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Transcript
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 2015 [email protected] 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. Topics that could be covered • • • • • • • • • • • • • • • Antibacterials Antimycobacterials Antifungals Narcotic analgesics Autonomic nervous system Anti seizure drugs Migraines Antidepressants Antianxiety agents Agents for insomnia Antidiabetics Antilipemics Antihypertensives Diuretics Nitrates Ref: Marc Riachi, RPh • • • • • • • • • • • • • Antiplatelets and anticoagulants Antiasthmatics BPH Erectile dysfunction Dementia Parkinson’s disease and schizophrenia Dyspepsia, GERD and PUD Antiemetics IBD IBS Osteoporosis Gout OTC drugs Topics to be covered in this lecture • • • • • • • • • • • • • • • Antibacterials Antimycobacterials Antifungals Narcotic analgesics Autonomic nervous system Anti seizure drugs Migraines Antidepressants Antianxiety agents Agents for insomnia Antidiabetics Antilipemics Antihypertensives Diuretics Nitrates • • • • • • • • • • • • • • Antiplatelets and anticoagulants Antiasthmatics BPH Erectile dysfunction Dementia Parkinson’s disease and schizophrenia Dyspepsia, GERD and PUD Antiemetics IBD IBS Osteoporosis Gout OTC drugs Appendix I & II 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 2015 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 • 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 Pharmaco-Dynamics (ie. Top 3 Side Effects) • Rare & Severe • Common & Bothersome Total: 3 minutes Review Pharmaco-Kinetics • Clearance: Renal or Hepatic? • Hepatic: CYP-450 or not? Review Mechanism of Action Pharmacology • Learn the drugs that will be part of your personal formulary. • Build your formulary wisely. • Brief, but 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? • [email protected] • Monday & Fridays: – 613-230-7788 ext 238 • Tuesday, Wednesday, Thursday: – 613-241-3344 ext 327 • Twitter: @Roland Halil, PharmD 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 2015 Objectives • To promote an efficient process for selecting optimal drug therapy for patients • To promote a process for applying populationlevel 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. 2. 3. 4. Efficacy Toxicity Cost Convenience Step 1: Efficacy (How good is good?) Efficacy Ask yourself about… 1. Type of intervention: What will reduce: 1. 2. 3. 4. Mortality Morbidity Surrogate markers Symptoms based on hard outcomes based on soft outcomes Efficacy 2. 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 2/14 Efficacy 3. Quality of evidence? (Hierarchy of evidence) Robert Yokl. Good Evidence: The Missing Link. Apr 08, 2013. http://valueanalysismag.com/good-evidence-the-missing-link/ Efficacy Therefore, the key is the prioritization of efficacy endpoints and evidence quality. Quantity (Effect Size) Mortality Morbidity Surrogate outcomes Symptomatic relief Quality 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 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?) Toxicity Like Efficacy, the key is prioritization of toxicity endpoints, effect size & evidence quality. • What will: 1. Kill me? 2. Maim me? 3. Make me feel crappy? (bothersome side effects) • Size of toxic effect (Quantity)? • Evidence Quality to show effect? Toxicity Likelihood Common Rare Not legal Who cares Bothersome Severity Severe Toxicity Time: The 3rd 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) Toxicity Age Before Beauty Prexige Prepulsid Arcoxia Meridia Vioxx Baycol Bextra Avandia Zelnorm Actos Newer agents Older agents = = Less Safety Data More Safety Data 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?) Cost ($) – Ask… Patient cost vs Societal cost • Rx cost? – Out of pocket • Provincial plan? – Tax dollars • Private plan? – Insurance premiums A simple example: Cost Choosing an ACEinh • 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): Oct 2014 Comparison Chart http://www.rxfiles.ca.proxy.bib.uottawa.ca/rxfiles/uploads/document s/members/CHT-HTN-ace-arb.pdf Accessed Nov 4/14 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 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! Comments, Questions & Requests? • [email protected] • Monday & Fridays: – 613-230-7788 ext 238 • Tuesday, Wednesday, Thursday: – 613-241-3344 ext 327 • Twitter: @Roland Halil, PharmD Antibiotic Review (80% of the knowledge, 80% of the time) Dr Roland Halil, BSc(Hon), BScPharm, ACPR, PharmD Pharmacist, Bruyere Academic FHT Assistant Professor, Dept Family Medicine, U of Ottawa March 2015 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” Gram Negative Aerobic β-Lactamase Negative Cocci (spheres) Bacilli (rods) Gram Positive Anaerobic β-Lactamase Positive Map the Bugs Aerobes Anaerobes Gram Positive Gram Negative Gram Positive Gram Negative Cocci Bacilli Cocci Bacilli Cocci Bacilli Cocci Bacilli b-L[+] b-L[-] b-L[+] b-L[-] 1 2 3 4 b-L[+] b-L[-] b-L[+] b-L[-] 5 6 7 8 b-L[+] b-L[-] b-L[+] b-L[-] b-L[+] b-L[-] b-L[+] b-L[-] 9 10 11 12 13 14 15 16 Anaerobes Above & below the diaphragm Oral •Simple organisms •Easily handled by penicillins (beta-lactams) Gut •Approx the same, except: – Eg. Actinomyces Bifidobacterium Fusobacterium Lactobacillus Peptococcus Peptostreptococcus Propionibacterium etc • Bacteroides fragilis (B.frag) • Clostridium difficile (C.diff) •Human pathogens: –More virulent bugs requiring ‘bigger guns’… Map the Bugs Anaerobes Aerobes Gram Positive Gram Negative Cocci Cocci Bacilli Above & Below diaphragm Bacilli B.Frag C.Diff b-L[+] b-L[-] b-L[+] b-L[-] 1 2 3 4 b-L[+] b-L[-] 5 6 b-L[+] b-L[-] 7 8 9 . Map the Bugs Anaerobes Aerobes Gram Positive Gram Negative Cocci Cocci Bacilli Below diaphragm Bacilli B.Frag C.Diff b-L[+] b-L[-] b-L[+] b-L[-] 1 2 3 4 b-L[+] b-L[-] 5 6 b-L[+] b-L[-] 7 8 9 . Gram[+] Bacilli • Not usually pathogenic – Major Exception: Listeria monocytogenes • Listeriosis – enteritis, sepsis, meningitis +/- encephalitis Map the Bugs Anaerobes Aerobes Gram Positive Gram Negative Cocci Cocci Bacilli Below diaphragm Bacilli B.Frag C.Diff (Listeria) β-L[+] β-L[-] 1 2 b-L[+] b-L[-] 3 4 β-L[+] β-L[-] 5 6 7 . Gm[-] Cocci • Not usually pathogenic – Major Exceptions: • Neisseria gonorrhea • Neisseria meningitidis and • Moraxella catarrhalis – (formerly thought to be a type of Neisseria) Map the Bugs Anaerobes Aerobes Gram Positive Gram Negative Cocci Cocci (Neisseria & Moraxella) β-L[+] β-L[-] 1 2 Bacilli (Listeria) Below diaphragm Bacilli B.Frag C.Diff β-L[+] 3 β-L[-] 4 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 Map the Bugs Anaerobes Aerobes Gram Positive Gram Negative Cocci Cocci (Neisseria & Moraxella) Bacilli (Listeria) β-L[+] β-L[-] 1 (G.A.S.) Bacilli B.Frag C.Diff β-L[+] 2 Below diaphragm 3 β-L[-] 4 . Map the Bugs Anaerobes Aerobes Gram Positive Gram Negative Cocci Below diaphragm Bacilli B.Frag C.Diff β-L[+] 1 both β-L[+]&[-] 2 3 . Map the Clinically Important Bugs Atypicals Aerobes Gram [+] Gram [-] Cocci Bacilli 1 2 1.Legionella pneumonia 2.Chlamydia pneumonia 3.Mycoplasma pneumonia 3 . Anaerobes (esp. Gut organisms) Eg. C-Diff & B-frag 4 . 