ACPR, PharmD Assistant Professor, Dept of Family Medicine, University of Ottawa Clinical Pharmacist, Bruyere Academic Family Health Team April 2016 rhalil@bruyere.org

Anticoagulants Warfarin – Vitamin K antagonist – (clotting factors 2,7,9,10, protein C & S) – For: Afib, VTE prophylaxis & tx, valvular disease Dabigatran – Direct thrombin inhibitor (factor 2) – For: Afib, VTE prophylaxis post-op TKR/THA – (N.B. Ximelagatran – withdrawan due to hepatotoxicity) Rivaroxaban – Factor Xa inhibitor – For: Afib, VTE prophylaxis post-op TKR/THA, DVT tx Apixaban – Factor Xa inhibitor – For: Afib, VTE prophylaxis post-op TKR/THA

Anticoagulants (VTE, Afib, Valve disease) AgentEfficacyToxicity Warfarin Excellent vs placebo or ASA 1.3% - 3.5% -- major bleed < 0.25% - 0.5%/yr -- ICH Dabigatran ~ same (~1% absolute difference) (RE-LY trial - industry funded) Less intracranial & More GI bleeds vs Warf ?More MI? More GI upset Untested > 79y.o. or CrCL < 30 NO reversal agent (Idarucizumab pending) Rivaroxaban ~ same (<1% abs diff) (ROCKET-AF trial – industry funded) Less intracranial & More GI bleeds vs Warf Untested > 79y.o. or CrCL < 30 NO reversal agent (Andexanet pending) Apixaban ~ same (<1% abs diff) (ARISTOTLE trial – industry funded) Less intracranial bleeds GI bleeding – no difference vs Warf Untested > 77y.o. or CrCL < 30 NO reversal agent (Andexanet pending)

Rxfiles.ca Comparison of Warfarin & New Oral Anticoagulants (NOACs) in Non-Valvular Atrial Fibrillation. Oct 2014c

Anticoagulants (VTE, Afib, Valve disease) Agent CostConvenience Warfarin ~ $40/mo (with INR monitoring) QD po INR q3d – q1mo (ODB covered) Dabigatran$110/mo BID po (ODB w/ LU code 431 for AFib) Rivaroxaban$100/mo QD with food (ODB w/ LU codes for Afib or VTE) Apixaban$140/mo BID po (ODB w/ LU code 448 for Afib) Rxfiles.ca Comparison of Warfarin & New Oral Anticoagulants (NOACs) in Non-Valvular Atrial Fibrillation. Oct 2014c

Summary Antiplatelets – Small differences in efficacy or toxicity, dictate that cost will drive selection. – = ASA – Combination therapy where indicated Anticoagulants – Small differences in efficacy and important unknowns in newer agents (age effects, renal dysfunction, lack of antidotes) dictate selection of warfarin except for carefully selected patients with significant compliance barriers due to the inconvenience of INR testing.

Anti-depressants & Anxiolytics Dr. Roland Halil, BSc(Hon), BScPharm, ACPR, PharmD Assistant Professor, Dept of Family Medicine, University of Ottawa Clinical Pharmacist, Bruyere Academic Family Health Team April 2016 rhalil@bruyere.org

Anti-depressants & Anxiolytics Selection of therapy: – Efficacy: All equivalent! N.B. Wouldn’t use Bupropion for anxiety – Therefore, tailor therapy based on potential toxicities! Meta-analyses that include grey literature trials show an over- estimation of efficacy and an under-appreciation of toxicity. SSRI’s: – Fluoxetine, sertraline, (es)citalopram, fluvoxamine, paroxetine SNRI’s: – (des)venlafaxine, duloxetine Mirtazapine Bupropion TCA’s: – Amitriptyline, nortriptyline, despramine, imipramine, clomipramine, doxepin MAOi’s: (+++ types) – Moclobemide (reversible) – Phenelzine (irreversible) etc. etc.

