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

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

1 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 (Partially adapted from slides by Marc Riachi, R.Ph.)

2 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

3 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.

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

5 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)

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

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

8 The End.

9 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?

10 Can J Cardiol Vol 25 No 10 October 2009

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

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

13 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

14 Correlation versus Causation

15 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: see: Accessed Apr 25/12.http://www.ncbi.nlm.nih.gov/pmc/articles/PMC /?tool=pubmed

16 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.

17 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.

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

19 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 Accessed Apr 26/12.

20 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/ do Rxfiles.ca. ENHANCE Trial Summary, June Accessed Apr 26/12.

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

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

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

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

25 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%

26 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 Nov 9.

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

28 Relative vs Absolute Risk

29 Time to Benefit How old is too old to start therapy? – Upper ages of trials ~ 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.

30 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

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

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

33 Cost All statins covered under ODB All statins are generic

34 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)

35 Comments, Questions & Requests? Monday & Fridays: – ext 238 Tuesday, Wednesday, Thursday: – ext 327 Halil, PharmD

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

37 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

38 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 mg QD-BID

39 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

40 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

41 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 Accessed Mar 2013

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

43 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

44 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 magnesium, 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)

45 Comments, Questions & Requests? Monday & Fridays: – ext 238 Tuesday, Wednesday, Thursday: – ext 327 Halil, PharmD

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

47 Objectives

48 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

49 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

50 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

51 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: – 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: Accessed Oct 31, /11http://www.clinmedres.org/content/5/1/19.long

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

53 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

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

55 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

56 Toxicity – Gastrointestinal Relative

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

58 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.

59 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 steroidOR = 2.2 – Hx heart dx OR = 1.8 NSAID comparison chart. p69 Oct 11 – Access Nov 11/11

60 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:

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

62 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

63 Toxicity - Cardiac (incl. PGI 2 )

64 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

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

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

67 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 / Meloxicam? ?Safer with Naproxen / 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

68 Opioids Efficacy: – 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)

69 Rxfiles.ca – Opioid Comparison Chart

70 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

71 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.

72 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

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

74 Comments, Questions & Requests? Monday & Fridays: – ext 238 Tuesday, Wednesday, Thursday: – ext 327 Halil, PharmD

75 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

76 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

77 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

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

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

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

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

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

83 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

84 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.

85 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, Accessed Apr 18/12http://www.findarticles.com/p/articles/mi_m3374/is_13_21/ai_ /pg_4

86 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

87 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

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

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

90 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!

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

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

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

94 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!

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

96 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

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

98 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)

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

100 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

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

102 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.

103 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!

104 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 February; 59(2): 239–243. see: Accessed Apr 18/12http://www.ncbi.nlm.nih.gov/pmc/articles/PMC /pdf/bcp pdf

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

106 Rarities (that never seem rare enough)

107 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 Volume Issue 6 - p 1291–1298 see: Accessed Apr 18/12.http://journals.lww.com/anesthesiology/Fulltext/2011/12000/Case_Scenario___Opioid_Association_with_Serotonin.24.aspx

108 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 Accessed Apr 18/12.http://www.medscape.com/viewarticle/582862

109 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

110 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)

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

112 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.

113 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

114 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

115 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 P450): 2.Get a good EMR – Most have interactions checkers – active while Rx’ing 3.Get a good drug database – (All have better interactions checkers in them!) Eg. Micromedex or Lexi-Comp 4.Get a good pharmacist – They are well positioned to help manage these cases

116 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!

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

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

119 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

120 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

121 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

122 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!

123 Comments, Questions & Requests? Monday & Fridays: – ext 238 Tuesday, Wednesday, Thursday: – ext 327 Halil, PharmD


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