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

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

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

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

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

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

Efficacy Only statins have any proven reduction in hard endpoints.

The End.

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

Can J Cardiol Vol 25 No 10 October 2009

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Relative vs Absolute Risk

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

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

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

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

Cost All statins covered under ODB All statins are generic

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

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

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

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

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

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

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

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

Helicobacter pylori 1-2-3: “one week, twice daily, 3 drugs” 14d versus 7-10d Rx: Superior efficacy, but elevated toxicity & cost Triple therapy (all BID): PPI + Clarithromycin + Amoxicillin PPI + Clarithromcyin + Metronidazole N.B. PPI + Amox + Metro – inferior regimen Quadruple therapy: (also 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 Increasing potency = Stool Softeners Eg. Docusate sodium Not a laxative: “All mush, no push” Bulk laxatives: Water absorption; peristalsis Eg. Psyllium, fibre, calcium polycarbophil (Prodiem®) Osmotic laxatives Osmotic + colonic acidification Eg. Milk of magnesium, mag citrate, sorbitol, lactulose, PEG solution, sodium phosphate, glycerin suppositories Stimulant laxatives Direct effect on mucosa Bisacodyl, sennosides Increasing potency = Increasing efficacy and Increasing side effects Cramps, pain, diarrhea Narcotic induced constipation requires at least an osmotic laxative, (usually stimulant laxative)

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

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

Objectives

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

Acetaminophen MOA: unknown Efficacy Toxicity Cost Convenience (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: EFFICACY: What are the endpoints of interest? Analgesia Anti-inflammation Antipyresis All NSAIDs are generally considered equivalent for each endpoint. Few useful comparative trials published

Efficacy - Analgesia See Oxford League Table (Table 1) 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 Some may feel that analyzing the different NSAIDs to eachother would be the point – but in primary care the point here is that they ALL work – all the NNT are low and similar. Do not choose NSAIDs based on miniscule differences in 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 52

Toxicity - Renal 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 Additive pharmacodynamic effects on renal vasculature ACEinh ARBs Aliskiren Diuretics NSAIDs NSAIDs equivalent

Toxicity – Renal Triple Whammy! 3) ACEinh / ARBs vasodilate efferent arterioles (blockade of ATii effects) 1) Diuretics reduce forward flow into kidney Result: ReducedGFR & Acute Renal Failure! 2) NSAIDs vasoconstrict afferent arterioles (inh of PG synthesis) 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: Ibuprofen INTERMEDIATE Risk: Naproxen, Diclofenac HIGH Risk: Ketorolac, Piroxicam

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

Toxicity - Gastrointestinal GI ULCER Risk: ~annual risk 1-4% Elevated odds ratio (OR) with: (Consider adding PPI) Hx of ulcer complication OR =13.5 Multiple NSAID OR = 9 High dose NSAID OR = 7 Concomitant anticoagulant OR = 6.4 Age≥70 OR = 5.6 Age ≥60 OR = 3.1 Concomitant steroid OR = 2.2 Hx heart dx OR = 1.8 NSAID comparison chart. p69 Oct 11 – Access Nov 11/11 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. celecoxib 400 mg twice daily, ibuprofen 800 mg 3 times daily, or diclofenac 75 mg twice daily. 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 61

Toxicity - Cardiac COX-2 selectivity increases cardiac risk Dose and duration dependent Ratio of COX-2 : COX-1 inhibition: Rofecoxib 80 : 1 Celecoxib 9 : 1 Ibuprofen 0.4 : 1 Naproxen 0.3 : 1

Toxicity - Cardiac (incl. PGI2)

Toxicity - Cardiac However, 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

Cost Cheapest = older & generic ($/30 days) Naproxen $17 Ibuprofen $12 ASA $19 Meloxicam $19 Indomethacin $17 Celecoxib $54 - $99

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

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

Rxfiles.ca – Opioid Comparison Chart

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

Neuropathic Agents Efficacy: ~ the same; but additive Antidepressants Presumed inhibition of fast, neuronal Na+ channels Antidepressants TCAs: Nortriptyline, Amitriptyline, etc. SNRIs: Duloxetine, Venlafaxine Anticonvulsants Gabapentin, Pregabalin, VPA, CBZ, phenytoin, topiramate 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? rhalil@bruyere.org 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 2013

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 Future support 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 Consequence Synergistic Additive Antagonistic Beneficial Increased therapeutic effect Reduced toxicity Adverse Reduced therapeutic effect Increased toxicity synergy - thaizide + Bbl - decr BP; additive - ACEi + Bbl - decr BP; antagonism - vasodilator + vasoconstrictor (NTG + NE) Eg. ASA 80mg + Ibuprofen

