Rami Khouzam, MD

Which one of the following tests would be POSITIVE:

a- BNP

b- Troponin I

c- Urine Na+

d- UDS

e- Urine Ca++ and Mg++

INDEX CASE 1

• 50 yo AA gentleman presents with:– One month hx of LEs edema– 3 days hx of SOB & DOE– Non-compliance with meds. (lately)

PMHx: – CHF– HTN

Meds: – Aldactone – Lasix – Diltiazem

PE:– Remarkable for: RR; 28, P:101, BP: 196/110,

O2 Sat: 93% on 4L– S1 S2 S4. PMI @ ant. axillary line– Bilat. diffuse lung crackles & wheezes– 2+ edema bilat. in LEs.

CXR: Interstitial markings consistent with

pulmonary edema– Cardiomegaly

INDEX CASE 2• 54 yo AA gentleman with 3-4 hrs. hx. of CP,

SOB, diaphoresis & palpitations

• Admits to not taking his meds x 3 days because he was more busy drinking whisky and smoking cocaine & marijuana

PHMX: – CHF– HTN– Gout

Meds:– Lasix– KCl– Aldactone

PE:– Remarkable for P: 220, RR: 32, BP: 113/60,

S1 S2. PMI laterally displaced

Adenosine 6mg, 12mg, 12mg

HR: 160 then 220 SVT (called @ 2:00 AM

from Med. ER)

Vagal maneuvers

Amiodarone 150mg IV over 10 minutes

• Cardizem 10mg IV

• HR: 105

Hospital day # 4:

• Left hospital AMA

• Called @ 3:00 AM from VA

• Patient found by EMT

• HR: 180

INDEX CASE 3• 45 Yo AA lady presented with CP, substernal,

8/10, pressure-like, radiating to left arm, accompanied with SOB, nausea & diaphoresis

PMHx:

• CAD.. MI x 2 in the past

Meds:

- ASA

- Metoprolol

- Zocor

PE:• Remarkable for: S1 S2, RR @ 110

EKG:• Sinus tachycardia• ST in I, aVL, V5, V6

Labs:• Trop: 1.8 2,4 8.0

Cath. Lab:• Lt. Cx: 80% Stenosis Stent

Which one of the following tests was POSITIVE:

(in the previous 3 cases)

a- BNP

b- Troponin I

c- Urine Na+

d- UDS

e- Urine Ca++ and Mg++

• Index case 1: Hypertensive emergency

• Index case 2: Life-threatening dysrhythmia

• Index case 3: NSTEMI

Correct answer: d

UDS + for COCAINE

HISTORY OF COCAINE• In pre-Columbian times, the

coca leaf was officially reserved for Inca royalty. The natives used coca for mystical, religious, social, nutritional and medicinal purposes

• Coca was initially banned by the Spanish

• 1551: the Bishop of Cuzco outlawed coca use on pain of death because it was "an evil agent of the Devil"

• The invaders discovered that without the Incan "gift of the gods", the natives could barely work the fields - or mine gold

• So it came to be cultivated even by the Catholic Church

• Coca leaves were distributed three or four times a day to the workers during brief rest breaks

• Returning Spanish conquistadores introduced coca

to Europe

• It is told that even Shakespeare may have smoked it

• 1814: an editorial in Gentleman's Magazine urged researchers to begin experimentation so that coca could be used as "a substitute for food so that people could live a month, now and then, without eating..."

• Around 1860: the active ingredient of the coca plant was first isolated in the West by Albert Niemann

• To Sherlock Holmes, cocaine was "so transcendentally stimulating and clarifying to the mind that its secondary action is a matter of small moment”

• Robert Louis Stephenson wrote The Strange Case of Dr Jekyll and Mr Hyde during a six-day cocaine-binge

• Cocaine was soon sold over-the-counter. Until 1916, one could buy it at Harrods

• Cocaine was widely used in tonics, toothache cure and patent medicines; in coca cigarettes "guaranteed to lift depression”; and in chocolate cocaine tablets

• When combined with alcohol, the cocaine alkaloid yields a further potently reinforcing compound, now known to be cocaethylene

