cocaine & beta-blockers liza halcomb, md journal club 1/17/2008
TRANSCRIPT
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Cocaine & Beta-Blockers
Liza Halcomb, MDJournal Club 1/17/2008
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Cocaine Chest Pain
• Common presentation.• Human cardiac catheterization studies have
shown cocaine to be a powerful coronary vasoconstrictor.
• In the case described, there was concern about ongoing tachycardia and hypertension in face of myocardial ischemia.
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Cocaine
• Causes HTN and tachycardia by inhibiting the reuptake of NE and DA.
• Sympathetic activation – Running away from a dinosaur:– Dilated Pupils – alpha receptors activated– Tachycardia – beta receptors activated– Hypertension – alpha receptors activated– Diaphoresis – sympathetic cholinergic
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Cocaine
• Lange et al. showed that cocaine induced coronary artery vasospasm in the cath lab.1
• Also has type Ia sodium channel blocking effects, can lead to arrhythmias.
• Accelerates CAD by increasing platelet aggregation and plaque formation.
• What about MI?
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Cocaine and MI
• Hollander et al. showed that patients with cocaine related CP had a low incidence of MI.2
– 5%
• On follow up of 203 patients over 408 days after visit for cocaine related CP, only 2 non-fatal MIs were reported in patients who continued to use cocaine.3
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Cocaine Chest Pain
Unlikely to have significant mortality or morbidity.
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Cocaine + UDS• Urine remains + for 3
days after use.• Tests for
benzylecognine, a metabolite.
• Exceedingly uncommon to have a false + result.
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Beta- Blockers
• Used in ED to treat tachycardia associated with possible ACS.
• Do not acutely lower BP.• Block both Beta 1 and Beta 2 receptors.– In asthmatics can cause bronchospasm– In pheochromcytoma can cause unopposed alpha
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Beta Blockers & AMI• Post-MI beta blocker vs. placebo to prevent six-month total
mortality for different risk groups:• Low risk (no PVC’s and no clinical CHF) NNT = 242• Medium risk (1-10 PVC’s and no CHF) NNT = 217• High risk (1-10 PVC’s and CHF) NNT = 44• Very High risk (> 10 PVC’s and CHF) NNT = 30
• For NNH, using the high-risk subset from the COMMIT trial – OR = 1.42 and Control Event Rate = 15.7% – NNH = 19
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Beta Blockers
WHAT IS UNOPPOSED ALPHA ACTIVATION?
WHY DON’T PEOPLE WHO TAKE BETA-BLOCKERS GET ORTHOSTATIC
HYPOTENSION?
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Beta Blockers
• Beta 2 receptors are located on the vasculature to the skeletal muscle.
• No orthostatic hypotension because these vessels constrict when beta-blockers are administered.
• In the presence of alpha activation, beta-blockade can exacerbate HTN.
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Beta Blockers and AMI
• Proven mortality benefit in the setting of MI• Adopted into quality of care guidelines• However, little data on administration in the
1st 12-24 hours of symptoms.• COMMIT trial suggests that early
administration decreases arrhythmias, however benefit offset by increase in cardiogenic shock.4
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Cocaine and Beta Blockers
• Propanolol was routinely used in treatment of cocaine intoxication in the 1970s
• Catravas conducted a lethality study in dogs – all cocaine intoxicated dogs that got propanolol died.5
– All animals that got diazepam survived.
• Led to removal of beta-blockers as 1st line treatment for cocaine intoxication.
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Now we’re back to square 1
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Article #1
• Retrospective review of 348 admissions to telemetry and ICU with + UDS for cocaine.6
• 60 people got beta-blockers.• Multivariate analysis showed decrease risk of
MI in patients who got beta-blockers (1.7% vs. 4.5%)
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Article #1
• Lots of fancy stats! • Parsimonious multivariate generalized
estimating equations.• Covariates considered for inclusion were
those with a P< 0.25 on bivariate analysis.• Propensity scores to address non-randomized
administration of beta-blockers.
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Remember with statistics…..
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Article #1 Problems
• < 50% of patients presented with CP (165/348).
