Cocaine & Beta-Blockers

Cocaine & Beta-Blockers

Liza Halcomb, MDJournal Club 1/17/2008

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.

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

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?

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

Cocaine Chest Pain

Unlikely to have significant mortality or morbidity.

Cocaine + UDS• Urine remains + for 3

days after use.• Tests for

benzylecognine, a metabolite.

• Exceedingly uncommon to have a false + result.

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

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

Beta Blockers

WHAT IS UNOPPOSED ALPHA ACTIVATION?

WHY DON’T PEOPLE WHO TAKE BETA-BLOCKERS GET ORTHOSTATIC

HYPOTENSION?

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.

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

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.

Now we’re back to square 1

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%)

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.

Remember with statistics…..

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.

Article #1

Look at the mortality table and tell me which of those patients should

get beta-blockers

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.

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.

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.

Beta blockers in Cocaine users

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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

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.

Article #4

With propranolol one subject had complete coronary-artery occlusion,

symptoms of myocardial ischemia, and electrocardiographic changes.

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

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.

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.