Toxicities Anti-cholinergic effects – Paroxetine – Mirtazipine – (des)Venlafaxine – TCAs: amitriptyline > nortriptyline > desipramine N.B. Anti-cholinergic, anti- histaminergic & weight gain effects often go hand- in-hand. – Wt gain is usually minimal – Some subpopulations gain++ Sedation – TCAs – Fluvoxamine Paroxetine (less extent) – Mirtazapine – Trazodone Activation – Fluoxetine – Bupropion – (des)Venlafaxine – Moclobemide

Toxicities GI side effects – Nausea - SSRIs – Constipation - TCAs – Diarrhea - sertraline, fluoxetine, paroxetine, duloxetine QTc prolongation (TdP) – TCA’s – Citalopram > 40mg/day – Escitalopram > 20mg/day Sexual dysfunction – SSRIs (>30% !) – TCAs N.B. More serotonin = less libido More dopamine = more libido Drug/disease interactions – Least with: (es)citalopram, mirtazapine, moclobemide, sertraline, (des)venlafaxine – Moclobemide: no tyramine restrictions (unlike irrev MAOi’s!)

Anti-depressants & Anxiolytics Cost – All ~ $25 - $35 / month – Newest agents, without generics cost more. Bupropion XL – $30-$47/mo Escitalopram – $65/mo – New generics; price is dropping Paroxetine CR – $69-$75/mo – Not covered under ODB Desvenlafaxine – $85/mo – Not covered under ODB Convenience – Most once daily – Bupropion SR – BID Bupropion XL – QD – Moclobemide - BID

The Evils of Benzodiazepines (Yes, this includes “z-drug, non-benzo alternatives” Eg. Zopiclone) Formerly one of the most commonly prescribed drug families of the 1960’s and ‘70’s. – In 1975 – 100 million Rxs written in USA alone – Efficacy – excellent SHORT term efficacy Sedation & anxiolysis Rapid tolerance is developed + Dependence – insidious combo! – Toxicity – addictive! D/C’ing is VERY hard Long term risk of dementia, falls, and memory impairment Severe withdrawal can be fatal (seizures) – Cost & Convenience – Who cares?; Fuggetabout-it ! http://www.youtube.com/watch?v=tfGYSHy1jQs http://www.youtube.com/watch?v=Zf0ZyoUn7Vk http://www.youtube.com/watch?v=J5Xu9UcOdj0 Maximum supply: Mitte: single digits! No refills.

Summary Highly variable response in efficacy – All ~ equivalent in efficacy Trial and error – Tailor to potential toxicities to maintain compliance Focus on relative toxicities! – Efficacy often overestimated – Toxicity often underestimated Avoid Benzodiazepines and Zopiclone (addictive) – Even Rx’s for 10 tabs often snowball into chronic use.

Anti-psychotics Dr. Roland Halil, BSc(Hon), BScPharm, ACPR, PharmD Assistant Professor, Dept of Family Medicine, University of Ottawa Clinical Pharmacist, Bruyere Academic Family Health Team April 2016 rhalil@bruyere.org

Anti-psychotics Typical (1 st gen / conventional) (Relative terms) Atypical (2 nd gen) Butyrophenones – Haloperidol & Droperidol Phenothiazines – Chlorpromazine & Fluphenazine – Perphenazine & Prochlorperazine – Thioridazine & Trifluoperazine – Mesoridazine & Periciazine – Promazine & Triflupromazine – Levomepromazine & Promethazine – Pimozide Thioxanthenes – Chlorprothixene & Clopenthixol – Flupenthixol & Thiothixene – Zuclopenthixol Clozapine Olanzapine Quetiapine Risperidone Aripiprazole Ziprasidone Paliperidone Asenapine etc.

