Transcript cocaine overdose symptoms

CNS STIMULANTS
CNS Stimulants

Stimulants are a family of compounds chemically
and pharmacologically dissimilar; when ingested in
sufficient dosage they cause a wide variety of
effects related to central stimulation

…….enhance the intensity of our reactions to
external stimuli……

“Heightened awareness, quick thinking, elevated
mood”
CNS Stimulants

Specific stimulant concerned are:

Amphetamine-like drugs

Cocaine

Methylxanthines
Amphetamine-like drugs

Numerous derivatives have been used over the years to
modify a variety of medical conditions
Narcolepsy,
 Hyperkinesis (Attention Deficit Hyperactivity Disorder (ADHD) ),
 Short-term treatment of obesity

In many states are nowadays banned, so their clinical
usage has declined significantly
 However, in many countries, despite the tight control,
amphetamine abuse, is still ranked overall as a very
significant medical problem

Amphetamines
• Amphetamine
• Methamphetamine
– (“speed”, “crack”, smoked form “ice”)
• Methylene-dioxy-amphetamine,
– (MDA)
• Methylene-dioxy-met-amphetamine,
– (MDMA, ecstasy, XTC)
Amphetamines
• Methylphenidate
– used to treat attention deficit disorder
and hyperactivity disorders in children
• Atomoxetine ADHD
• Phenmetrazine
– (no more used to treat obesity)
Amphetamines-like

Modafinil is a non-amphetamine stimulant used in
the treatment of narcolepsy

Cathinone (found in the shrub Catha edulis, or khat),
methcathinone,
and
mephedrone
(4methylmethcathinone) are chemically related drugs
with amphetamine-like effects…..

…..Sold on internet as ‘bath salts”
Mechanism of Toxicity

Amphetamine and related drugs activate the
sympathetic nervous system
1.
Induce peripheral release of catecholamines
2.
Inhibition
of
neuronal
catecholamines, and
3.
Inhibition of monoamine oxidase
4.
Some also cause serotonin release and block
neuronal serotonin uptake.
reuptake
of
Toxicokinetics

All these drugs are well absorbed orally
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Have large volumes of distribution (Vd = 3–33 L/kg)
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They are generally extensively metabolized by the
liver
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Excretion of most amphetamines is highly
dependent on urine pH…….eliminated more rapidly
in an acidic urine
TOXIC DOSES

Low therapeutic index, with toxicity at levels only
slightly above usual doses…BUT high degree of
tolerance

Acute ingestion of more than 1 mg/kg of
dextroamphetamine is considered potentially lifethreatening
Characteristics of amphetamine toxicity grouped by severity
S&S
Severity
Euphoria, restlessness, irritability, insomnia, tremor,
hyperreflexia, sweating, mydriasis
+1
Hyperactivity, confusion, tachypnea, tachycardia,
hypertension, mild fever
+2
Delirium, mania, arrhythmias, hyperpyrexia
+3
All above+ convulsion, coma, circulatory collapse,
death
+4
CLINICAL PRESENTATION

Death may be caused by ventricular arrhythmia,
status epilepticus, intracranial hemorrhage or
hyperthermia

Hyperthermia results from seizures and muscular
hyperactivity (cause rhabdomyolysis) and druginduced vasoconstriction (especially in athletes
abusers prior to race)

The toxic lethal dose varies but has been reported as
20-25mg/kg
CHRONIC EFFECTS
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AMPETAMINE ABUSE INCLUDES:
Weight loss,
Cardiomyopathy,
Pulmonary hypertension,
Dental changes,
Stereotypic behavior (eg, picking at the skin),
Paranoid psychosis
After cessation of habitual use, patients may
experience fatigue, hypersomnia, hyperphagia, and
depression lasting several days.
Treatment
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ABC
Treat agitation, seizures, coma, and hyperthermia if
they occur
Continuously monitor the temperature, other vital
signs, and the ECG for a minimum of 6 hours
Agitation: benzodiazepines usually satisfactory.
Antipsychotics (haloperidol, olanzapine) may be
needed
Hypertension best treated with sedation. If not
effective, a parenteral vasodilator (phentolamine or
nitroprusside)
Treatment

Treat tachyarrhythmias with propranolol or esmolol!!

