DR. Jekyll & Mr. Hyde

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DR. Jekyll & Mr. Hyde. 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 - PowerPoint PPT Presentation

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  • Rami Khouzam, MD

  • Which one of the following tests would be POSITIVE:

    a- BNPb- Troponin Ic- Urine Na+d- UDSe- Urine Ca++ and Mg++

  • INDEX CASE 150 yo AA gentleman presents with:One month hx of LEs edema3 days hx of SOB & DOENon-compliance with meds. (lately)

    PMHx: CHFHTN

  • Meds: Aldactone Lasix Diltiazem

    PE:Remarkable for: RR; 28, P:101, BP: 196/110, O2 Sat: 93% on 4LS1 S2 S4. PMI @ ant. axillary lineBilat. diffuse lung crackles & wheezes2+ edema bilat. in LEs.

  • CXR: Interstitial markings consistent with pulmonary edema Cardiomegaly

  • INDEX CASE 254 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: CHFHTNGout

  • Meds:LasixKClAldactone

    PE:Remarkable for P: 220, RR: 32, BP: 113/60, S1 S2. PMI laterally displaced

  • Adenosine 6mg, 12mg, 12mgHR: 160 then 220 SVT (called @ 2:00 AM from Med. ER)Vagal maneuversAmiodarone 150mg IV over 10 minutes

  • Cardizem 10mg IV

  • HR: 105

  • Hospital day # 4:Left hospital AMACalled @ 3:00 AM from VAPatient found by EMTHR: 180

  • INDEX CASE 345 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 tachycardiaST 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- BNPb- Troponin Ic- Urine Na+d- UDSe- Urine Ca++ and Mg++

  • Index case 1: Hypertensive emergencyIndex case 2: Life-threatening dysrhythmiaIndex case 3: NSTEMI

    Correct answer: dUDS + for COCAINE

  • HISTORY OF COCAINEIn 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 Frdrick-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 Heart1911: 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)

  • Cocaine Pharmacology by Route of Administration(Braunwald)

    ROUTE

    FORMULA

    ONSET OF ACTION

    PEAK EFFECT

    DURATION

    Inhalation

    Crack

    8 seconds

    2-5 minutes

    10-20 minutes

    Intranasal

    Cocaine HCl

    2-5 minutes

    5-10 minutes

    30 minutes

    Intravenous

    Cocaine HCl

    Seconds

    2-5 minutes

    10-20 minutes

    Oral

    Cocaine HCl

    10 minutes

    30-60 minutes

    60 minutes

  • Exploited by humans for at least 5000 years

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

  • Cocaine2nd. 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

  • AdulterantsSugars

    Stimulants (ephedrine, caffeine, amphetamines)

    Quinine, strychnine

    Local anesthetics

  • Review of Simple PhysiologyCaliber 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) SympatheticNorepinephrine 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 drugPharmacological effects:Blocking reuptake of cathecholamines in the presynaptic neurons: Norepinephrine Dopamine and SerotoninCholinergic stimulationBlocking 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 edemaArrhythmiasMyocardial ischemia and infarction

    Acute aortic dissection or rupture to strokeSudden deathAcute reversible myocarditisDilated cardiomyopathy

    (Pasternack, PF Am J Cardiol 1985)

  • Hypertensive EmergenciesPhentolamine 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)

  • DysrhythmiasAtrial 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 COCAINEErythroxylon 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-COCAINETo 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 COCAINEC17H21NO4

    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 PackersCocaine 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 AMI1) 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 StudiesHale 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 coronariesEgashira K, J Clin Invest 1991

  • B- Human StudiesHuman 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 cocaines metabolites, benzoylecgonine, ethyl methyl ecgonine)

    (Brogan WC, Ann Int Med 1992)

  • [II] VASOCONSTRICTION A- Animal StudiesFriedrichs 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 ThrombostasisIntravascular thrombosis:CoronaryPulmonary circulationPeripheral venous circulationSkin 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/infarctionBenzodiazepines, ASA, & NitratesCa.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 CocaineKolodgie 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)

  • SUMMARYCocaine: 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 short I entered this country without a passport Ever since then I've made lots of scum rich Some 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 books I'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 kill When 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, I...