Anti-psychotics Efficacy – No clinically relevant differences (variable responses) ?Olanzapine superiority? – See CATIE trial – Exception: Clozapine – clearly superior As ever, when efficacy is ~ equivalent, choose therapy based on potential toxicities

Anti-psychotics Toxicities: – Clozapine: Agranulocytosis (10x higher risk vs other antipsychotics) Hence, mandatory CBC q2-4weeks Therefore, last line therapy, despite superior efficacy

Toxicities Sedation – Quetiapine – Olanzapine – Clozapine – Typicals – Least: haloperidol, risperidone, aripiprazole?, ziprasidone? Weight gain – Clozapine – Olanzapine – Quetiapine – Least: haloperidol, risperidone, aripiprazole?, ziprasidone? Tardive Dyskinesia – Typicals – Least: Clozapine (esp), all atypicals Anticholinergic effects – Clozapine – Typicals – Least: risperidone, quetiapine, haloperidol

Toxicities EPS – Typicals – Least: atypicals QTc prolongation – Clozapine – Paliperidone – Ziprasidone – Pimozide – Asenapine – Thioridazine – Least: Risperidone, haloperidol, aripiprazole, olanzapine, low dose quetiapine Hypotension – Clozapine – Risperidone – Typicals – Least: olanzapine, haloperidol, ziprasidone, paliperidone

Antipsychotics Cost ~ $20 - $40/month More expensive: – Newest agents: – ($60-$160/month) Aripiprazole Ziprasidone Paliperidone Asenapine – Clozapine – Quetiapine (XR) – Olanzapine (Zydis) Convenience – Most BID po – Olanzapine Zydis (melts) – Risperidone M-tab (melts) – Some I.M. long acting forms: Risperidone q2wk Paliperidone q4wk Flupentixol q2wk Fluphenazine q4wk Zuclopenthixol q3wk Haloperidol q4wk

Summary Choose anti-psychotics based on potential toxicities – Learn two or three very well that complement each other. – Low threshold to confer with psychiatry or pharmacy Rxfiles.ca – excellent comparison charts to help guide therapy – http://www.rxfiles.ca.proxy.bib.uottawa.ca/rxfiles/uploads/do cuments/members/Cht-Psyc-Neuroleptics.pdf http://www.rxfiles.ca.proxy.bib.uottawa.ca/rxfiles/uploads/do cuments/members/Cht-Psyc-Neuroleptics.pdf

Gout (Get Out the Gout) Dr. Roland Halil, BSc(Hon), BScPharm, ACPR, PharmD Assistant Professor, Dept of Family Medicine, University of Ottawa Clinical Pharmacist, Bruyere Academic Family Health Team April 2016 rhalil@bruyere.org

Pathophysiology Precipitation of monosodium urate crystals in avascular tissues – (cartilage, epiphyseal bone, periarticular bone) – Hyperuricemia likely asymptomatic for years The acute attack: – Crystals activate plasma proteases – Can activate factor XII & C5 – Can adsorb opsonins in area, attracting phagocytes!

Phagocytosis fails. Crystals lyse phagocytes. Tophi are released Enzymes released into synovial fluid Damage tissue, activate complement etc MORE PHAGOCYTES ARRIVE - Lactic acid is a byproduct of phagocytosis Inflammation lowers pH in the joint Urate precipitates out of solution = tophi Pathophysiology – Acute Attack

A vicious cycle. Acute attacks probably self-limited due to heat of inflammation re-dissolving the crystals

Principles of Management 1.Terminate acute attacks 2.Prevent recurrence – Eliminate urate crystals from joints & tissues 3.Address co-morbidities – Obesity – Hypertriglyceridemia – Hypertension – Diabetes mellitus – Excessive alcohol

1)Treatment of Acute Attacks Directed at WBC inflammatory response Options: 1.NSAIDs 2.Colchicine 3.Corticosteroids Choice depends on toxicity, cost & convenience since efficacy is ~ equivalent – More importantly – rapidity of treatment selection! – Keep agent close at all times; start PRN A.S.A.P. Especially with poor renal function: N.B. A slower response = increased drug exposure over the course of a flare

Colchicine vs NSAIDs 1.Untreated  Bellainy et al. (1987); 2.Placebo group  Ahern el al. (1987); 3.Colchicine  Aliern et al.(1987); 4.Indomethacin  Ruotsi Vainio (1978); 2 1)Management of Gout With Colchicine http://www.theberries.ns.ca/Archives/colchicine.html Accessed Nov 1/07http://www.theberries.ns.ca/Archives/colchicine.html 2)Ahern MJ, et al. Does colchicine work? The results of the first controlled study in acute gout. Aust N Z J Med 1987;17:301-4.