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. 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 “Hard” to Kill •Serratia •Pseudomonas •Acinetobacter •Citrobacter •Enterobacter – (Moraxella catarrhalis) (actually a Gm[-] coccus) PEcKSS-HiM 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 pores Gm[+]: molecules < 100kDa pass easily. Gm[-]: b-lactamases concentrated in periplasmic space Gm[+]: b-lactamases diffuse outside cell; Atypicals: • Mycoplasma pneumo • Chlamydia pneumo • Legionella pneumo Map the Bugs • Gram positive aerobes: – Cocci Summary Anaerobes: •Oral •Gut – Bfrag & Cdiff • Gram negative aerobes: – Bacilli • Staph – Aureus » MRSA (~8-10%) » MSSA – Epiderimidis » MRSE (~65%) » MSSE • 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) • Strep – – – – Group A strep (pyogenes) Group B strep (agalactiae) Strep Viridans Strep pneumo etc. • Enterococcus – Faecalis – Faecium – Bacilli • Listeria – Cocci • Neisseria – gonorrhaea – meningitidis • Moraxella catarhallis Map the Bugs - Summary Otitis media: S.pneumo, Hi,M Conjunctivitis: viral Sinusitis: viral AECOPD: S.pneumo, Hi,M Oral abscess: oral anaerobes C.A.P: S.pneumo, atypicals – CAP+comorb./risk factors, or NHAP: also HiM bugs Pharyngitis: viral (Group A Strep) Bronchitis: viral Skin abscess: anaerobes, staph, strep N.B. Boils = Staph Cellulitis: MSSA, GAS, GBS Pyelonephritis: PEcK H.pylori: Cdiff / Bfrag: UTI (Cystitis): 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” Fluoroquinolones Penicillins Tetracyclines Aminoglycosides Vancomycin Macrolides Carbapenems Cephalosporins Clindamycin Metronidazole Antibiotics – Mechanisms of Action From: http://commons.wikimedia.org/wiki/File:Antibiotics_Mechanisms_of_action.png Accessed Dec 28/12 Beta-Lactams - Penicillins Penicillin Anti-Staph Anti-Strep Amoxicillin / Ampicillin (po) (iv) Amox + Clavulanic acid Cloxacillin / Methicillin (clinic) (lab) Beta-Lactams - Cephalosporins – Cephalexin (Keflex™)(or Cefadroxil) (po) – Cefazolin (Ancef™) (iv) • 2nd Generation – Cefuroxime (po & iv) • 3rd Generation – Ceftriaxone, Cefotaxime, Ceftazidime (iv) – Cefixime (Suprax™) (po) • 4th Generation – Cefepime (iv) Increasing Gram[-] coverage • 1st Generation Beta-Lactams – Other (FYI) (IV only, inpatient use only) • Piperacillin (plus tazobactam) – big gun, tazo = suicide substrate, like clavulanic acid • Carbapenems – Meropenem – Imipenem – Ertapenem • Monobactams – Aztreonam Broad spectrum, big gun antibiotics that cover Gm[+], both easy and hard to kill Gm[-] bugs, even some anaerobes. Antibiotics – Mechanisms of Action From: http://commons.wikimedia.org/wiki/File:Antibiotics_Mechanisms_of_action.png Accessed Dec 28/12 Fluoroquinolones • 2nd generation – Ofloxacin – Ciprofloxacin – Norfloxacin • 3rd generation – Levofloxacin • 4th generation – Moxifloxacin • Covers: Gm[-]’s – PEcKSS-HiM & SPACE bugs – 3rd and 4th 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 concn 1. Levofloxacin – the more active Lenantiomer 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 Antibiotics – Mechanisms of Action From: http://commons.wikimedia.org/wiki/File:Antibiotics_Mechanisms_of_action.png Accessed Dec 28/12 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) Antibiotics – Mechanisms of Action From: http://commons.wikimedia.org/wiki/File:Antibiotics_Mechanisms_of_action.png Accessed Dec 28/12 Aminoglycosides 1. Gentamicin 2. Tobramycin – Reserved for Pseudomonas aeruginosa 3. Amikacin • Efficacy: excellent Gm[-] • Toxicity: – Nephrotoxicity – Ototoxicity – Less now with daily dosing • Cost: • All excellent Gram[-] coverage: – PEcKSS-HiM and SPACE bugs – 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 Log [Conc] Time Dependent Killing • Time over MIC matters • i.e. Independent of peak concentration. Determined by length of time over MIC • Eg. B-lactams (Pen, Ceph etc) Log [Conc] Peak MIC MIC Time (h) Time (h) Pharmacodynamics Relationship between Abx Concentration & Effect Concentration Dependent Killing • 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: • Higher the peak, better the kill • i.e. Ratio of peak drug concentration and M.I.C. determines rate of kill. • Eg. FQs, AGs Log [Conc] Peak Log [Conc] Peak MIC Time (h) MIC Time (h) • If CrCL = 90mL/min Levofloxacin 750mg q24h po • If CrCL = 30mL/min – Levofloxacin 750mg q48h po 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 For: TB, MRSA For: skin, dental infx (staph, strep, & anaerobes) From: http://commons.wikimedia.org/wiki/File:Antibiotics_Mechanisms_of_action.png Accessed Dec 28/12 Part 3 – Map the Battlefield Map the Battlefield Rational Prescribing Individual Population 1. Efficacy 1.Efficacy – Could be reduced, BUT: – Empiric tx still effective if it is well chosen – Maintained long term with lower resistance rates 2.Toxicity • (Lower risk infections, properly dosed, clinically stable, true indication etc.) – Reduced since lifespan of older drugs is maintained 3.Cost 2. Toxicity – Reduced with narrow spectrum tx 3. Cost – Reduced with older tx 4. Convenience – Usually less convenient VS. – Reduced insurance costs, economic losses, hospital costs dealing with superbugs 4.Convenience Map the Battlefield Map the Bugs - Summary Otitis media: S.pneumo, Hi,M Conjunctivitis: viral Sinusitis: viral AECOPD: S.pneumo, Hi,M C.A.P: S.pneumo, atypicals – CAP+comorb./risk factors, or NHAP: also HiM bugs Oral abscess: oral anaerobes Pharyngitis: viral (Group A Strep) Bronchitis: viral Skin abscess: Cellulitis: MSSA, GAS, GBS Pyelonephritis: PEcK Cdiff / Bfrag: anaerobes, staph, strep (GAS, GBS) N.B. boils = staph H.pylori: UTI (Cystitis): PEcK Traveller’s Diarrhea: (80% bacterial): EcSS, (campylobacter) Map the Battlefield Otitis media: S.pneumo, Hi,M Conjunctivitis: viral – no tx (Amox +/- Clav, Cef2, Septra) Sinusitis: viral – no tx AECOPD: S.pneumo, Hi,M Oral anaerobes: abscess drainage +/- tx (Amox +/- Clav, Cef2, Septra) (Amox 2g – pre dental sx?) C.A.P: S.pneumo, atypicals – (Amox, Macrolides (Clarithro/Azithro)) Pharyngitis: viral – no tx CAP+comorb./risk factors, or NHAP: also HiM bugs (Combine (Group A Strep – Pen VK) AmoxClav or Cef2 + Macrolide (or use FQ)) Bronchitis: viral – no tx Skin abscess: drainage +/- tx Cellulitis: MSSA, GAS, GBS (Clox, Cef1, & Clinda (more resistant) H.pylori: triple po tx PPI + (Clarithro +/Amox +/- Metro) Pyelonephritis: PEcK – (Septra, Amox-Clav, FQ (not Norflox) Cdiff / Bfrag: Metro / po Vanco UTI (Cystitis): PEcK – (Septra, Traveller’s Diarrhea: (80% bacterial): EcSS, (campylobacter) Macrobid, Amox+/-Clav, Norflox) - Septra, FQ, (Azithro) Map the Battlefield Penicillin (Group A Strep, oral anaerobes, Neisseria) Amoxicillin / Ampicillin (Strep & Enterococcus plus Easy-to-Kill Gm[-](ie. PEcKSS)) Cloxacillin (Staph aureus, Staph epi) Amox/Clav (Vancomycin) (for Strep & Entero & PEcKSS-HiM) (H.flu & Moraxella can be ~35% amox resistant) (for MRSA / MRSE) (~8-10% / ~ 65% resistant) Beta-Lactams - Cephalosporins – Cephalexin (Keflex™) or Cefadroxil (po) – Cefazolin (Ancef™) (iv) • 2nd Generation – Cefuroxime (po & iv) • 3rd Generation To boost: for PEcKSS-HiM (same as Amox/Clav) SPACE bugs: The Big Guns – Ceftriaxone, Cefotaxime, Ceftazidime (iv) – Cefixime (Suprax™) (po) • 4th Generation – Cefipime (iv) Increasing Gram[-] coverage • 1st Generation MSSA and Strep & PEcKSS (same as Amox) N.B. never Enterococcus! SPACE bugs • The Big Guns: – 3rd and 4th generation Cephalosporins – Carbapenems (Meropenem) – Piperacillin/Tazobactam – Aminoglycosides (Gentamicin, Tobramicin) – Fluoroquinolones (Levofloxacin, Moxi, Cipro) Reserved for Pseudomonas • Ciprofloxacin (FQ) – The only PO agent! – (Use Norfloxacin for UTI if a FQ is needed) • • • • • Ceftazidime (Cef3) Cefipime (Cef4) Tobramycin (AG) Piperacillin/Tazobactam Meropenem Need for Bigger guns • There is a higher risk of Gram negative SPACE bugs with: – More risk factors / comorbidities – COPD, HIV, Diabetes, CKD etc – More institutionalized settings • Community Retirement Home Nursing Home Hospital ward ICU ventilated pt in ICU. Map the Battlefield • PEN – for 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 – 1. . 2. . 3. . 1. . flat, blotchy, spread over days but did not change by the hour 5. Anaphylaxis 2. . Penicillin: BL-ve aer obic GPC oral anaer obes N.meni ngitidi s Lacking Activity Vs. Atypical Organis m s BL+ Ae robic GPC Ae robic GNB Gut anaerobe s (B. fragilis) 95% of Staph. specie s are BL +ve MRSA(7%)/ MRSE (>65%) MSSA/MSSE TMP/SM X Clindam ycin Easy to Kill GNB Macrolide s : Erythromycin Clarithromycin Azithromycin TMP/SM X Tetracyclines Res pirator y Fluor oquinolone s Gatif loxacin Levofloxacin Moxif loxacin Vancom ycin Rifam pin Fus idic Acid Line zolid Syner cid Me tronidazole Am picillin/Am oxicillin: HiPEELSS Isoxazoyl PCNs : e g. Cloxacillin, Nafcillin 1st Ge ne ration Cephs : (Cefazolin iv / Ce phalexin po) PEcKSS Second Gener ation Ce phs Am oxicillin/Clavulanic acid Am picillin/Sulbactam Ce furoxim e Ce furoxim e axetil Ce faclor B. fragi li s H. i nfluenza e Ce fote tan Ce foxitin Difficult to Kill GNB 3rd Gener ation Ce phs. Ce ftriaxone Ce fotaxim e Ce ftazidim e 4th Ge ne ration Cephs : Ce fe pim e No Ce phalos porin cover s: MRSA / MRSE enterococcus sp. Listeri a monocytogenes AM Gs: Ge ntam icin Tobram ycin Am ik acin Pipe racillin: (P.aerugi nosa , Enter obacter) Never Us e Alone ! Pipe racillin/Tazobactam Ticarcillin/Clavulanic Acid FQs : ciprofloxacin ofloxacin norf loxacin Carbape ne m s : Im ipenem Me rope ne m Adapted fr om : Wins lade N. On Continuing Practice 1990-1, volum es 17-18. Prepare d By: Sandr a A.N. Tailor, Pharm .D. Clinical Coor dinator - Infectious Dise as e s Sunnybrook Health Science Ce ntre Depar tm e nt of Pharm acy 11/11/02 Comments, Questions & Requests? • [email protected] • Monday & Fridays: – 613-230-7788 ext 238 • Tuesday, Wednesday, Thursday: – 613-241-3344 ext 327 • Twitter: @Roland Halil, PharmD 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, 2013 Treatment – Latent TB • SAP = self-administered prophylaxis, DOP = directly observed prophylaxis. • INH – monitor LFTs – Hepatitis (rare < 20y.o.; >2% in >50y.o.) – Drug interactions! • RIF – GI toxicities, major drug interactions! – Huge inducer of cytochrome P450 Ref: PHAC. Canadian Tuberuclosis Standards, 7th Ed. 2013 p. 14 http://www.respiratoryguidelines.ca/sites/all/files/Chapter%206.pdf Accessed Dec 20, 2013 Which agents to use in active disease? • Pulmonary or extrapulmonary disease: – INH+RIF+PZA+ETB • If resistant to INH: – RIF+PZA+ETB (+FQ if severe) • If resistant to RIF: – INH+PZA+ETB+FQ • if resistant to INH and RIF: – PZA+ETB+FQ+amikacin • If resistant to INH, RIF and PZA or ETB – ETB (or PZA)+FQ+amikacin+two 2nd line agents Ref: Marc Riachi, RPh Comments, Questions & Requests? • [email protected] • Monday & Fridays: – 613-230-7788 ext 238 • Tuesday, Wednesday, Thursday: – 613-241-3344 ext 327 • Twitter: @Roland Halil, PharmD 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 Ref: Marc Riachi, RPh • • 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 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 Ref: Marc Riachi, RPh • 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 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 Comments, Questions & Requests? • [email protected] • Monday & Fridays: – 613-230-7788 ext 238 • Tuesday, Wednesday, Thursday: – 613-241-3344 ext 327 • Twitter: @Roland Halil, PharmD Hypertension and BP Meds (The ABCD’s of HTN) Dr Roland Halil, BSc(Hon), BScPharm, ACPR, PharmD Pharmacist, Bruyere Academic FHT Assistant Professor, Dept Family Medicine, U of Ottawa March 2015 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 Vascular Disease CAD / ACS CVA Hypertension CKD CHF PVD Rational Prescribing • Rational prescribing requires a process for selecting therapy: (in order) 1. 2. 3. 