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

Back to BasicsPractical 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 2013rhalil@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, PharmDPharmacist, Bruyere Academic FHT

Assistant Professor, Dept Family Medicine, U of OttawaMarch 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:1. EFFICACY

2. TOXICITY

3. COST

4. 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, & Gemfibrozil3. Ezetimibe

• (Inhibits absorption of cholesterol at the brush border of the small intestine via the sterol transporter, Niemann-Pick C1-Like1 (NPC1L1)).

4. Niacin5. Cholestyramine

• (Bile acid sequestrant)

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

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 orInconvenience of any others?

Can J Cardiol Vol 25 No 10 October 2009

Cdn Dyslipidemia Guidelines 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.”

Correlation versus Causation

Why statins?

• Lipid lowering effectsvs• 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….• 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

– 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.

• “ …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, 2012. Accessed Apr 25/12Rxfiles.ca. AIM-HIGH Trial Summary, Dec 2011. Accessed Apr 29/12.

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 trialN 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.”

“…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

– 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)

• 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

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:

– Find minimally effective, safest dose

• Step-down Therapy: – Immediate relief first, then reduce

• Hiatus Hernia with symptoms: PPI QD-BID for prevention of Barrett’s esophagus

Peptic Ulcer DiseaseH.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

Laxatives1. 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)

– 613-230-7788 ext 238

Analgesics

Dr Roland Halil, BSc(Hon), BScPharm, ACPR, PharmD

Pharmacist, Bruyere Academic FHTAssistant Professor, Dept Family Medicine, U of Ottawa

March 2013

Objectives

Pain: Somatic vs Neuropathic

Somatic• WHO Pain Ladder:

1. Acetaminophen2. NSAID3. 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. Analgesia2. Anti-inflammation3. 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!

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

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:

ReducedGFR & Acute Renal Failure!

Toxicity – GastrointestinalMechanism

• 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 – GastrointestinalRelative

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)

• “… an interim report of the first 6 months of data from 2 trials that lasted 12 and 16 months.” – “… at …16 months there was no difference in GI adverse

effects between celecoxib and traditional NSAID groups.” • Discovered because crucial info was posted on FDA

website– Not included in Canadian disclosures.

1) Lexhin, J et al. CMAJ • NOV. 23, 2004; 171 (11)2) Silverstein FE, et al. Celecoxib Long-term Arthritis Safety Study. JAMA 2000;284(10):1247-55

12 mo 16 mo

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

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

Convenience

• All po– Some IV, some PR

• Shorter effect (q4-6h)– Ibuprofen– Indomethacin– ASA

• Longer effect (q8-12h)– Naproxen– Diclofenac

Summary1. Efficacy – equivalent at equipotent doses2. 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

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)

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

~ 12:1

Neuropathic Agents• Efficacy: ~ the same; but additive

– Presumed inhibition of fast, neuronal Na+ channels

1.Antidepressants – TCAs: Nortriptyline, Amitriptyline, etc. – SNRIs: Duloxetine, Venlafaxine

2.Anticonvulsants– Gabapentin, Pregabalin, VPA, CBZ, phenytoin,

topiramate

3.Topicals– Lidocaine 5%, capscaicin, NSAIDs, compounded

agents above etc.

Neuropathic Agents• If Efficacy is ~ equivalent; choose based on potential

toxicity, cost, and convenience factors• Toxicity:

– TCA’s: anticholinergic, sedation, QTc prolongation– Gabapentin & Pregabalin: sedation, edema, dizziness– Duloxetine & Venlafaxine : CNS effects, GI effects – Anti-epileptics: hepatitis, GI effects, CBC alterations, drug

interactions

• Cost: – Pregabalin & duloxetine – pricey, (since no generics)

• Convenience: all ~ qhs or BID

Rxfiles.ca - Neuropathic Agents

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

– 613-230-7788 ext 238

Drug-Drug Interactions

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. Absorption2. Distribution3. Metabolism4. Excretion

2. Pharmacodynamic (PD)– What the drug does to the body

PK – 1) Absorption Interactions

• Important in family practice: – Chelation (binding interactions)

• Less commonly clinically relevant:– Alteration of gastric pH– Alteration of GI motility

1. Aymard JP et al. Med Toxicol Adverse Drug Exp 1988;3:430-48.2. Murray J.J. et al. JAMDA 1991;1:p.3. Lomaestro BM et al. Drug Intell Clin Pharm 1991;25: 1249-58.