NSAIDs No difference in Efficacy Choose based on: Toxicity, Cost, Convenience – Toxicity: N/V/D, GI bleeding, fluid retention, ARF, etc So: avoid in PUD/GERD, CHF, peripheral edema, CKD etc – Cost Rx vs OTC – Convenience Choose NSAID with a shorter half-life (t½) (ss = 3 - 5 t½’s!) – Fast in = achieves steady state faster for acute pain, – Fast out = smaller footprint on CrCL (renal strain) – Eg. Ibuprofen (2-4hrs); Diclofenac (2hrs); Indomethacin (4.5hrs);

Colchicine Used for centuries Most specific agent in use – Decreases leukocyte motility Binds to tubulin and inhibits microtubule formation, arresting neutrophil motility – Decreases phagocytosis in joints Decreases lactic acid production OVERALL EFFECT: – Interruption of inflammatory process – PO or IV Avoid IV - Potentially fatal if mis-dosed! – Risk of arrhythmia Colchicum autumnale (autumn crocus) (meadow saffron)

Colchicine Traditional dosing: – 0.6mg q1-2hrs until: Improved sxs OR GI distress OR 10 doses with no effect – Too rigourous for most patients! (Esp elderly) - GI distress in 50-80% of patients! Narrow therapeutic window

Colchicine 1 mg & 0.6 mg tablets - scored Alternative regimens – 1mg loading dose, then 0.5mg q2-6hrs OR – 0.5 - 1mg TID OR – 1.2mg initially, then 0.6mg BID Most effective w/i first 12hrs of attack Dose low! Try TID dosing first D/C if GI distress develops

Corticosteroids Reserved for: – Intolerant of NSAIDs or colchicine – Co-morbidities that prohibit use of other meds Good alternative for elderly w/ poor renal function – Few trials – choice is empiric – Eg. Prednisone 20-60mg /day PO Lower doses may be less effective – Flares noted in transplant patients on 7.5 mg - 15 mg/day – Methylprednisolone 125mg/day IV or IM q1-4 days prn Can give intra-articular injection, but avoid if joint is septic!

Serum Urate Rising urate levels can provoke flare – For reasons unknown, lowering serum urate can as well. Worse with more rapid or severe changes in urate Occurs in ~ 25% of patients N.B. Do not alter existing gout meds during acute flare! (ie. allopurinol)

Summary Treatment of Acute Attacks Start treatment A.S.A.P.! Do not change doses of any med that can alter urate levels when treating acute attacks (ie. allopurinol) Consider NSAIDs, colchicine, steroids at low doses and in combination (different MOA’s; additive benefits) Avoid NSAIDs in CKD, CHF Avoid / Reduce colchicine dose in CKD, liver dz, neutropenia, on diuretics, statins, or cyclosporin

2)Preventing Recurrence Eliminate excess body urate – Else, tophi may continue to enlarge – Result: chronic arthritis due to chronic inflammatory response destroying cartilage & bone – Target: Urate < 360 umol/L High likelihood of recurrence – 62% w/i 1 yr – 78% w/i 2 yrs – 90% w/i 5 yrs

Preventing Recurrence Recall that: Lowering urate can precipitate a flare! Start 2-3 weeks after flare resolved – Uricosuric agents – increase UA excretion Probenecid Sulfinpyrazone – Xanthine Oxidase inhibitors – decrease UA production Allopurinol – agent of choice Febuxostat – new agent (ULORIC™) May consider prophylaxis before urate lowering therapy (eg. low dose colchicine or NSAID daily) – Continue 3-6 months and/or [urate] < 360 umol/L

