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)
Cocaine Pharmacology by
Route of Administration
ROUTE FORMULA ONSET OF PEAK DURATION
ACTION EFFECT
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
(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
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 Dysrhythmia
Cocaine (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 Myocarditis
1) 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] VASOCONSTRICTION
A- 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 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, It's all up to you
The 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)