cocaine toxicity
Week 8 content – Sympathomimetic toxidrome:
In general sympathomimetic toxidrome is one of adrenergic excess.
Sympathomimetic drugs like cocaine and methamphetamine cause a sharp increase in the amounts of adrenaline, noradrenaline and dopamine circulating in the blood stream. Otherwise known as a catecholamine surge which heavily stimulates the fight or flight side of the peripheral nervous system.
Drugs or toxins:
Range and intensity of a sympathomimetic toxidrome is influenced by whether the responsible drug primarily exhibits adrenergic, dopaminergic or serotonergic effects.
Medications:
- Beta adrenergic receptor agonists (salbutamol)
- Catecholamines (adrenaline, dopamine, noradrenaline, phenylephrine).
- Indirect sympathomimetics (dexamphetamine, lisdexamfetamine, methylphenidate, phentermine, pseudoephedrine)
- Monoamine oxidase inhibitors
- SNRIS
- Xanthines (caffeine. Theophylline)
Illicit stimulants:
- Amphetamines and their derivatives (methamphetamine, MDMA)
- Beta adrenergic receptor agonists (clenbuterol).
- Cocaine
- Novel psychoactive substances.
Clinical presentations:
- CV effects – tachycardia, hypertension, arrhythmias, ACS, hypotension, MI, myocardial depression, pulmonary oedem.
- CNS effects – Excitation, anxiety, euphoria, agitation, tachypnoea, delirium.
o Acute behaviour disturbances (mainly with amfetamines – aggression, violence, psychosis)
o Thrombotic and haemorrhagic strokes and intracranial haemorrhage.
- Neuromuscular effects – hyperreflexia, tremor.
- Autonomic effects – hyperthermia, sweating, mydriasis, flushing, pallor
- Metabolic effects – hypokalaemia, hyperglycaemia, lactic acidosis.
- GI effects – nausea, vomiting, diarrhoea.
- Dilated pupils, dry mucus membrane, sweating and fever, tachycardia and hypertension
How to determine sympathomimetic syndrome from anticholinergic syndrome?
- Skin!!
- Anticholinergic syndrome usually leads to dry skin but sympathomimetic syndrome leads to sweating.
General treatment:
Aim – gain prompt control of severe hyperthermia, agitation or delirium.
Benzos are the preferred treatment 10mg IV over 2-5 mins every 10 mins until sedation max 30mg/event or 60mg/24 hours.
- If agitation is still severe with signs of excited delirium use droperidol.
- If hypertension persists despite sedation à IV GTN should be considered.
Hyperthermic pts – despite having raised BP and tachycarida are usually volume depleted therefore COLD IV fluid therapy.
BB generally CI due to risk of unopposed alpha agonism à potentially cause heart attack.
Cocaine Toxicity:
Cocaine is currently an approved pharmaceutical used for topical anaesthesia in treating cutaneous lacerations or during otolaryngology and ocular procedures as a vasoconstrictor an aesthetic.
Cocaine toxicity causes a potentially life threatening sympathomimetic syndrome with sodium channel blockage. Between 2000-2021 there were 884 cocaine related deaths in Australia.
Different preps:
- Cocaine hydrochloride powder or paste – processed from the alkaloid extracted from cocoa leaves. Cannot be smoked
- Cocaine base (crack cocaine) or free base: created by combining cocaine hydrochloride with an alkaline substance. It is heat stable and is therefore smokable.
Mechanism of toxicity:
Cocaine inhibits the reuptake of biogenic amines particularly affecting serotonin and the catecholamines dopamine, norepinephrine and epinephrine.
Although its reuptake blockade effect is insufficicent to account for its clinical manifestations in toxicity. Increase in psychomotor agitation, seizures and hyperthermia effects most likely result from an interaction between cocaine and excitatory amino acids.
Toxicodynamics:
- Reversible sodium channel blocking effects in peripheral nerves.
- Blockade of presynaptic catecholamine re uptake
o Stimulates alpha 1 and 3, beta 1 and 2 adrenergic receptors through increased levels of norepinephrine.
- Blockade of myocardial fast sodium channels:
o Inhibits the rapid inward sodium current responsible for phase 0 depolarization à QRS widening
o Also blocks cardiac potassium channels resulting in QT prolongation
- CNS excitation:
o Increases the concentration of the excitatory amino acids glutamate and aspartate in the brain.
o Euphoric effects are from the inhibition of neuronal serotonin reuptake in the CNS.
o Addiction has been linked to effects on dopamine reuptake.
- Haematological:
o Activated human platelets results in platelet aggregation.
o In the absence of injuring cocaine enhances the activity of plasminogen activator inhibitor type 1 therefore impairing clot lysis.
Toxicokinetic:
- Rapidly absorbed after all routes of exposure
- Highly lipid soluble, 90% protein bound.