• Cocaine was a popular ingredient in wines, notably Vin Mariani

• Coca wine received endorsement from prime-ministers, royalty and even the Pope

• Architect Frédérick-Auguste Bartholdi remarked that if only he had used Vin Mariani earlier in his life, then he would have engineered the Statue of Liberty a few hundred meters higher

Cocaine & The Heart

• 1911: the earliest report of cocaine damaging the heart

• Price & Leaky reported that cocaine use for local dental anesthesia could induce severe myocardial damage leading to death

(Braunwald)

ROUTE FORMULA ONSET OFACTION

PEAKEFFECT

DURATION

Inhalation “Crack” 8 seconds 2-5 minutes 10-20 minutesIntranasal Cocaine HCl 2-5 minutes 5-10 minutes 30 minutesIntravenous Cocaine HCl Seconds 2-5 minutes 10-20 minutesOral Cocaine HCl 10 minutes 30-60 minutes 60 minutes

Cocaine Pharmacology by Route of Administration

(Braunwald)

• Exploited by humans for at least 5000 years

• Except for medicinal purposes, the drug is illegal in North America

Cocaine

• 2nd. most commonly used illicit drug in the US (after Marijuana)

• ~ 30 million (~ 11%) persons in the US have used cocaine at some time

• 5-6 million on regular basis

Adulterants• Sugars

• Stimulants (ephedrine, caffeine, amphetamines)

• Quinine, strychnine

• Local anesthetics

Review of Simple Physiology

• Caliber of the coronary arteries is controlled by a complex interplay between:– Local metabolic factors

AND – Neural input

• Oxygen delivery to the myocardium is achieved through changes in coronary artery caliber

A) Sympathetic

• Norepinephrine from presynaptic vesicles onto alpha-and B2- receptors

coronary v.c.2 coronary v.d. (mild)

B) Parasympathetic:

• Acetylcholine on M3 Cholinergic receptors v.d.

(Gutterman DG. The heart and cardiovascular system. 2nd ed. 1991)

Cocaine, more than just an illicit drug

• Pharmacological effects:– Blocking reuptake of cathecholamines in the

presynaptic neurons: Norepinephrine Dopamine and Serotonin– Cholinergic stimulation– Blocking sodium channels : Local anesthetic Class I antiarrhythmic

Effects of cocaine on Hemodynamics

HR, BP myocardial contractility cardiac output Cardiac function (Direct myocardial

toxicity)

• CVS toxicity:

– Hypertensive emergency/ Pulmonary edema– Arrhythmias– Myocardial ischemia and infarction

– Acute aortic dissection or rupture to stroke– Sudden death– Acute reversible myocarditis– Dilated cardiomyopathy

(Pasternack, PF Am J Cardiol 1985)

Hypertensive Emergencies

• Phentolamine or direct -adrenergic antagonist: the antihypertensive of choice

• Should -B be avoided with cocaine because of paradoxical hypertension ?

(class IIa for SBP > 150 or HR > 100)

• IV NTG or nitroprusside can be used

(Braunwald)

Dysrhythmias

• Atrial or ventricular

• Sinus tachycardia: most common

• A. fib, SVT (sympathetic stimulation)

• Respond to sedation with benzodiadepines

• Other standard therapies to slow rate

Cardiac DysrhythmiaCocaine (lidocaine-like effect) Rhabdomyolysis & ischemia

Blockade of fast Na+ channels Hyperkalemia

slowing depolarization

Wide complex tachycardia

(Braunwald)

• Wide complex tachycardia from cocaine of unknown etiology iv bolus of sodium bicarbonate, 1-2 mEq/kg will empirically treat sodium channel blockade as well as cardiotoxicity from hyperkalemia

(Braunwald)

Mechanism of Myocarditis1) Direct effect on lymphocyte activity

2) natural killer cell activity in blood cytotoxic to myocardial cells

3) Cocaine-related eosinophilic infiltrate hypersensitivity reaction

4) Focal myocarditis also direct, negative inotropic effect on cardiac muscle

• Cathecolamine excess Contraction band necrosis anatomic substrate for ventricular dysrhythmias

• Autopsy support scattered foci of necrosis, myocarditis independent of CAD

(Braunwald)