• ~ 30% of the patients who presented with CP had an MI. (51/165)– “Beta-blocker use was of borderline significance in
reducing the risk of a myocardial infarction (OR 0.05; 95% CI 0.00-2.08)”
• + UDS cutoff level may remain + for up to 2 weeks in chronic users.
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Article #1
Look at the mortality table and tell me which of those patients should
get beta-blockers
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Article #2
• Prospective study in 15 patients undergoing cardiac catheteriztation.7
• All got low dose of intranasal cocaine (1/2 of that used for intranasal anesthesia for ENT)
• 6 got saline.• 9 got labetalol.• Conclusion: Labetalol reduces MAP, but not
coronary vasoconstriction.
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Article #2
• Look at Table #1• Trend to increased vasoconstriction although
this is not statistically significant.• Conclusion: Not much of a benefit if coronary
artery diameter does decrease in size.
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Article #3
• Prospective study of 7 patients all under 50 years of age.8
• All had recent cocaine use or + UDS.• Got 0.5 mg/kg esmolol followed by infusion of
0.05 mg/kg/min• Outcome: 3 patients had “good” outcome, 3
patients “failed”, 1 patient “equivocal”.• Conclusion: Cannot recommend routine use of
esmolol.
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Beta blockers in Cocaine users
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BP A
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Article #4
• Randomized double-blind placebo controlled prospective study of 30 patients.9
• 15 got intranasal saline, 15 got intranasal cocaine.
• 5/15 in saline group got propanolol• 15/15 in cocaine group got propanolol
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Article #4
• Cocaine decreased coronary-sinus blood flow from 139 to 120 ml per minute.
• Propranolol further decreased coronary-sinus blood flow to 100 ml per minute.
• Coronary vascular resistance rose from a base-line value of 0.87 mm Hg /ml/min to 1.05 mm Hg/ml/min after cocaine and 1.20 mm Hg/ml/min after propranolol.
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Article #4
With propranolol one subject had complete coronary-artery occlusion,
symptoms of myocardial ischemia, and electrocardiographic changes.
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Evidence Based Medicine + Toxicology
• Very difficult, unable to conduct randomized controlled trial where half the study group is poisoned and half not.
• How to decide what is best?– Physiologic principles– Pharmacologic principles– Animal studies– Case reports– Human studies
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Cocaine and Beta Blockers
• Physiologic principles suggest that it is contraindicated.
• Pharmacologic principles suggest that it is contraindicated.
• Animal studies suggest that it is contraindicated.• Case reports suggest that it is contraindicated.• Randomized trials in humans suggest that it is
contraindicated.
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References1. Lange RA, Cigarroa RG, Yancy CW Jr, et al. Cocaine-induced coronary-artery vasoconstriction. N Engl J
Med 1989;321:1557-1562. 2. Hollander JE, Hoffman RS, Gennis P, et al. Prospective multicenter evaluation of cocaine associated
chest pain (COCHPA) study group. Acad Emerg Med. 1994;1:330-339.3. Hollander JE, Hoffman RS, Gennis P, et al. Cocaine associated chest pain: one year follow up. Acad
Emerg Med 1995;2:179-84.4. Chen ZM, Pan HC, Chen YP, et al. COMMIT (ClOpidogrel and metoprolol in myocardial infarction trial)
collaborative group. Early intravenous then oral metoprolol in45,852 patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet. 2005;366;1622-1632.
5. Catravas JD, Waters IW. Acute cocaine intoxication in the conscious dog: studies on the mechanism of lethality. J Pharmacol Exp Ther. 1981;217:350-356.
6. Dattilo PB, Hailpern SM, Fearon K, etal. B-blockers are associated with reduced risk of myocardial infarction after cocaine use. Ann Emerg Med. 2007, IN press.
7. Boehrer JD et al. Influence of Labetolol on Cocaine-Induced Coronary Vasoconstriction in Humans. Am J Med 1993;94:608-610
8. Sand IC, Brody SL, Wrenn KD, Slovis CM. Experience with esmolol for the treatment of cocaine-associated cardiovascular complications. Am J Emerg Med 1991;9:161-163.
9. Lange RA, Cigarroa RG, Flores ED, et al. Potentiation of cocaine-induced coronary vasoconstriction by beta-adrenergic blockade. Ann Intern Med 1990;112:897-903.