4. Efficacy Toxicity Cost Convenience Essential Hypertension A A B C ACEinh ARB (B-bl) betablockers DHP-CCB (dihydropyridine) "-pril" "-sartan" "-olol" "-dipine" enalapril lisinopril ramipril valsartan irbesartan candesartan bisoprolol metoprolol propranolol nifedipine amlodipine felodipine 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 1st line 1st line D Thiazide Diuretic hydrochlorothiazide chlorthalidone indapamide Reduces Reduction in sympathetic Relaxes systemic vascular outflow & heart peripheral resistance (not rate & renal smooth muscle diuresis) AT2 production 1st line (if < 60y.o.) 1st line 1st line Essential Hypertension Efficacy Toxicity Monitor Cost Convenience (eg.) A (ACEinh) A (ARB) B C D 1st line 1st line 1st line 1st line 1st line Hypotension Hypotension hyperK+ hyperK+ (< 60yo) Hypotension Hypotension Hypotension Orthostatic Bradycardia hypoK+, hypoNa+ hypotension Acute renal failure (ARF) ARF Bronchoconstric tion in brittle asthmatics (esp high dose, esp non-cardioselective) BP, SCr, K+ BP, SCr, K+ BP, HR, RR Edema ARF BP, OH, edema BP, SCr, K+, Na+ cheap, generic still expensive, Cheap & expensive, (except Coversyl new generics, generic, generics, & Mavik), ODB covered ODB covered ODB covered ODB covered QD Ramipril 2.5mg - 10mg QD Losartan 25mg - 100mg QD Bisoprolol 2.5mg - 10mg QD Amlodipine 2.5mg - 10mg VERY cheap, generic, ODB covered QAM Chlorthalidone 25mg Choosing Therapy • If efficacy (#1), cost (#3) and convenience (#4) are all more or less equivalent: – Choose based on potential Toxicities (#2) – Tailor the meds to the individual patient! • 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) B D (ALLHAT) HTN MI (HOPE) CHF (CONSENSUS, SOLVD, ATLAS) DM2 (HOPE) (IDNT, IRMA-2, RENAAL) CVA (HOPE, PROGRESS) (LIFE, SCOPE, MOSES) PVD (HOPE) Angina C (VALIANT) (CAPRICORN, BHAT) (MERIT-HF, CIBIS II, COPERNICUS) (ALLHAT, PROGRESS) RAASystem Second Line Therapy • What if you have used all available 1st line options? • 2nd 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 1st choice of 2nd line tx • Dual treatment of BPH & BP if also needed in male patients • Spironolactone – Efficacy: mortality benefit in late stage CHF (NYHA class III or IV) – Toxicity: risk of hyperK+ • esp with ARBs or ACEinh’s – Cost: cheap generic – 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: • Dose response curves – Flatten at top half – Less bang for your buck BP – increase dose • If far from target: – start new drug mg Comments, Questions & Requests? • [email protected] • Monday & Fridays: – 613-230-7788 ext 238 • Tuesday, Wednesday, Thursday: – 613-241-3344 ext 327 • Twitter: @Roland Halil, PharmD 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 2015 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 • (reduction in mortality) 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 ) • Fibrates for high TGs – treatment of gout risk factors 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. 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 • Fibrates – Rare/Severe: • Myopathy, even Myositis/Rhabdomyolysis • Hepatotoxicty • Memory impairment • ?Diabetes?? – discuss – Common/Bothersome: • Myalgias – 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) Comments, Questions & Requests? • [email protected] • Monday & Fridays: – 613-230-7788 ext 238 • Tuesday, Wednesday, Thursday: – 613-241-3344 ext 327 • Twitter: @Roland Halil, PharmD 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 2015 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 2) Plaque Control Mortality benefit with: – Statin plus – Beta-blocker (see: HTN section) (see: Dyslipidemia section) CAD / ACS 3) Clot Prevention Anti-Thrombotics – lots! From: http://en.wikipedia.org/wiki/Direct_thrombin_inhibitor Antiplatelets Options • Primary prevention ACS – ASA – Clopidogrel • Primary prevention CVA – ASA – Clopidogrel • Secondary prevention ACS • Secondary prevention CVA – ASA + – Clopidogrel – Prasugrel – Ticagrelor – ASA – Clopidogrel – ASA + Dipyridamole MR 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 P2Y12 • 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 P2Y12 How to Choose? (if only there was a process…) 1. 2. 3. 4. Efficacy Toxicity Cost 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’15: 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 2015 Primary Prevention – ACS & CVA 3) Cost 4) Convenience – ASA – ASA • Pennies! ($4/mo) • 81mg costs > 325mg – Can cut 325mg in 1/4th • 75-325mg once daily – Clopidogrel • 75mg once daily – Clopidogrel • ~ $40/mo From: www.Rxfiles.ca ORAL ANTIPLATELET & ANTITHROMBOTIC AGENTS Comparison Table; Jan 2015 Bottom Line: 1o Prevention ACS & CVA • ASA. – Most evidence, well tolerated, cheap cheap!, QD • Ongoing efficacy studies for primary prevention – http://www.aspree.org/usa/aspree-content/aspirin/other-aspirin-studies.aspx – 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 2015 Secondary Prevention – ACS Efficacy Agent Monotherapy Combo 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 Prasugrel untested (CURE trial) (ACS, PCI various durations) 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 2015 From: Antiplatelet treatment http://cks.nice.org.uk/antiplatelet-treatment#!management Accessed Apr 4/13 From: http://www.nice.org.uk/nicemedia/live/13588/56819/56819.pdf Accessed Apr 4/13. Secondary Prevention – ACS Toxicity Agent ASA Clopidogrel Prasugrel Ticagrelor Monotherapy Combo w/ 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) -- ~ equivalent in absolute sense Slightly less GI bleed & GI events except diarrhea; More Rash More major bleeding vs ASA alone untested More fatal & lifethreatening bleeds vs Clopid + ASA untested More major & minor bleeds vs Clopid + ASA More dyspnea & increased urate Secondary Prevention – ACS Toxicity Agent Monotherapy Combo 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) Prasugrel Ticagrelor 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) untested More fatal and lifethreatening bleeds vs clopid + ASA untested More major and minor bleeds vs clopid + ASA More dyspnea, & incr UA Secondary Prevention – ACS 3) Cost – ASA • Pennies! (only 325mg covered) – Clopidogrel • ~ $40/mo • LU code for ACS – Prasugrel • ~ $100/mo;covered w/ LU code – Ticagrelor 4) Convenience – ASA • 75-325mg once daily – Clopidogrel • 75mg once daily – Prasugrel • 10mg once daily – Tigagrelor • 90mg BID • ~ $108/mo; covered w/ LU code From: www.Rxfiles.ca ORAL ANTIPLATELET & ANTITHROMBOTIC AGENTS Comparison Table; Jan 2015 Bottom Line: 2o 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 Agent ASA Monotherapy Combo w/ ASA ASA ~23% RRR > placebo NNT ~ 50-100 x1 year to prevent any vascular event. (50-325mg) -- (CAST, IST, SALT, Dutch-TIA trials) Clopidogrel Aggrenox® Equivalent to ASA (extremely small absolute improvement per CAPRIE trial) Possible improvement for 1st 21 days post CVA (CHANCE trial) No benefit long term (CHARISMA, MATCH trials) Superior to ASA (ESPRIT & ESPS2 trials), but Equivalent to Clopidogrel (PRoFESS trial) whaaa…?? From: www.Rxfiles.ca ORAL ANTIPLATELET & ANTITHROMBOTIC AGENTS Comparison Table; Feb 2013 From: Antiplatelet treatment http://cks.nice.org.uk/antiplatelet-treatment#!management Accessed Apr 4/13 From: http://www.nice.org.uk/nicemedia/live/13588/56819/56819.pdf Accessed Apr 4/13. -- Secondary Prevention – CVA Toxicity Agent Monotherapy Combo w/ ASA Low, but look at additive bleeding risk factors: ASA (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.) ~ equivalent in absolute sense Clopidogrel Slightly less GI bleed & GI events except diarrhea; More Rash Aggrenox® More headache, diarrhea, GI upset, dizziness, & early D/C vs ASA or Clopidogrel More intracranial bleed vs Clopidogrel -More bleeding vs ASA alone (CHARISMA & MATCH trials) -- Secondary Prevention – CVA 3) Cost – ASA • Pennies! ($4/mo) – Clopidogrel • ~ $40/mo • LU code for ASA intolerance only – Aggrenox® 4) Convenience – ASA • 75-325mg once daily – Clopidogrel • 75mg once daily – Aggrenox® • 200/25mg BID po • ~ $66/mo • LU code for CVA From: www.Rxfiles.ca ORAL ANTIPLATELET & ANTITHROMBOTIC AGENTS Comparison Table; Jan 2015 Bottom Line 2o 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 1st! • BP control with ACEinh (or ARB) + b-blocker – (For stroke: ACEinh (or ARB) + Thiazide) • “LDL” control with statin • Clot prevention with ASA (+/- Clopidogrel) Comments, Questions & Requests? • [email protected] • Monday & Fridays: – 613-230-7788 ext 238 • Tuesday, Wednesday, Thursday: – 613-241-3344 ext 327 • Twitter: @Roland Halil, PharmD (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 2015 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 2) Plaque Control Mortality benefit with: – Statin plus – Beta-blocker (see: HTN section) (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+ ! • Digoxin – Morbidity benefit – (See DIG trial, PROVED trial) – Reduction in hospitalizations due to CHF • Not seen with preserved ejection fraction • Furosemide – Reduction in CHF symptoms – No morbidity nor mortality benefit. Questions? CKD & PVD Dr Roland Halil, BSc(Hon), BScPharm, ACPR, PharmD Pharmacist, Bruyere Academic FHT Assistant Professor, Dept Family Medicine, U of Ottawa March 2015 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 MVO2 Comments, Questions & Requests? • [email protected] • Monday & Fridays: – 613-230-7788 ext 238 • Tuesday, Wednesday, Thursday: – 613-241-3344 ext 327 • Twitter: @Roland Halil, PharmD Hypoglycemic Drugs Dr Roland Halil, BSc(Hon), BScPharm, ACPR, PharmD Pharmacist, Bruyere Academic FHT Assistant Professor, Dept Family Medicine, U of Ottawa March 2015 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 Category FPG 2-hour And/or after OGTT IFG 6.1-6.9 IFG (isolated) 6.1-6.9 IGT (Isolated) < 6.1 7.8-11.0 6.1-6.9 7.8-11.0 IFG and IGT N/A AND < 7.8 Can J Diabetes 2003;27(2);S11 Diabetes: complications MACROvascular Stroke Heart disease & hypertension MICROvascular Diabetic eye disease (retinopathy & cataracts) Nephropathy Peripheral vascular disease Neuropathy Foot problems Foot problems Kumamoto Study – HbA1c & Complications • Intensive vs. conventional insulin therapy (N=110) • Median A1c - 7.1% vs. 9.4% 16 14 Retinopathy 16 14 12 Nephropathy 12 10 10 8 6 4 2 0 8 6 7% 5 6 7 7% 4 2 0 8 9 HbA1c (%) 10 11 5 6 7 8 9 HbA1c (%) 10 11 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 Study Drug DPP Metformin 850mg BID 2.8 31 STOPNIDDM Acarbose 100mg TID 3.3 30 DREAM Rosiglitazone 8mg daily 3.0 55 Orlistat 120mg TID 4.0 37 XENDOS Duration (years) RRR (%) 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 Sensitizers Secretagogues Other Drug Classes Sensitizers Secretagogues • Metformin • Glitazones • Sulfonylureas – Eg. Glyburide, Gliclazide • Meglitinides – Rosiglitazone (AVANDIA) – Pioglitazone (ACTOS) – Eg Repaglinide (GLUCONORM) Other • Alpha glucosidase inhibitors (Acarbose) SGLT2 inhibitors (Canagliflozin)(Dapagliflozin ) • DPP4 inhibitors (Gliptins) Incretin (GLP1) Analogues • Sitagliptin, Linagliptin • Saxagliptin, Alogliptin * Liraglutide (VICTOZA) (sc inj) * 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 1st phase insulin secretion; primarily affects 2nd phase • Beta-cell sensitizer – primes glucose mediated insulin secretion (1st phase) Secretagogues • Sulfonylureas – Eg. Glyburide, Gliclazide • Meglitinides – Eg Repaglinide (GLUCONORM) Drug Classes: Other • Alpha glucosidase inhibitors (Acarbose) • Competitive inhibitor of pancreatic α-amylase and intestinal brush border α-glucosidases, resulting in delayed hydrolysis of ingested complex carbohydrates and disaccharides and absorption of glucose; Dose-dependent reduction in postprandial serum insulin and glucose peaks; inhibits the metabolism of sucrose to glucose and fructose • 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 – UKPDS-34 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 Sulfonylureas Repaglinide Glitazones (TZDs) Canagliflozin (1% - 2%) (1% - 2%) (1% - 1.5%) (0.4% - 1.5%) (0.8 – 1%) ~ 0.5% to 0.8% • • • • Acarbose DPP4 inhibitors (‘Gliptins) Nateglinide Dapagliflozin Nathan DM, et al. Diabetes Care 2008 (Dec);31:1-11. EFFICACY B) Surrogate Outcome - Insulin Sparing Effect – METFORMIN – ACARBOSE – GLITAZONE’s (Pioglitazone) – Gliptins (Sitagliptin, Saxagliptin) – Incretin Analogies (Liraglutide, Exenatide) – 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 – – – – • Secretatgogues CHF Fractures M.I. (Sulfonylureas & Meglitinides) • – Severe Hypoglycemia (rosiglitazone) Bladder Cancer • (pioglitazone) TOXICITY – Serious / Fatal • SGLT2 inhibitors (Canagliflozin) (Dapagliflozin) – 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. Risk Factors - Lactic Acidosis • Severe renal impairment – (caution if CrCl < 30ml/min) and • • • • • • • Hepatic disease alcoholism CHF COPD CRF Pneumonia Ongoing acidosis – Lactic, keto etc. TOXICITY - Bothersome 1) METFORMIN – GI upset / diarrhea – Start low, go slow! • Initial dose 250mg QDaily to BID – B12 / folate deficiency / anemia (6 - 8/100) • Reduced absorption – so, supplement – Anorexia – usually transient – Metallic taste TOXICITY - Bothersome 2) Sulfonylureas: – Sulfa skin reactions • Rash / photosensitivity ~1% – Weight gain (2-3kg) – Mild Hypoglycemia: • Most with glyburide. Least w/ glimepiride & gliclazide • Requires consistent food intake • Major episodes 1-2% (esp. in elderly) TOXICITY - Bothersome 3) Glitazones: – 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, GU infection Cost • From Rxfiles May 2013 • Cost per 100 days therapy (in