Decontamination. Administer activated charcoal orally if
conditions are appropriate. Gastric lavage is not
necessary after small to moderate ingestions
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Dialysis and hemoperfusion are not effective
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Renal elimination may be enhanced by urine
acidification……BUT not recommended....may aggravate
nephrotoxicity of myoglobinuria
Cocaine
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Cocaine is one of the most popular drugs of abuse
May be sniffed (snorted), smoked, or injected IV
Occasionally injected combined with heroin
("speedball“)
Purchased on the street may contain adulterants
(lidocaine, benzocaine, caffeine, methamphetamine,
ephedrine, and phencyclidine)
Most contains levamisole, an antiparasitic drug that
can cause agranulocytosis
Mechanism of toxicity

The primary actions are local anesthetic effects,
CNS stimulation, and

Inhibition of neuronal uptake of catecholamines

Results in a state of generalized sympathetic
stimulation very similar to that of amphetamine
intoxication
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Has also some affinity to the DAT and SERT
Toxicokinetics
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Well absorbed from all routes, local anesthetic toxicity
after mucosal application
Smoking and IV injection produce maximum effects
within 1–2 minutes,
Oral or mucosal absorption may take up to 20–30
minutes
Elimination by metabolism and hydrolysis, T1/2 ~60
minutes
With ethanol, it is transesterified to cocaethylene…..
similar pharmacologic effects but longer T1/2
Cocaine Toxicity
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Variety of S & S….
Euphoria followed by anxiety, agitation, delirium,
psychosis, muscle rigidity or hyperactivity, and
seizures
Hyperthermia, intracranial hemorrhage, HTN and
coma, hypovolemia
CV toxicity: tachycardia, hypertension with
hemorrhagic stroke, fibrillation
Most common cause of drug-induced stroke
Cocaine Toxicity
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Death due to arrhythmia, status epilepticus, intracranial
hemorrhage, or hyperthermia
Hyperthermia is usually caused by seizures, muscular
hyperactivity, or rigidity…..
…….may cause rhabdomyolysis, myoglobinuric renal failure
Following an initial period of HTN….blood pressure falls
and cardiac depression ensues
Respiratory system: initial stimulation resulting in
tachypnea followed by respiratory arrest…..cause of death!
Management
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ABC
Treat coma, agitation, seizures, hyperthermia,
arrhythmias,
Tachycardia,
and
Ventricular
dysrhythmias, and hypotension if they occur
Benzodiazepines are a good choice for initial
management of hypertension and tachycardia
associated with agitation
Hyperthermia must be controlled
Cocaine-induced psychosis: neuroleptic agents or
lithium
Management
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
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Decontamination

Activated charcoal….if necessary gastric
lavage

Most cocaine use occurs by intravenous or by
nasal routes……
Dialysis is not effective
Acidification of the urine not effective and may
aggravate myoglobinuric renal failure
Methylxanthines