THE ORIGIN OF COCAINE• Erythroxylon coca is a densely-

leafed plant native to the eastern slopes of the Andes

• Coca is widely cultivated in Bolivia, Peru and Ecuador, but the lead producer is Colombia, currently the source of 80% of the world's cocaine

• There are around 250 species of erythroxylon plants. At least 20 produce cocaine. Only 2 of them typically yield enough cocaine to justify commercial cultivation

• Typically, coca thrives in warm, moist, frost-free valleys between 1500 and 6000 metres above sea level

• The plant grows to a height of up to 8 feet and can be harvested 4 times a year

• The leaves are rich in vitamins, protein, calcium, iron and fiber

• The cocaine content of the leaves ranges from O.1% to 0.9%

CRACK-COCAINE• To obtain crack-cocaine,

ordinary cocaine hydrochloride is concentrated by heating the drug in a solution of baking soda until the water evaporates.

• This type of base-cocaine makes a cracking sound when heated; hence the name “Crack”

• Base-cocaine vaporizes at a low temperature, so it can be easily inhaled via a heated pipe

CHEMISTRY OF COCAINE• C17H21NO4

• Cocaine can be manufactured by converting tropinone into 2-carbomethoxytropinone, reducing this to ecgonine,and then converting the ecgonine to cocaine

• This isn't as easy as it sounds

Cocaine Body Packers• Cocaine is smuggled by a variety of

techniques

• Body packers ingest cocaine wrapped tightly into condoms or other latex products before crossing international borders

• Each packet can contain up to 10g of cocaine and packers may swallow as many as 150 packets

• On arrival at their destination: cathartic

• Unfortunately rupture of cocaine packet can result in death, as each packet contains close to 10 times the lethal dose

(Braunwald)

Mechanisms of AMI

1) HR + BP myocardial oxygen demand

2) coronary artery flow, coronary vasospasm or thrombosis

3) Active myocarditis (hypersensitivity or toxicity)

• A recreational dose of cocaine: HR ~ 30 beats/min.– Also BP by 20/10 mm Hg.(equivalent to mild

exercise)

• Not sufficient to result in myocardial ischemia

[I] VASOCONSTRICTIONA- Animal Studies

• Hale et al: anesthetized dogs: IV bolus cocaine 10 mg/kg 15% in circumflex artery diameter

(This dose ~ 5 times the dose used recreationally by humans)

(Hale SL, Am Heart J 1989)

• Kuhn et al: cocaine 2mg/kg in a dog model LAD diameter by 19% & coronary blood flow of 55%

– Attenuation of the effects of cocaine: pretreating with phentolamine: VC

– Potentiation of the effects of cocaine:

pretreating with propanolol: VC

(Kuhn FE, J Am Coll Cardiol 1990)

• Egashira et al: a swine model

– Significant in v.c. associated with denuded coronaries compared with native ones (59% cross-sectional area reduction vs 48%)

– Vasoreactivity to cocaine may be greater in diseased coronaries

Egashira K, J Clin Invest 1991

B- Human Studies

• Human coronary arteries differ from animal arteries in a number of ways

• Difference in the density and distribution of alpha-and beta-receptors

• Most human studies have documented a in coronary artery diameter ranging from 4% to 29% associated with cocaine use

• Lange et al: phentolamine abolishment of cocaine-induced V.C.

• Flores et al: 13% reduction in coronary caliber was observed in disease-free coronary arteries, a 29% reduction in caliber in coronary arteries with significant stenoses (>50%)

• Moliterno et al: cigarette smoking + cocaine significant v.c.

(19% decrease in coronary diameter in cocaine plus cigarette smoking versus 7% in cocaine alone)

(Flores ED, J Am Coll Cardiol 1990)

Time factor • Brogan et al: – At 30 minutes: 17% in coronary artery caliber

(maximal serum concentration of cocaine)

– At 60 minutes: coronary diameter returns to baseline

– At 90 minutes: 21% in diameter (Serum concentrations of cocaine’s metabolites,

benzoylecgonine, ethyl methyl ecgonine)

(Brogan WC, Ann Int Med 1992)

[II] VASOCONSTRICTION A- Animal Studies

• Friedrichs et al: coronary v.d. within the first minute of I.V. cocaine

• A 13% and 68% in coronary perfusion pressure were measured, respectively, with 2mg/kg and 10mg/kg intravenous cocaine

• Same with lidocaine (of the same class as cocaine) similar decreases in coronary perfusion pressure (vasodilatory effects ? due to the anesthetic properties of cocaine)

(Friedrichs GS, J Physiol Pharmacol 1990)

• Zimring et al: early increase in coronary blood flow by 30% within the first 2 minutes of administration

(Zimring HJ, Circulation 1994)

– Dual effect: a- Early v.d. b- Followed by a more sustained v.c.