Metabolism- complex but has 3 major pathways:
- Undergoes N-demethylation in the liver to form norcocaine (which readily crosses the BBB and can produce similar effects to cocaine).
- Roughly half the cocaine dose is hydrolysed to form benzoylecgonine (BE) which is a potent vasoconstrictor
- Plasma cholinesterase (PChE) and other esterases metabolise cocaine into ecgonine methyl ester (EME) ( a vasodilator, sedative and anticonvulsant and may protect against lethal doses of cocaine)
- Ethanol uniquely interacts with cocaine via a transesterification reaction producing ethylbenzoylecgonine (ethyl cocaine)
Elimination – 1% excreted unchanged in the urine.
- Metabolites may persist in the blood and urine for up to 36 hours.
Risk assessment:
Toxic dose is highly variable:
- 1-3mg/kg – safe local anaesthetic dose
- 20-30mg- usual recreational dose when a line of cocaine is snorted.
- >1g is potentially lethal.
Potentially life threatening complications symptoms – hyperthermia, headache, cardiac conduction abnormalities, focal neurological signs or chest paain.
Concomitant ethanol use can enhance the effects of cocaine.
Those with pre existing CV conditions are at an increased risk of toxicity.
Pregnancy and lactation:
- Teratogenic – increased incidence of miscarriage and foetal demise.
- Excreted in breast milk – infant intoxication and withdrawal syndromes are possible.
Secondary risks:
Levamisole: - an antihelminthic agents used as a cutting agent for cocaine. Toxicity of levamisole include agranulocytosis and vasculitis.
Clinical features:
Typically presents as sympathomimetic toxidrome and increased hR and BP in a dose dependent manner, enhancing arousal, vigilance, alertness and inducing euphoria and self confidence.
Neurological:
- Headaches
- Euphoria
- Anxiety, dysphoria, agitation and aggression
o Psychomotor agitation can lead to hyperthermia when peripheral vasoconstriction hinders the body’s ability to dissipate heat generated by continuous agitation.
- Paranoid psychosis with visual and tactile hallucination.
- Hyperthermia, rigidity and myoclonic movements.
- Seizures.
- Focal neurological deficits and coma – possible ue to TIA, ischaemic stroke and intracerebral haemorrhage.
Cardiovascular:
- Tachycardia and hypertension my be severe.
- Arrhythmia, QRS widening, supraventricular
- Chest pain indicative of ACS
- QT prolongation
- Acute pulmonary oedema.
Peripheral sympathomimetic
- Hyperthermia
- Muscle fasciculations, sweating and tremor, rhabdomyolysis
- Mydriasis
Complications:
- Hyperthermia induced rhabdomyolysis, renal failure and cerebral oedema
- Aortic and carotid dissection
- Subarachnoid and intracerebral haemorrhage.
- Ischaemic colitis
Coke nose: caused by excessively snorting of coke, occurs gradually over may years. Arises when blood supply is cut off to the nasal membranes
Symptoms – sinus issues, runny nose all the time, rotting ski on the bottom of the nose, flattened or collapsed nasal bridge, disfiguration on the nose, loss of smell, pain in the nasal area.
Disfiguration of the nose can also be severe and may require plastic surgery to repair.
Key investigations:
- UEC- renal failure and hyponatraemia
- ECG, CK and troponin – ACS, QT prolongation and rhabdomyolysis.
- CXR- aortic dissection, aspiration
- CT head – intracranial haemorrhage
- BGL – especially if seizing.
- Serum or urine cocaine levels – not useful for management but can help suspected drug addiction cases etc.
Treatment:
Resuscitation, supportive care and monitorint:
- QRS widening on ECG – Sodium bicarb IV every 3-5 mins (monitor potassium levels due to intracellular shift)
- Chest pain and ACS:
o May resolve with titrated IV benzos for agitation or hypertension.
o Aspirin 300mg STAT
o GTN if no response to benzos
o CCBs as last line
o AVOID BB as they can worsen vasoconstriction.
- Hypertension an tachycardia:
o IV benzos if agitated
o If refractory to sedations – GTN
o AVOID BB
- Seizures and agitated delirium:
o Correct hypoglycaemia if required with IV glucose.
o 5-10mg diazepam IV over 2-5 mins repeat in 5 mins id seizure continues.
o Consider Sodium bicarb if evidence of sodium channel blockage.
o Avoid phenytoin.
- Hyperthermia
o Benzos for sedation and cold IV fluid therapy.
Decontamination – AC only indicated in body packers or following intubation.
Body packer – individual who smuggles large quantities of illicit drugs in securely sealed packages inside them.
Body stuffer – individual who hurriedly ingests illicit drubs in insecure packages to avoid arrest.