Three alkaloids
present naturally
 Caffeine
 Theophylline
 Theobromine
Caffeine
 Most widely used psychoactive substance!
 Present in coffee, tea, colas, chocolate, and
 Many OTC / prescription oral medications (injectable
caffeine sodium benzoate occasionally used for
neonatal apnea)
Caffeine
 Occasionally
(MDMA)
combined
with
other
stimulants
 Has a wide therapeutic index, BUT there are cases of
accidental, suicidal, and iatrogenic intoxication, some
resulting in death
Physiologic effects
Caffeine
 Stimulate CNS (sleep suppressant)
 Stimulate cardiac function
 Anorectant
 Promote gastric acid secretion
 Induce diuresis
 Caffeine used as co-analgesic
Mechanism of toxicity
1.
2.
3.
nonselective inhibition of adenosine receptors….variety of
response……
Bronchial smooth muscle relaxation, peripheral
vasoconstriction, and increase cardiac pacemaker
discharge
Promote
release
of
endogenous
catecholamines….positive inotropic and chronotropic
cardiac activity
Directly stimulate the respiratory and vasomotor center
of the brain to increase rate and depth of breathing
Pharmacokinetics
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Caffeine is rapidly and completely absorbed orally (Vd 0.7–
0.8 L/kg)
Metabolized in the liver by cytochrome P-450 (CYP),
Metabolism is inhibited by oral contraceptives, cimetidine,
norfloxacin, and alcohol
Tobacco (and marijuana) smoking accelerates caffeine
metabolism
Elimination half-life 4–6 hours (range from 3 hours in
healthy smokers to 10 hours in nonsmokers)
Toxic dose
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The reported lethal oral dose of caffeine is 10 g
In children, ingestion of 35 mg/kg…..moderate toxicity
Coffee contains 50–200 mg (tea, 40–100 mg) of
caffeine/cup
No-Doz and other sleep suppressants contain about
200 mg per tablet
"Thermogenic" energy beverages (eg, Red Bull), bars,
capsules, tablets, or liquid drops, contain 40–200 mg
of caffeine per serving
Clinical Manifestations
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The earliest symptoms of ACUTE caffeine poisoning
are usually anorexia, tremor, and restlessness,
followed by nausea, vomiting, tachycardia, and
agitation
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With serious intoxication: delirium, seizures,
supraventricular and ventricular tachyarrhythmias,
Clinical Manifestations

Metabolic derangements due to catecholamines
stimulation, renal wasting, and vomiting:
hypokalemia and hyperglycemia

Ingestion of caffeine-containing diet is associated
with sudden death in people with bulimia or
laxative abuse….most likely due to aggravation of
hypokalemia
Clinical Manifestations

Hypotension is caused by excessive beta2-mediated
vasodilation….characterized by a low diastolic
pressure and a wide pulse pressure

Chronic high-dose caffeine intake “caffeinism”
causes
nervousness,
irritability,
anxiety,
tremulousness, muscle twitching, insomnia,
palpitations, and hyperreflexia
Management

Maintain an open airway and assist ventilation if
necessary
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Treat seizures with diazepam, lorazepam

Treat hypotension and tachyarrhythmias with
propranolol, or esmolol
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If vasopressors
phenylephrine
are
required,
vasopressin
or
Management

Hypokalemia usually resolves without Tx. but
in severe poisonings may need treatment

Monitor ECG and vital signs for at least 6 hours
after ingestion
Management

Activated charcoal: extremely effective in
limiting gut absorption
Seriously intoxicated patients:
 ….with multiple seizures, tachyarrhythmias, or
intractable
hypotension
may
require
hemodialysis or charcoal hemoperfusion

Theophylline
 Methylxanthine used for the treatment of asthma
 Mechanism of toxicity:
 Exact mechanism not known….BUT:
i.
Antagonist of adenosine receptors, and
ii. Inhibits phosphodiesterase at high levels, increasing
intracellular cAMP
iii. Also known to release endogenous catecholamines
at therapeutic concentrations
Pharmacokinetics

Absorption may be delayed with sustained-release
preparations
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The normal elimination half-life is 4–6 hours
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May be doubled by illnesses (eg, liver disease,
congestive heart failure, influenza) OR
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Interacting with drugs (eg, erythromycin,
cimetidine) that slow hepatic metabolism
Toxic Levels
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Serum levels are essential for diagnosis and
determination of emergency treatment
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After acute oral overdose, obtain repeated levels
every 2–4 hours
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Levels <80–100 mg/L after acute overdose usually
are not associated with severe symptoms (mild)

With chronic intoxication, severe toxicity may
occur with levels of 40–60 mg/L
Clinical Presentation

Acute single overdose: due to suicidal attempt, or
accidental childhood ingestion but also accidental or
iatrogenic misuse :
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