PK – 1) Absorption InteractionsChelation

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

• Cytochrome P450 isoforms – so many!• Family - Subfamily - Genotype (eg. 2-C-19) (18) (42) (60)

– Substrates, inhibitors, & inducers for each isoform!– 3A4 - most common

• Inducers:

• Ask: Time to effect?– ~ 2 weeks to kick in– ~ 2 weeks to fade out

• Substrates:

– Ask: Consequences of sub-therapeutic doses?

Flockhart D.A. P450 Table www.medicine.iupui.edu/flockhart/table.htm Accessed Sept 19/04.

• Inducers of 3A4:– Rifampin / Rifabutin– Efavirenz / Nevirapine– Glucocorticoids– Phenytoin– Carbamazepine– Barbiturates– St. John's Wort– Pioglitazone

• Substrates of 3A4:– Clarithro / Erythromycin– Alpraz / Diaz / Midazolam– CSA / Tacrolimus– Indinavir / Nelfinavir

Ritonavir / Saquinavir– Amlodipine / Felodipine

Nifedipine / Verap / Dilt– Atorva / Simvastatin– Estrogen– Carbamazepine

PK – 3) Metabolism InteractionsClinical Scenarios

• 50 y.o. male - PMHx of HTN, MI x3, COPD on:– Ramipril 10mg daily– HCTZ 25mg qAM – Amlodipine 10mg daily

– BP control borderline/high– COPD exacerbation

• Rx: PREDNISONE 25mg qAM for 7 days

• Issues?» NO!

• 50 y.o. female – PMHx of DM2, renal transplant on:– Ramipril 10mg daily– Amlodipine 10mg daily– Tacrolimus 10mg BID– Cyclosporine 15mg BID

– Endo Rx: ACTOS 30mg qd– N.D.: St John’s Wort i qd

• Issues?» YES!

• Inducers of 1A2:

– Nicotine

– Smoking cessation…

• Substrates of 1A2:

– Caffeine

– Sweaty, anxious, nauseous, sleepless…

– Nicotine withdrawal?– No! Caffeine overdose!

PK – 3) Metabolism InteractionsPearl

• Inhibitors:

• Ask: Time to effect?– Immediate effect– Hours/days to fade

• Substrates:

– Ask: Consequences of supra-therapeutic doses?

• 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

PK – 3) Metabolism InteractionsClinical Scenarios

• 60 y.o. female – PMHx of HTN on: – Nifedipine XL 60mg qd– BP: 105/60

– Enjoys a fresh grapefruit when in season.

• Issues?» No!

• 60 y.o. male – PMHx of NSTEMI, CHF on:– Lipitor 80mg qd– Ramipril 10mg qd– ASA 81mg qd– Bisoprolol 5mg qd

– New onset Afib – Cardio Rx: Amiodarone 200mg daily

• Issues?» Yes, two!

• Inhibitor of 2C19:

– Omeprazole• ?All PPI’s

– Time to effect is immediate

• Substrates of 2C19:

– Clopidogrel

– Lack of metabolism from pro-drug to active form

– Sub-therapeutic effect!

PK – 3) Metabolism InteractionsPearl

PK – 3) MetabolismSummary

• Inducers– Remember: time to effect ~

2 weeks • Longer treatments will

result in more significant interactions

• Harder to see the temporal correlation

– Lower doses of affected substrate need to be clinically relevant

• Inhibitors– Remember: time to effect

is immediate• Shorter treatments will

result in more significant interactions

• N.B. Drugs with long half-lives will take longer to show their effect!