Sask.) • Alternatively, check ODB eformulary – 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 • 1st line – METFORMIN • 2nd line - SULFONYLUREA or INSULIN – Meglitinide – if poor CrCL or irregular eating • 3rd line – any other hypoglycemic if patients absolutely REFUSE insulin NEVER USE GLITAZONEs! Did I say, never? I meant NEVER! www.rxfiles.ca Individualization of Drug Therapy Patient Factor Renal Failure Consider→ Possibly preferred drugs Repaglinide, Acarbose, ‘Gliptins Also: insulin Hepatic Disease Insulin, repaglinide, acarbose, Caution: glyburide, metformin, glitazones Hyoglycemia Metformin, Acarbose, (DPP4 inh),(SGLT2 inh) Also, repaglinide, gliclazide Obese Metformin, Acarbose Irregular Mealtimes Repaglinide (may be preferred over SU) Comments, Questions & Requests? • [email protected] • Monday & Fridays: – 613-230-7788 ext 238 • Tuesday, Wednesday, Thursday: – 613-241-3344 ext 327 • Twitter: @Roland Halil, PharmD Insulins Dr Roland Halil, BSc(Hon), BScPharm, ACPR, PharmD Pharmacist, Bruyere Academic FHT Assistant Professor, Dept Family Medicine, U of Ottawa March 2015 New Drugs/Drug News vol 24 (3): May/June 2006 Insulins - Simplified • Long = Basal • Short = Prandial – NPH, (N) – Glargine (Lantus) – Detemir (Levemir) – Short • Regular (R) • Toronto – Rapid • Lispro (Humalog) • Aspart (NovoRapid) • Glulisine (Apidra) • Premixed • 30/70 (and 10/90, 20/80, 40/60, 50/50) • Humalog Mix-25, NovoMix-30 Which to choose? Basic Concepts • Hyperglycemia = Chronic Hypoglycemia = Acute – So, go after Hypo’s first! • Fed: 6h/24h = 25% • Fasting: 18h/24h = 75% – So, go after Fastings first! • AM affects PM & HS – So, go after AM first! 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) • Premixed • 30/70 (and 10/90, 20/80, 40/60, 50/50) • Humalog Mix-25, NovoMix-30 (R + NPH) (Rapid + NPH) Now, which to choose? 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 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 OTC – NPH: ~ $40 – Lantus: ~ $90 – Levemir: ~ $100 • Convenience: – All sc injections, via penfills – All QD – BID Bottom Line – Basal Insulins • All equivalent • Choose therapy based on cost (NPH) – For the very small proportion suffering from hypoglycemia due to the peak effect of NPH or lamenting BID dosing, consider Lantus or Levemir. Starting Basal Insulin • Fancy Way: – calculate unit/kg dose = 0.1 - 0.2u/kg/day sc • Risk hypoglycemia on first dose – lose your patient’s buy-in forever. • Primary Care Method: – Initiate 5u or 10u qhs sc – Titrate by 1-2u q3-4d until AM FBS = 4 - 7 mmol/L • 10% titrations – If dose = 30’s – increase by 3 units – If dose = 40’s – increase by 4 units – etc. etc. Rx 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 10/90, 20/80, 40/60, 50/50) • Humalog Mix-25, NovoMix-30 (R + NPH) (Rapid + NPH) Short – Prandial Insulins • Efficacy – Equivalent reduction in morbidity, HgbA1c Short – Prandial Insulins • Toxicity – Hypoglycemia – Rapid insulins better reflect physiological effect of pancreatic insulin (vs Regular insulin) • More important in CKD (=longer insulin t½ ) Short – Prandial Insulins • Cost – All covered under ODB • • • • Regular (R) / Toronto ~ $40 NovoRapid (aspart) ~ $56 Humalog (lispro) ~ $55 Apidra (glulisine) ~ $48 • Convenience – All injected with meals – Regular insulin injected 30-45 min before meal – Rapid insulin can be taken with meal • Reduced risk of hypo if pt injects, then forgets to eat Bottom Line – Prandial Insulins • All equivalent • Choose therapy based on cost / familiarity – Rapid insulins reflect pancreatic insulin release better than [R]/Toronto. – The worse the CrCL, the more important this fact becomes. Starting Prandial Insulin • Fancy Way: – Total dose: 0.5u/kg – 40% of total dose - basal insulin qHS – 20% of total dose TID with meals (60%) – prandial insulin 1530 min before meals • Eg. 80kg pt – 0.5u/kg = 16u basal (40%); 8u TID (20% x 3 = 60%) • Primary Care Method: – Start 5u sc with meals • Titrate AM to HS to target – Monitor 2h PPG • Start injection TID or only single meal as required – If poor control: inj TID sc; If mediocre control: inj qAM sc • Still aim for ~ 2/3rds split (40% basal / 60% prandial) Insulins • Long = Basal – NPH, (N) – Glargine (Lantus) – Detemir (Levemir) • Short = Prandial – Short • Regular (R) • Toronto – Rapid • Lispro (Humalog) • Aspart (NovoRapid) • Glulisine (Apidra) • Premixed • 30/70 (and 10/90, 20/80, 40/60, 50/50) (Reg + NPH) • Humalog Mix-25, NovoMix-30 (Rapid + NPH) Pre-mixed Insulins • NovoMix-30 = Humalog Mix25 (equivalent) • Efficacy – All ~ 30% short / 70% long • Toxicity – Hypoglycemia (less with Rapid vs Regular insulin) • Cost: ~$53 (Rapids) ~$40 (Regular 30/70) • Convenience ~ Rapids can be injected with meal Starting Pre-mixed Insulins • Fancy Way: – Estimate total starting daily dose • (0.3-0.6 units/kg) – Divide daily dose: • 2/3 before breakfast; 1/3 before supper • Primary Care Method: – From scratch: Start 5-10u QD-BID and titrate – From other insulins: Calculate approximate amount of basal and prandial units and divide 2/3rd - 1/3rd AM and PM Pearls • Insulin is 2nd line after metformin – No need to save it for last! • Better than adding a 3rd PO drug – Better efficacy, lower toxicity, better studied • Improve buy-in from patient: – “Natural” supplement – Only BID glucochecking at alternating times required: • • • • • • • FBS AM + PPG AM, then FBS AM + FBS noon, then FBS AM + PPG noon, then FBS AM + FBS PM, then FBS AM + PPG PM, then FBS AM + FBS HS repeat Pearls (cont’d) • D/C secretagogues after starting insulin to reduce risk of hypo’s. – Eg. Sulfonylureas, meglitinides – Black box warning against combo with glitizones! (Actos, Avandia) Comments, Questions & Requests? • [email protected] • Monday & Fridays: – 613-230-7788 ext 238 • Tuesday, Wednesday, Thursday: – 613-241-3344 ext 327 • Twitter: @Roland Halil, PharmD GI Meds Dr Roland Halil, BSc(Hon), BScPharm, ACPR, PharmD Pharmacist, Bruyere Academic FHT Assistant Professor, Dept Family Medicine, U of Ottawa March 2015 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: • 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 Options • 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: • Proton Pump Inhibitors (PPI) – Eg. Omeprazole 20mg, (esomeprazole 20mg), rabeprazole 20mg, pantoprazole 40mg, lansoprazole 30mg, (dexlansoprazole 30mg) Options • 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? – MOA: suppresses gastric basal and stimulated acid secretion by • Cost: generic, ODB and OTC – Tecta (pantoprazole magnesium) inhibiting the parietal and Pariet (rabeprazole) – ODB cell H+/K+ ATP pump 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 NSAID-Induced H.pylori-Induced • Cause most H.pylori• 90% of DU, 70% of GU negative PUD • Once diagnosed, treat with at least triple therapy • Assess risk factors! – Single and dual therapy are not effective enough – 14 day tx more effective than 7-10 day tx Rxfiles Comparison Charts. p40 Aug 2012. Accessed Mar 2013 – – – – – – – 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) 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 1st 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? • [email protected] • 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 2015 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.