Drug Interactions – Mechanism Pharmacokinetic (PK) What the body does to the drug Absorption Distribution Metabolism Excretion 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 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 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! Bisphosphonates plus minerals Risk of osteoporotic fracture 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 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: Ask: Time to effect? ~ 2 weeks to kick in ~ 2 weeks to fade out Substrates: Ask: Consequences of sub-therapeutic doses? fewer inducers than inhibitors. (time to onset much longer too; since requires time to upregulate P450 synthesis) (onset and duration dep on t1/2 of agent vs t1/2 of P450 turnover (~1-6 days)) Those listed are only SOME of the inducers of 3A4; (don’t forget all the other isoforms!) Often easiest to try to remember the most common culprits that YOU encounter in your practice. (give chance to scan the list and compare to substrates it could affect) N.B. inducers affect other drugs that are metabolized by the same isoform. Clinically significant DI with inducers involve those drugs that require tight control of blood level (I.e. risk poor outcomes acutely if too low secondary to inducers) N.B. CBZ = autoinducer of 3A4: t1/2 changes depending on single dose vs multidose vs mutlidose with other AEDs. (36h vs 16-24h vs 10h) - important to re-dose after 2 weeks to maintain levels. N.B. Any inducer with antibiotics can lead to treatment failure and should be avoided N.B. any inducer with CSA/tacrolimus could lead to transplant rejection and should be avoided. (closest thing to an absolute contraindication) N.B. RIF + OCP - could lead to failure of contraception - use barrier method for 2 weeks post RIF; Recommend this for anyone on E2 OCP and a 3A4 inducer. Flockhart D.A. P450 Table www.medicine.iupui.edu/flockhart/table.htm Accessed Sept 19/04.

PK – 3) Metabolism Interactions Inducers of 3A4: Rifampin / Rifabutin Efavirenz / Nevirapine Glucocorticoids Phenytoin Carbamazepine Barbiturates St. John's Wort Pioglitazone etc Substrates of 3A4: Clarithro / Erythromycin Alpraz / Diaz / Midazolam CSA / Tacrolimus Indinavir / Nelfinavir Ritonavir / Saquinavir Amlodipine / Felodipine Nifedipine / Verap / Dilt Atorva / Simvastatin Estrogen Carbamazepine etc fewer inducers than inhibitors. (time to onset much longer too; since requires time to upregulate P450 synthesis) (onset and duration dep on t1/2 of agent vs t1/2 of P450 turnover (~1-6 days)) Those listed are only SOME of the inducers of 3A4; (don’t forget all the other isoforms!) Often easiest to try to remember the most common culprits that YOU encounter in your practice. (give chance to scan the list and compare to substrates it could affect) N.B. inducers affect other drugs that are metabolized by the same isoform. Clinically significant DI with inducers involve those drugs that require tight control of blood level (I.e. risk poor outcomes acutely if too low secondary to inducers) N.B. CBZ = autoinducer of 3A4: t1/2 changes depending on single dose vs multidose vs mutlidose with other AEDs. (36h vs 16-24h vs 10h) - important to re-dose after 2 weeks to maintain levels. N.B. Any inducer with antibiotics can lead to treatment failure and should be avoided N.B. any inducer with CSA/tacrolimus could lead to transplant rejection and should be avoided. (closest thing to an absolute contraindication) N.B. RIF + OCP - could lead to failure of contraception - use barrier method for 2 weeks post RIF; Recommend this for anyone on E2 OCP and a 3A4 inducer. 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 Issues? NO! 50 y.o. female – PMHx of DM2, renal transplant on: Ramipril 10mg daily Amlodipine 10mg daily Tacrolimus 10mg BID Cyclosporine 15mg BID Endo Rx: ACTOS 30mg qd N.D.: St John’s Wort i qd Issues? YES! 1 – no - Prednisone induction of amlodipine metabolism – negligible – only 7 d tx. 2- yes – pio and st john’s wort both induce tacro and Csa levels – risk of graft rejection

