Pharmacology of Illicit Drugs and Anaesthetic Interactions

Introduction

• Illicit drug use presents significant challenges in perioperative care through direct pharmacological effects, cardiovascular complications, withdrawal syndromes, and drug-drug interactions.
• Understanding these mechanisms is essential for safe anaesthetic management.

Stimulants

Cocaine

Mechanism of Action:

• Cocaine blocks presynaptic reuptake of noradrenaline, dopamine, and serotonin, causing accumulation of catecholamines at nerve terminals.
• It also produces local anaesthetic effects through voltage-gated sodium channel blockade.
• Peak plasma concentration occurs 30-60 minutes after nasal insufflation, with a half-life of 60-90 minutes.
• Metabolism occurs via plasma and hepatic cholinesterases to benzoylecgonine and ecgonine methylester.

Cardiovascular Effects:

• Hypertension and tachycardia from sympathetic stimulation
• Coronary vasospasm causing myocardial ischaemia and infarction
• Increased myocardial oxygen consumption
• Arrhythmias including ventricular tachycardia and fibrillation
• Acute left ventricular dysfunction
• Accelerated atherosclerosis with chronic use
• QT prolongation at toxic doses

Anaesthetic Interactions:

• The combination of cocaine with volatile anaesthetics (particularly halothane) increases arrhythmia risk through myocardial sensitisation to catecholamines.
• Direct-acting vasopressors (phenylephrine, adrenaline) produce exaggerated hypertensive responses due to catecholamine accumulation.
• Indirect-acting agents (ephedrine) may demonstrate reduced efficacy after acute use due to catecholamine depletion, though unpredictable responses occur.
• Succinylcholine metabolism is prolonged in cocaine users due to plasma cholinesterase inhibition, potentially extending paralysis.
• Ester local anaesthetics compete for the same metabolic pathway, increasing toxicity risk.

Acute Intoxication Management:

• Benzodiazepines are first-line for agitation and seizures.
• Beta-blockers are relatively contraindicated due to unopposed alpha-stimulation causing paradoxical hypertension and coronary vasoconstriction.
• Alpha-blockers (phentolamine 1-5 mg IV) or combined alpha-beta blockers (labetalol) are preferred for hypertensive crises.

Amphetamines and Methamphetamine

Mechanism of Action:

• Amphetamines increase synaptic catecholamine concentrations through multiple mechanisms: stimulating release from presynaptic terminals, inhibiting reuptake, and inhibiting monoamine oxidase.
• Methamphetamine crosses the blood-brain barrier more readily than amphetamine due to increased lipophilicity.
• Half-life ranges from 9-15 hours for methamphetamine, with renal elimination heavily dependent on urine pH.

Cardiovascular Effects:

• Dose-dependent hypertension and tachycardia
• Cardiomyopathy with chronic use
• Pulmonary hypertension
• Increased risk of dissection and intracerebral haemorrhage
• Arrhythmias including supraventricular and ventricular dysrhythmias

Anaesthetic Interactions:

• Similar to cocaine, exaggerated responses to direct-acting vasopressors occur, while indirect-acting agents become unreliable.
• Chronic amphetamine use depletes catecholamine stores, potentially causing severe hypotension during induction.
• Volatile anaesthetics sensitise the myocardium to circulating catecholamines, increasing arrhythmia risk.
• MAC requirements may be decreased acutely (due to increased synaptic catecholamines providing analgesic and anaesthetic effects) but increased with chronic use due to receptor downregulation.
• Caution with monoamine oxidase inhibitors in chronic users, though most clinical MAOIs used therapeutically carry higher risk.

MDMA (3,4-Methylenedioxymethamphetamine)

Mechanism of Action:

• MDMA combines amphetamine-like effects with serotonergic activity.
• It stimulates release and inhibits reuptake of serotonin, noradrenaline, and dopamine.
• Peak effects occur 1-2 hours post-ingestion with a half-life of 8-9 hours.

Unique Toxicities:

• Serotonin syndrome: hyperthermia, rigidity, autonomic instability, altered mental status
• Syndrome of inappropriate antidiuretic hormone secretion (SIADH) causing hyponatraemia (often exacerbated by excessive water consumption)
• Hyperthermia from increased metabolic rate, muscle activity, and impaired thermoregulation
• Hepatotoxicity and acute liver failure
• Bruxism and jaw clenching

Anaesthetic Considerations:

• Risk of serotonin syndrome when combined with other serotonergic agents including tramadol, pethidine, fentanyl (theoretical), and linezolid.
• Symptoms include hyperthermia, muscle rigidity, hyperreflexia, clonus, and autonomic instability.
• Management involves benzodiazepines, active cooling, and cyproheptadine (4-8 mg oral/NG, repeated hourly to maximum 32 mg/day) as a serotonin antagonist.