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, /11 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, /11 Toxicity - 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! 1) Diuretics reduce forward flow into kidney 2) NSAIDs vasoconstrict afferent arterioles (inh of PG synthesis) 3) ACEinh / ARBs vasodilate efferent arterioles (blockade of ATii effects) Result: Reduced GFR & Acute Renal Failure! 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 31/11 Toxicity – 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+html Toxicity – Gastrointestinal Relative Toxicity - Gastrointestinal • In general: – LOW Risk: – INTERMEDIATE Risk: – HIGH Risk: Ibuprofen Naproxen, Diclofenac 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 Multiple NSAID High dose NSAID Concomitant anticoagulant Age≥70 SSRI use Age ≥60 Concomitant steroid Hx heart dx OR =13.5 OR = 9 OR = 7 OR = 6.4 OR = 5.6 OR = 4.8 OR = 3.1 OR = 2.2 OR = 1.8 Rxfiles. NSAID comparison chart. p98 Jan 2015 – Access Mar 10/15 www.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) 12 mo 16 mo 6 mo • “… 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 Toxicity - Cardiac • COX-2 selectivity increases cardiac risk – Dose and duration dependent • Ratio of COX-2 : COX-1 inhibition: – Rofecoxib – Celecoxib – Ibuprofen – Naproxen 80 : 1 9:1 0.4 : 1 0.3 : 1 Toxicity - Cardiac (incl. PGI2) (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 10/15 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 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.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 ~ 5:1 ~ 2:1 ~ 12:1 • N.B. conversion requires calculation that takes into account possible incomplete cross tolerance 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 Comments, Questions & Requests? • [email protected] • Monday & Fridays: – 613-230-7788 ext 238 • Tuesday, Wednesday, Thursday: – 613-241-3344 ext 327 • Twitter: @Roland Halil, PharmD Drug-Drug Interactions Dr Roland Halil, BSc(Hon), BScPharm, ACPR, PharmD Pharmacist, Bruyere Academic FHT Assistant Professor, Dept Family Medicine, U of Ottawa March 2015 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 – 2/3rds 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. 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. 2. 3. 4. Absorption Distribution Metabolism 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. 2. 3. Aymard JP et al. Med Toxicol Adverse Drug Exp 1988;3:430-48. Murray J.J. et al. JAMDA 1991;1:p. 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 (Ca2+) , magnesium (Mg2+) , iron (Fe3+) , aluminum (Al3+)] [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 18/12 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 PK – 3) Metabolism Interactions • Inducers: • Substrates: • Ask: Time to effect? – ~ 2 weeks to kick in – ~ 2 weeks to fade out Flockhart D.A. P450 Table www.medicine.iupui.edu/flockhart/table.htm Accessed Sept 19/04. – Ask: Consequences of sub-therapeutic doses? PK – 3) Metabolism Interactions • Inducers of 3A4: – – – – – – – – • Substrates of 3A4: Rifampin / Rifabutin Efavirenz / Nevirapine Glucocorticoids Phenytoin Carbamazepine Barbiturates St. John's Wort Pioglitazone etc – – – – – – – – 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. 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 • 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? • Issues? » NO! » YES! PK – 3) Metabolism Interactions Pearl • Inducers of 1A2: • Substrates of 1A2: – Nicotine – Caffeine – Smoking cessation… – 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. PK – 3) Metabolism Interactions • Inhibitors: • Substrates: • Ask: Time to effect? – Immediate effect – Hours/days to fade Flockhart D.A. P450 Table www.medicine.iupui.edu/flockhart/table.htm Accessed Sept 19/04. – Ask: Consequences of supra-therapeutic doses? PK – 3) Metabolism Interactions • Inhibitors of 3A4: • Substrates of 3A4: – – – – – – Clarithro / Erythro Ciprofloxacin Fluco / Itra / Ketoconazole Grapefruit juice Amiodarone Indinavir / Nelfinavir Ritonavir /Saquinavir Delaviridine – Verapamil / Diltiazem – Cimetidine Flockhart D.A. P450 Table www.medicine.iupui.edu/flockhart/table.htm Accessed Sept 19/04. – Alpraz / Diaz / Midazolam – CSA / Tacrolimus – Amlodipine / Felodipine Nifedipine / Verap / Dilt – Atorva / Simvastatin – Clarithro / Erythromycin – Indinavir / Nelfinavir Ritonavir / Saquinavir – Estrogen – Carbamazepine etc 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. • 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? • Issues? » No! » Yes, two! PK – 3) Metabolism Interactions Pearl • Inhibitor of 2C19: • Substrates of 2C19: – Omeprazole – Clopidogrel • ?All PPI’s – Time to effect is immediate Flockhart D.A. P450 Table www.medicine.iupui.edu/flockhart/table.htm Accessed Sept 19/04. – Lack of metabolism from pro-drug to active form – Sub-therapeutic effect! 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 halflives will take longer to show their effect! – Higher doses of affected substrate need to be clinically relevant PK – 4) Excretion Interactions • 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 / NH4Cl – Competition for tubular transporters • Anion: Probenecid + beta-lactams (osteomyelitis) • Cation: Itraconazole /cimetidine + digoxin / quinidine 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 PD interactions are common and best prevented by understanding the MOA of drugs used in practice. • Constipation • • • • • • Loperamide Opioids Calcium / antacids Anticholinergics Metamucil Etc • Diarrhea • • • • • Laxatives Erythromcyin Antibiotics Magnesium So many more! 