PK – 3) Metabolism Interactions Pearl Inducers of 1A2: Nicotine Smoking cessation… Substrates of 1A2: Caffeine Sweaty, anxious, nauseous, sleepless… Nicotine withdrawal? No! Caffeine overdose! fewer inducers than inhibitors. (time to onset much longer too; since requires time to upregulate P450 synthesis) (onset and duration dep on t1/2 of agent vs t1/2 of P450 turnover (~1-6 days)) Those listed are only SOME of the inducers of 3A4; (don’t forget all the other isoforms!) Often easiest to try to remember the most common culprits that YOU encounter in your practice. (give chance to scan the list and compare to substrates it could affect) N.B. inducers affect other drugs that are metabolized by the same isoform. Clinically significant DI with inducers involve those drugs that require tight control of blood level (I.e. risk poor outcomes acutely if too low secondary to inducers) N.B. CBZ = autoinducer of 3A4: t1/2 changes depending on single dose vs multidose vs mutlidose with other AEDs. (36h vs 16-24h vs 10h) - important to re-dose after 2 weeks to maintain levels. N.B. Any inducer with antibiotics can lead to treatment failure and should be avoided N.B. any inducer with CSA/tacrolimus could lead to transplant rejection and should be avoided. (closest thing to an absolute contraindication) N.B. RIF + OCP - could lead to failure of contraception - use barrier method for 2 weeks post RIF; Recommend this for anyone on E2 OCP and a 3A4 inducer. Flockhart D.A. P450 Table www.medicine.iupui.edu/flockhart/table.htm Accessed Sept 19/04.

PK – 3) Metabolism Interactions Inhibitors: Ask: Time to effect? Immediate effect Hours/days to fade Substrates: Ask: Consequences of supra-therapeutic doses? fewer inducers than inhibitors. (time to onset much longer too; since requires time to upregulate P450 synthesis) (onset and duration dep on t1/2 of agent vs t1/2 of P450 turnover (~1-6 days)) Those listed are only SOME of the inducers of 3A4; (don’t forget all the other isoforms!) Often easiest to try to remember the most common culprits that YOU encounter in your practice. (give chance to scan the list and compare to substrates it could affect) N.B. inducers affect other drugs that are metabolized by the same isoform. Clinically significant DI with inducers involve those drugs that require tight control of blood level (I.e. risk poor outcomes acutely if too low secondary to inducers) N.B. CBZ = autoinducer of 3A4: t1/2 changes depending on single dose vs multidose vs mutlidose with other AEDs. (36h vs 16-24h vs 10h) - important to re-dose after 2 weeks to maintain levels. N.B. Any inducer with antibiotics can lead to treatment failure and should be avoided N.B. any inducer with CSA/tacrolimus could lead to transplant rejection and should be avoided. (closest thing to an absolute contraindication) N.B. RIF + OCP - could lead to failure of contraception - use barrier method for 2 weeks post RIF; Recommend this for anyone on E2 OCP and a 3A4 inducer. Flockhart D.A. P450 Table www.medicine.iupui.edu/flockhart/table.htm Accessed Sept 19/04.

PK – 3) Metabolism Interactions Inhibitors of 3A4: Clarithro / Erythro Ciprofloxacin Fluco / Itra / Ketoconazole Grapefruit juice Amiodarone Indinavir / Nelfinavir Ritonavir /Saquinavir Delaviridine Verapamil / Diltiazem Cimetidine Substrates of 3A4: Alpraz / Diaz / Midazolam CSA / Tacrolimus Amlodipine / Felodipine Nifedipine / Verap / Dilt Atorva / Simvastatin Clarithro / Erythromycin Indinavir / Nelfinavir Ritonavir / Saquinavir Estrogen Carbamazepine etc fewer inducers than inhibitors. (time to onset much longer too; since requires time to upregulate P450 synthesis) (onset and duration dep on t1/2 of agent vs t1/2 of P450 turnover (~1-6 days)) Those listed are only SOME of the inducers of 3A4; (don’t forget all the other isoforms!) Often easiest to try to remember the most common culprits that YOU encounter in your practice. (give chance to scan the list and compare to substrates it could affect) N.B. inducers affect other drugs that are metabolized by the same isoform. Clinically significant DI with inducers involve those drugs that require tight control of blood level (I.e. risk poor outcomes acutely if too low secondary to inducers) N.B. CBZ = autoinducer of 3A4: t1/2 changes depending on single dose vs multidose vs mutlidose with other AEDs. (36h vs 16-24h vs 10h) - important to re-dose after 2 weeks to maintain levels. N.B. Any inducer with antibiotics can lead to treatment failure and should be avoided N.B. any inducer with CSA/tacrolimus could lead to transplant rejection and should be avoided. (closest thing to an absolute contraindication) N.B. RIF + OCP - could lead to failure of contraception - use barrier method for 2 weeks post RIF; Recommend this for anyone on E2 OCP and a 3A4 inducer. Flockhart D.A. P450 Table www.medicine.iupui.edu/flockhart/table.htm Accessed Sept 19/04.

