Cocaine & Beta-Blockers

1. Cocaine & Beta-Blockers Liza Halcomb, MDJournal Club 1/17/2008

2. 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.

3. 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

4. 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?

5. 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

6. Cocaine Chest Pain Unlikely to have significant mortality or morbidity.

7. Cocaine + UDS • Urine remains + for 3 days after use. • Tests for benzylecognine, a metabolite. • Exceedingly uncommon to have a false + result.

8. 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

9. 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

10. Beta Blockers WHAT IS UNOPPOSED ALPHA ACTIVATION? WHY DON’T PEOPLE WHO TAKE BETA-BLOCKERS GET ORTHOSTATIC HYPOTENSION?

11. 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.

12. 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

13. 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.

14. Now we’re back to square 1

15. 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%)

16. 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.

18. Remember with statistics…..

19. 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.

20. Article #1 Look at the mortality table and tell me which of those patients should get beta-blockers

21. 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.

22. 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.

23. 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.

25. 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

26. 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.

27. Article #4 With propranolol one subject had complete coronary-artery occlusion, symptoms of myocardial ischemia, and electrocardiographic changes.

28. 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

29. 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.

30. References • 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. • Hollander JE, Hoffman RS, Gennis P, et al. Cocaine associated chest pain: one year follow up. Acad Emerg Med 1995;2:179-84. • 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. • 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. • 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. • 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.