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 18/12 1) Diuretics reduce forward flow into kidney 3) ACEinh / ARBs vasodilate efferent arterioles (blockade of ATii effects) Result: 2) NSAIDs vasoconstrict afferent arterioles (inh of PG synthesis) Reduced GFR & Acute Renal Failure! 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 31/11 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. Serotonin Syndrome • Important Meds: – – – – SSRIs TCAs Triptans Opioids (incl. DM syrup) - SNRIs - MAOinh’s - St John’s Wort - 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. 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) 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 Elderly Myocarditis Bradycardia Myocardial infarction Stroke Long QT Syndrome (congenital form) Syncope of unknown cause - Hypokalemia - Hypothyroidism -Hypomagnesemia - Hypothermia - Hypocalcemia - Hypoglycemia 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) ? Ca2+ & Synthroid co-administration? • 2) ? Ca2+ & 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 – HCTZ 12.5mg – Amitriptyline 25mg – Insulin NPH & R – Haloperidol 1mg - Atenolol 25mg - ASA 81mg - Trazodone 50mg - Glycopyrrolate 2mg - 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! Comments, Questions & Requests? • [email protected] • Monday & Fridays: – 613-230-7788 ext 238 • Tuesday, Wednesday, Thursday: – 613-241-3344 ext 327 • Twitter: @Roland Halil, PharmD 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 2015 [email protected] 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) Agent Warfarin Dabigatran Rivaroxaban Efficacy Toxicity Excellent vs placebo or ASA 1.3% - 3.5% -- major bleed < 0.25% - 0.5%/yr -- ICH ~ same N.B. (~1% absolute difference) (RE-LY trial - industry funded) ~ same N.B. (<1% absolute difference) (ROCKET-AF trial – industry funded) ~ same Apixaban N.B. (<1% absolute difference) (ARISTOTLE trial – industry funded) Less intracranial & More GI bleeds; ?More MI? Untested > 79y.o. or CrCL < 30 NO reversal agent Less intracranial & More GI bleeds Untested > 79y.o. or CrCL < 30 NO reversal agent Less intracranial bleeds GI bleeding – no difference Untested > 77y.o. or CrCL < 30 NO reversal agent Rxfiles.ca Comparison of Warfarin & New Oral Anticoagulants (NOACs) in Non-Valvular Atrial Fibrillation. Oct 2014c (VTE, Afib, Valve disease) Agent Warfarin Dabigatran Rivaroxaban Apixaban Cost Convenience ~ $40/mo (with INR monitoring) QD po INR q3d – q1mo $110/mo $100/mo $140/mo (ODB covered) BID po (ODB w/ LU code 431 for AFib) QD with food (ODB w/ LU codes for Afib or VTE) 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 Anticoagulants 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 2015 [email protected] 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 overestimation 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, antihistaminergic & weight gain effects often go handin-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 • Convenience – 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 – 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 1970’s. – In 1975 – 100 million Rxs written in USA alone – Efficacy – excellent SHORT term efficacy • Sedation & anxiolysis • Rapid tolerance is developed – Toxicity – addictive! • D/C’ing after tolerance develops is VERY hard • Long term risk of dementia, falls, and memory impairment • Severe withdrawal can be fatal – Cost & Convenience – Hey!, Fuggetabout-it! • • • http://www.youtube.com/watch?v=tfGYSHy1jQs http://www.youtube.com/watch?v=Zf0ZyoUn7Vk http://www.youtube.com/watch?v=J5Xu9UcOdj0 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 2015 [email protected] Anti-psychotics Typical (1st gen / conventional) (Relative terms) • Butyrophenones – Haloperidol & Droperidol • Phenothiazines – – – – – – – Chlorpromazine & Fluphenazine Perphenazine & Prochlorperazine Thioridazine & Trifluoperazine Mesoridazine & Periciazine Promazine & Triflupromazine Levomepromazine & Promethazine Pimozide • Thioxanthenes – Chlorprothixene & Clopenthixol – Flupenthixol & Thiothixene – Zuclopenthixol Atypical (2nd gen) • 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: • • • • Aripiprazole Ziprasidone Paliperidone Asenapine – Clozapine – Quetiapine (XR) – Olanzapine (Zydis) • Convenience – Most BID po – Some injectable, long acting forms • • • • • • • Risperidone Paliperidone Flupentixol Pipotiazine Fluphenazine Zuclopenthixol Haloperidol – Olanzapine Zydis (melts) – Risperidone M-tab (melts) 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 – excellent comparison charts to help guide therapy – http://www.rxfiles.ca.proxy.bib.uottawa.ca/rxfiles/uploads/do cuments/members/Cht-Psyc-Neuroleptics.pdf Comments, Questions & Requests? • [email protected] • Monday & Fridays: – 613-230-7788 ext 238 • Tuesday, Wednesday, Thursday: – 613-241-3344 ext 327 • Twitter: @Roland Halil, PharmD 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 2015 [email protected] 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! Pathophysiology – Acute Attack Inflammation lowers pH in the joint Urate precipitates out of solution = tophi Phagocytosis fails. Crystals lyse phagocytes. Tophi are released MORE PHAGOCYTES ARRIVE - Lactic acid is a byproduct of phagocytosis Enzymes released into synovial fluid Damage tissue, activate complement etc 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 2. Aliern et al.(1987); Indomethacin 1) 2) Ahern el al. (1987); Colchicine 4. 2 Placebo group 3. Bellainy et al. (1987); Ruotsi Vainio (1978); Management of Gout With Colchicine http://www.theberries.ns.ca/Archives/colchicine.html Accessed Nov 1/07 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. – More potent than Allopurinol • Efficacy vs Allopurinol: – Lower frequency of gout flares • N.B. Higher frequency of flare with initiation at higher doses! – Improved serum urate lowering effect – 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 7th, 2011. Febuxostat (ULORIC™) • 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 ~ $65/ month; – (no ODB coverage) • Treat the same as allopurinol 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 • ~ 1/3rd 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? 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 will inform your monitoring & Toxicities • Build your Personal Formulary in residency – Learn: MOA, Kinetics (P450 metabolism (Y/N)), Top 3 side effects • Focus your studying where it is needed! – Eg. With equivalent efficacy – focus on learning the potential toxicities