( Dose dependent and Different pharmacological properties)

B- Human Studies

Similar Results

IS IT ALL ABOUT CORONARY DIAMETER?

Effects of Cocaine on Platelets and Thrombostasis

• Intravascular thrombosis:– Coronary– Pulmonary circulation– Peripheral venous circulation– Skin – Renal vasculature

• Composed of platelet rich-aggregates or in the setting of atypical atheromatous lesions

(Minor RL, Ann Int Med 1991)

• Echhorn et al: aortic segment of rabbits, daily IV cocaine (2 mg/kg) 6-12 weeks

• Endothelium produced high levels of thromboxane A2

• In humans: Moliterno et al: intranasal cocaine (2 mg/kg) in the level of plasminogen activator inhibitor

(Moliterno DJ, Am J Med 1994)

• Cocaine 166% in platelet fibrinogen binding

(Kugelmass AD, Circulation 1993)

• Prothrombogenic & Antibibrilolytic

Treatment of cocaine-induced ischemia/infarction

– Benzodiazepines, ASA, & Nitrates

– Ca.ch Blockers

Cocaine and -B ??

-B ( including labetalol), should be avoided during acute cocaine toxicity

• Patients with previously documented coronary insufficiency who present without acute intoxication may be candidates for

-B beginning with low doses

Coronary Atherosclerosis and LV Hypertrophy Associated with

Cocaine

• Kolodgie et al: Autopsy: 495 patients, 6 (1.2%) had total thrombotic occlusion of a major coronary a.

number of adventitial mast cells

• Proliferation of coronary mast cells accelerated atherosclerosis and the promotion of thrombosis

(Kolodgie FD, J Am Coll Cardiol 1991)

• Cocaine also associated with LV mass: substrate for development of ischemia

(Chakko S, J Am Coll Cardiol 1992)

SUMMARY

• Cocaine: Many adverse effects

• CVS and CNS toxicity (among others…)

• Cocaine-induced myocardial ischemia and infarction : multiple and distinct pathogenic mechanisms beyond v.c.

myocardial oxygen demand by HR & BP + in coronary artery diameter (V.C.)

• Directly or indirectly activates platelets

• Shift in endothelial prostaglandin balance milieu that is favorable to thrombosis

• Long-term cocaine use accelerated and often more severe coronary artery atherosclerosis and LV hypertrophy

• 1886: Coca-Cola was introduced as "a valuable brain-tonic and cure for all nervous afflictions".

• Coca-cola was promoted as a temperance drink "offering the virtues of coca without the vices of alcohol".

• Until 1903, a typical serving contained around 60mg of cocaine

• Today, it still contains an extract of coca-leaves only for flavoring since the drug has been removed

• The Coca-Cola Company imports 8 tons from South America each year

My name is Cocaine - call me Coke for shortI entered this country without a passport

Ever since then I've made lots of scum richSome have been murdered and found in a ditch

I'm more valued than diamonds, more treasured than gold Use me just once and you too will be sold

I'll make a schoolboy forget his booksI'll make a beauty queen forget her looks

I'll make a schoolteacher forget how to teach I'll make a preacher not want to preach

I'll take all your rent money and you'll get evicted I'll murder your babies or they'll be born addicted

I'll make you rob and steal and killWhen you're under my power you have no will

Remember my friend my name is " Big C "If you try me just one time you may never be free

I've destroyed actors, politicians and many a hero I've decreased bank accounts from millions to zero

Now that you know me what will you do ?You'll have to decide, It's all up to youThe day you agree to sit in my saddle

The decision is one that no one can straddle Listen to me, and please listen well

When you ride with cocaine you are headed for hell !!!

(Anonymous)