PK – 3) Metabolism Interactions Clinical Scenarios 60 y.o. female – PMHx of HTN on: Nifedipine XL 60mg qd BP: 105/60 Enjoys a fresh grapefruit when in season. Issues? No! 60 y.o. male – PMHx of NSTEMI, CHF on: Lipitor 80mg qd Ramipril 10mg qd ASA 81mg qd Bisoprolol 5mg qd New onset Afib – Cardio Rx: Amiodarone 200mg daily Issues? Yes, two! 1 –no – occasional, fresh grapefruit – negligible effect on BP through adalat 2 – yes – amio – inh of statin now and long half-life means long time before max effect of the med is seen (months later!)

PK – 3) Metabolism Interactions Pearl Inhibitor of 2C19: Omeprazole ?All PPI’s Time to effect is immediate Substrates of 2C19: Clopidogrel Lack of metabolism from pro-drug to active form Sub-therapeutic effect! fewer inducers than inhibitors. (time to onset much longer too; since requires time to upregulate P450 synthesis) (onset and duration dep on t1/2 of agent vs t1/2 of P450 turnover (~1-6 days)) Those listed are only SOME of the inducers of 3A4; (don’t forget all the other isoforms!) Often easiest to try to remember the most common culprits that YOU encounter in your practice. (give chance to scan the list and compare to substrates it could affect) N.B. inducers affect other drugs that are metabolized by the same isoform. Clinically significant DI with inducers involve those drugs that require tight control of blood level (I.e. risk poor outcomes acutely if too low secondary to inducers) N.B. CBZ = autoinducer of 3A4: t1/2 changes depending on single dose vs multidose vs mutlidose with other AEDs. (36h vs 16-24h vs 10h) - important to re-dose after 2 weeks to maintain levels. N.B. Any inducer with antibiotics can lead to treatment failure and should be avoided N.B. any inducer with CSA/tacrolimus could lead to transplant rejection and should be avoided. (closest thing to an absolute contraindication) N.B. RIF + OCP - could lead to failure of contraception - use barrier method for 2 weeks post RIF; Recommend this for anyone on E2 OCP and a 3A4 inducer. Flockhart D.A. P450 Table www.medicine.iupui.edu/flockhart/table.htm Accessed Sept 19/04. 95

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

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 rarely sig. Used for therapeutic purposes in OD, outpt iv cef w/ probenecid in OM,

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

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

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

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

2) NSAIDs vasoconstrict afferent arterioles (inh of PG synthesis) 1) Diuretics reduce forward flow into kidney 3) ACEinh / ARBs vasodilate efferent arterioles (blockade of ATii effects) Result: Reduced GFR & Acute Renal Failure! 2) NSAIDs vasoconstrict afferent arterioles (inh of PG synthesis) 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 - SNRIs TCAs - MAOinh’s Triptans - St John’s Wort Opioids (incl. DM syrup) - MDMA (ecstasy) Opioids may affect serotonin levels Tramadol, fentanyl, methadone, meperidine, dextromethorphan Weak SSRI’s and also increase release of 5HT into the synapse Possibly also morphine, hydromorphone, oxycodone and buprenorphine (which lack SSRI activity) Joel Lamoure. How Common or Significant Is Serotonin Syndrome? Medscape 11/10/2008 http://www.medscape.com/viewarticle/582862 Accessed Apr 18/12.

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) 1 – TCA + SSRI (worrisome) 2 – SSRI low dose (encouraging) 3 – TCA low dose (encouraging) 4 – triptan will add 5HT load (worrisome) 5 – freq of triptan PRN will matter

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.torsades.org or www.qtdrugs.org

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

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

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

Summary - Resources Learn the basic mechanism of action of the drugs in your personal formulary Most interactions you’ll see are pharmacodynamic For pharmacokinetic interactions (usu P450): Get a good EMR Most have interactions checkers – active while Rx’ing Get a good drug database (All have better interactions checkers in them!) Eg. Micromedex or Lexi-Comp 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 - Atenolol 25mg HCTZ 12.5mg - ASA 81mg Amitriptyline 25mg - Trazodone 50mg Insulin NPH & R - Glycopyrrolate 2mg Haloperidol 1mg - Demerol 50mg

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

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

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