Vomiting (sometimes hematemesis), tremor, anxiety,
and tachycardia
Metabolic effects include pronounced hypokalemia,
hypophosphatemia, hyperglycemia, and metabolic
acidosis
Severe intoxication (levels > 90–100 mg/L):
hypotension, ventricular arrhythmias, and seizures
Clinical Presentation

Chronic intoxication: If doses administered over
time or intercurrent illness or interacting drug
interferes with the hepatic metabolism
 Vomiting
may occur but not as common as in acute
overdose
 Tachycardia is common, but hypotension is rare
 No hypokalemia, no hyperglycemia
 Seizures may occur with lower serum levels (eg, 40–60
mg/L)
Treatment
 Maintain
an open airway and assist ventilation if
necessary
 Treat seizures, arrhythmias, and hypotension if they occur
 Tachyarrhythmias and hypotension are best treated with
propranolol or esmolol
 Hypokalemia due to intracellular movement of potassium
(does not reflect total body deficit)….usually resolves
spontaneously
 Monitor vital signs, ECG, and serial theophylline levels for
at least 16–18 hours after a significant oral overdose
Treatment
Decontamination.
Administer activated charcoal
orally if conditions are appropriate
Consider repeated doses of activated charcoal and
WBI after a large ingestion of a sustained-released
formulation
Enhanced
elimination. Hemodialysis, or charcoal
hemoperfusion are effective (small Vd 0.5 L/kg),
It is protein-bound at therapeutic concentrations, BUT
the free fraction dominates at higher levels
DEXTROMETHORPHAN
(DXM)
Dextromethorphan
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Common antitussive agent found in many OTC
cough and cold preparations
Found in combination products containing
antihistamines, decongestants, ethanol, or
acetaminophen
Structurally related to opioids (codeine), but no
activity at mu or kappa receptors and not typical
opioid syndrome in overdose
Mechanism of toxicity
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Metabolized in the liver by the cyt. P-450 to
dextrorphan
Antagonize
N-methyl-d-aspartate
(NMDA)
glutamate receptors (dextrorphan is more potent
and responsible for the psychoactive effects)
Extensive metabolizers are more likely to
experience the “desirable” psychoactive effects
with
recreational
use….hallucination
and
dissociation from reality
Mechanism of toxicity

Dextromethorphan and dextrorphan inhibit reuptake
of serotonin and may lead to seratonin syndrome
…..especially with SSRI or MAOI

Inhibits adrenergic neurotransmitter reuptake in the
peripheral and central nervous system

Serotoninergic effects, as well as NMDA glutamate
receptor inhibition, may explain the acute and
chronic abuse potential of dextromethorphan
Clinical presentation
 Mild
to moderate intoxication. N, V, nystagmus,
mydriasis or miosis, tachycardia, HTN, dizziness,
lethargy, agitation, ataxia, euphoria, dysphoria, and
auditory and visual hallucinations
 Severe
poisoning. Disorientation, stupor, psychosis,
dissociative
hallucinations,
seizures,
coma,
hyperthermia, respiratory depression, pulmonary and
cerebral edema, and death can occur
Clinical presentation
 Serotonin
syndrome. Severe hyperthermia, muscle
rigidity, altered mental status, and hypertension
 Withdrawal
syndrome. Abdominal pain, vomiting,
diarrhea, tachycardia, hypertension, depression,
dysphoria, insomnia, tremor, myalgias, restlessness,
and drug craving have been reported
Treatment
 Most
patients with mild symptoms (ie, restlessness,
ataxia, or mild drowsiness) can be observed for 4–6 hours
 Maintain an open airway and assist ventilation if needed
 Treat seizures and coma if they occur
 Rarely, DXM poisoning is associated with profound coma
and, respiratory depression may respond to naloxone
 Decontamination. Administer activated charcoal orally if
conditions are appropriate
 Enhanced elimination. The Vd is very large, and there is
no role for enhanced removal procedures