– Higher doses of affected substrate need to be clinically relevant

• Rarely significant, but…– Enterohepatic circulation:

• Bile acid sequestrants + Warfarin or L-T4 or Estrogen

– Alteration in urine pH• Ion trapping

– Eg. Management of ASA overdose with bicarb– Eg. Methamphetamine overdose with Vit C / NH4Cl

– Competition for tubular transporters• Anion: Probenecid + beta-lactams (osteomyelitis)• Cation: Itraconazole /cimetidine + digoxin / quinidine

PK – 4) Excretion Interactions

Pharmacodynamic (PD) Interactions

• Think: Review of Systems– Head to Toe

• Bottom Line: – The molecular mechanism is

irrelevant. – The physiological effect is

important.• These effects are additive.

– (or synergistic or antagonistic)

PD - CNS• Eg. CNS depression

– Alcohol– Opioids – Benzodiazepines – Antihistamines

• Diphenydramine, hydroxyzine, etc

– Antipsychotics (typical & atypical)– Antidepressants (TCAs, SSRIs etc)– Barbiturates – Etc.

What to do?

• Monitor more closely for tolerance– Temporal correlations will be helpful

• Other classic pearls of prescribing:– Avoid the combo if possible

• Explore alternatives using the 4 steps of rational prescribing

– Use the lowest effective dose– Limit duration of treatment– Start low, go slow

PD - CV

• Bradycardia– Beta blockers– Diltiazem, Verapamil– Digoxin– Amiodarone

• Hypertension– NSAIDs & COX-2 inh– Corticosteroids– EPO– Estrogens– Cyclosporine– Sympathomimetics

• phenylephrine• caffeine• pseudoephedrine

PD• Respiratory Depression

– Opioids– Barbiturates– Benzodiazepines– Alcohol

• Constipation• Loperamide• Opioids• Calcium / antacids• Anticholinergics • Metamucil• Etc

• Diarrhea• Laxatives• Erythromcyin • Antibiotics • Magnesium• So many more!

PD interactions are common and best prevented by understanding the MOA of drugs used in practice.

Prescribing Cascades

• Very common in primary care• Unrecognized side effects of one drug lead to

prescribing of another to compensate. – Chain linked pharmacodynamic interactions!– Have seen up to 20 drugs in elderly patients

accumulate over the years!

Renal Triple Whammy

• Commonly overlooked in Primary Care• ACEinh (or ARB) + diuretic + NSAID

Katarzyna K Loboz et al. Drug combinations and impaired renal function – the ‘triple whammy’. Br J Clin Pharmacol. 2005 February; 59(2): 239–243. see: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1884747/pdf/bcp0059-0239.pdf Accessed Apr 18/12

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

3) ACEinh / ARBs vasodilate efferent arterioles (blockade of ATii effects)

2) NSAIDs vasoconstrict afferent arterioles (inh of PG synthesis)

1) Diuretics reduce forward flow into kidney

Result:

Reduced GFR & Acute Renal Failure!

Rarities (that never seem rare enough)

Serotonin Syndrome

– Hyperstimulation of 5-HT 1A & 2A receptors• Peripherally and centrally

– Concentration dependent symptoms • Mild - tremors and diarrhea • Severe – hyperthermia and rigidity, even death.

– Rare in monotherapy• Usually with polypharmacy

Rastogi, Rahul et al. Case Scenario: Opioid Association with Serotonin Syndrome: Implications to the Practitioners. Anesthesiology: December 2011 - Volume 115 - Issue 6 - p 1291–1298 see: http://journals.lww.com/anesthesiology/Fulltext/2011/12000/Case_Scenario___Opioid_Association_with_Serotonin.24.aspx Accessed Apr 18/12.

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)

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:

– Domperidone, Citalopram, Escitalopram

• Macrolides – Erythromycin > Clarithromycin > Azithromycin

• Fluoroquinolones – Ciprofloxacin, Levofloxacin, Moxifloxacin, Norfloxacin

• Miscellaneous – Clindamycin, Trimethoprim/Sulfamethoxazole

• Azole Antifungals – Fluconazole, Itraconazole, Ketoconazole

• Antipsychotics • SSRI’s• TCAsEtc.

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 ProlongationClinical 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 - Resources1. 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

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

• 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

• 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!

– 613-230-7788 ext 238

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

convenience slide

causation slide

fatal stroke reduction

hard endpoints reduction

efficacy endpoints

j cardiol vol

proven reduction

plaque size reduction

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