Allopurinol Start Allopurinol at low dose and titrate up to avoid precipitating event – Eg. 100mg, increasing by 100mg q2-4 weeks to target dose – With renal dysfunction: 50mg initiation, increase by 50mg

Febuxostat (ULORIC™) A non-purine, selective xanthine oxidase inh. Efficacy vs Allopurinol: – Similar frequency of gout flares N.B. Higher frequency of flare with initiation at higher doses! – More potent reduction of UA than Allopurinol – Limited RCTs - need more evidence in: Renal dysfunction, concomitant use of urate raising drugs (eg. ASA, thiazides), comparison against non-fixed doses of Allopurinol See: Gaffo LA et al. Febuxostat: the evidence for its use in the treatment of hyperuricemia and gout. Core Evid. 2009; 4: 25–36. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2899777/?tool=pubmed Accessed Feb 7 th, 2011. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2899777/?tool=pubmed

Start 40mg daily (+/- food) – Up to 80mg or 120mg qd after 2 weeks if UA > 360 umol/L – CrCL > 30mL/min – no dose adjustment – CrCL < 30 mL/min – unstudied – avoid Side effects: – Rash (1% to 2%) – Liver function abnormalities (5% to 7%) F/U LFTs in 2 & 4 months after starting tx – Arthralgia (1%) Cost: 80mg tabs ~ $60/ month; – (no ODB coverage) Treat the same as allopurinol Febuxostat (ULORIC™)

Note Bene (N.B.) No prophylaxis without urate lowering tx! – Acute flare prevented but crystal deposition in tissue continues! – Hence no warning signs of continued cartilage and bone damage and deposition in organs, especially kidneys! – Remember: Cochicine is NOT uricosuric!

Preventing Recurrence - Summary Allopurinol – Most common Febuxostat – New kid on the block! – Improved efficacy – Lacking sufficient safety data for some populations – No ODB coverage Probenecid or Sulfinpyrazone: (unlikely) – only if CrcL > 50mL/min – No hx of kidney stones – No ASA > 2g/day Interference with uricosuric effects

Preventing Recurrence -Allopurinol Dosing: – 50mg to 800mg qd (usually 300mg) – N.B. Only 21-55% attain urate < 360 umol/L on “standard” dose Most insufficient doses – main barrier to control N.B. Dose adjust for renal function – Dosing according to CrCL may not attain control GOAL: lowest dose to target urate < 360 umol/L ADRs: (well tolerated) – Common: GI upset, Rash – (esp if on Amox/Amp or Cyclophosphamide) – Rare: Blood dyscrasias Jaundice TEN Hypersensitivity Syndrome (including rash) – If mild rash occurs, hold and re-challenge

Preventing Recurrence Sulfinpyrazone: – Up to 800mg /day divided bid – Start: 100mg BID Increase q1wk – May decrease to 200mg/d once urate controlled – ADRs: GI upset, rash Probenecid: – 500mg to 3g /day divided bid-tid – Start: 250mg BID Increase by 500mg q4wk – May decrease by 500mg q6mo if stable > 6 mo till urate starts to rise – ADRs: GI upset, rash

Useless Trivia With Which To Impress Your Patients Urate levels in humans are 10 times higher than other mammals because we lack the enzyme uricase! – PEGlyated-uricase (Pegloticase) (Krystexxa™) Only approved in USA for refractory gout

Summary of Gout Prevention High likelihood of recurrence Eliminate excess body urate to prevent chronic destructive changes – Colchicine is not uricosuric! – No prophylaxis without urate lowering therapy! Manage risk factors – Drugs, diet, co-morbidities Allopurinol – drug of choice – Start low, go slow – May have to push dose to attain control N.B. Must differentiate mild rash from a serious hypersensitivity syndrome

3) Address Co-Morbid Conditions Obesity Hypertriglyceridemia Hypertension and Diabetes Mellitus Excessive Alcohol

Obesity & Hypertriglyceridemia Weight loss independently lowers urate levels Decreased alcohol consumption, regular exercise and weight reduction will lower TGs – Fibrates Especially fenofibrate – mild uricosuric effect

Diet Restriction Total diet restriction only lowers urate levels by ~ 52.9 umol/L (1mg/dL) – Very unpalatable – Poor compliance Purine sources matter – Increase with meat & seafood – Decrease with dairy Daily consumption lowers urate levels – Oatmeal and purine rich vegetables do not increase risk of gout Peas, mushrooms, lentils, spinach, cauliflower

Dietary sources High-Purine Content Anchovies Beer Bouillon (meat based) Brains Broth (meat based) Clams Consommé Goose Grain alcohol Gravy Heart Herring Kidney Lobster Mackerel Meat extracts Mincemeat Mussels Oysters Partridge Roe (fish eggs) Sardines Scallops Shrimp Sweetbreads Yeast (baker's and brewer's) taken as a supplement Moderate-Purine Content Beans, dried Fish (except those in the high-purine content list) Lentils Meat (except those in the high-purine content list) Mushrooms

Hypertension ~ 1/3 rd with gout have HTN Major cardiac risk factor – Caution with thiazides and ASA! – N.B. LOSARTAN – mild uricosuric effect!

Excessive alcohol Mechanisms: 1.Purine content of beverage BEER! (lots of guanosine) 2.Chronic alcohol stimulates de novo purine biosynthesis in liver 3.Binge drinking results in lactic acidemia, lowering renal urate excretion Moderate wine ok, but any alcohol is a risk factor – RR 1.32 (10 - 15 g/day) – RR 1.49 (15 - 30 g/day) – RR 1.96 (30 - 50 g/day) > 30g/d in females; > 45g/d in males ↑ risk of liver disease – RR 2.53 (> 50 g/day)

Summary of Lifestyle Modification Lose weight Lower TG’s (esp with Fenofibrate) Lower BP (esp with Losartan) – Avoid diuretics and ASA if you can Elimination alcohol Avoid eating brainsssss

Patient Education Urate crystals Gout attack Colchicine or NSAIDs Treatment delay Prophylactic colchicine Uricosuric agent (eg. Allopurinol) Matches Matches catch fire Put out the fire More matches catch fire Dampen matches Eliminates matches

Questions?

TB drugs Adapted from: Marc Riachi, RPh

Mycobacterium 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. 3x/weekly dosing must be D.O.T.) Ref: PHAC. Canadian Tuberuclosis Standards, 7th Ed. 2013 p. 37A http://www.respiratoryguidelines.ca/sites/all/files/Chapter%205_final1_0.pdf Accessed Dec 20, 2013http://www.respiratoryguidelines.ca/sites/all/files/Chapter%205_final1_0.pdf

Treatment – Latent TB SAP = self-administered prophylaxis, DOP = directly observed prophylaxis. 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, 7th Ed. 2013 p. 14 http://www.respiratoryguidelines.ca/sites/all/files/Chapter%206.pdf Accessed Dec 20, 2013http://www.respiratoryguidelines.ca/sites/all/files/Chapter%206.pdf

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

Anti-fungals Adapted from: Marc Riachi, RPh

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

Antifungals Oral – Azole anti-fungals Active vs. yeast and dermatophytes Itra- (Sporanox), flu- (Diflucan), vori-, posa- ketoconazole (Nizoral) – 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

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

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

Grande Finale Remember the Four Steps of Rational Prescribing! – 1) Efficacy, 2) Toxicity, 3) Cost, and 4) Convenience – This will save you a LOT of time & confusion Your EBM skills will inform your Efficacy – When evidence is weak; First, Do No Harm ie. (Toxicity outweighs Efficacy) Study your Pharmacology! – Pharmacology will inform your Therapeutics – Mechanism of action and basic PK/PD data (P450 metabolism (Y/N) and Top 3 side effects) will inform your monitoring & Toxicities Build your Personal Formulary in residency – Focus your studying where it is needed! Eg. With equivalent efficacy – focus on learning the potential toxicities

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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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:

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