CNS Depressants

Heroin and Opioids

Mechanism of Action:

• Heroin (diacetylmorphine) is a prodrug rapidly deacetylated to 6-monoacetylmorphine and morphine.
• It crosses the blood-brain barrier more readily than morphine due to increased lipophilicity.
• Effects mediated through mu, delta, and kappa opioid receptors.

Chronic Use Adaptations:

• Opioid tolerance develops rapidly, requiring higher doses for equivalent effect
• Tolerance to respiratory depression develops more slowly than analgesia
• Hyperalgesia may develop with chronic use
• Physical dependence with characteristic withdrawal syndrome

Anaesthetic Implications:

• Significantly increased opioid requirements for postoperative analgesia.
• Baseline opioid consumption should be maintained perioperatively to prevent withdrawal.
• Regional techniques and multimodal analgesia become particularly important.
• Risk of acute opioid toxicity in non-tolerant individuals or with variable illicit drug purity.
• The classic triad includes decreased consciousness, respiratory depression, and miosis.
• Naloxone reversal should be carefully titrated (40-80 mcg IV boluses) to avoid precipitating acute withdrawal while restoring adequate ventilation.
• Duration of action of naloxone (30-45 minutes) may be shorter than the opioid being reversed, requiring repeated dosing or infusion (typically 2-10 mcg/kg/hour).
• Patients on buprenorphine maintenance therapy present unique challenges.
• Buprenorphine is a partial mu agonist with high receptor affinity and slow dissociation, making acute pain management difficult.
• Options include continuing buprenorphine and adding full agonists (requiring higher doses), temporarily ceasing buprenorphine 72 hours preoperatively, or using regional techniques.

Benzodiazepines

Mechanism of Action: Benzodiazepines enhance GABA-A receptor function by increasing frequency of chloride channel opening, causing hyperpolarisation and reduced neuronal excitability.

Chronic Use Effects:

• Cross-tolerance develops with alcohol and other GABAergic agents.
• MAC requirements may be increased due to receptor downregulation.
• Paradoxical reactions (agitation, aggression) are more common in those with chronic use.

Withdrawal Syndrome:

• Occurs 1-7 days after cessation depending on half-life.
• Features include anxiety, tremor, insomnia, perceptual disturbances, seizures, and potentially fatal delirium.
• Perioperative continuation or substitution with equivalent doses of long-acting benzodiazepines is essential.
• Diazepam 5 mg is approximately equivalent to lorazepam 0.5 mg or alprazolam 0.5 mg.

Cannabis

Mechanism of Action:

• Δ9-tetrahydrocannabinol (THC) is the primary psychoactive component, acting as a partial agonist at CB1 (central nervous system) and CB2 (immune system) cannabinoid receptors.
• Highly lipophilic with accumulation in adipose tissue.
• Half-life of 20-30 hours but detectable in urine for weeks with chronic use.

Cardiovascular Effects:

• Biphasic response: initial tachycardia and increased cardiac output (increased sympathetic activity and catecholamine release) followed by hypotension with orthostatic effects (peripheral vasodilation).
• Chronic use associated with coronary vasospasm and myocardial infarction in susceptible individuals.

Respiratory Effects:

• Smoking causes airway inflammation, increased mucus production, and bronchospasm.
• Chronic use associated with bullous lung disease.
• Despite this, acute use causes bronchodilation through smooth muscle relaxation.

Anaesthetic Interactions:

• Increased sedative and analgesic requirements in chronic users due to CB1 receptor downregulation and cross-tolerance with opioids.
• Propofol requirements may be increased.
• Some evidence suggests increased pain sensitivity (hyperalgesia) with chronic cannabis use.
• Cannabis smoke contains similar carcinogens to tobacco smoke, warranting similar perioperative respiratory precautions.
• Perioperative abstinence from smoking recommended for at least 8 weeks to optimise wound healing and reduce respiratory complications.

Synthetic cannabinoids ("Spice", "K2") are more potent CB1 agonists causing more severe toxicity including seizures, acute kidney injury, and cardiovascular collapse.

Hallucinogens

Lysergic Acid Diethylamide (LSD)

Mechanism of Action:

• Serotonin 5-HT2A receptor agonist with effects on perception, mood, and cognition.
• Peak effects 2-4 hours post-ingestion with duration of 8-12 hours.
• Half-life approximately 3-4 hours.

Anaesthetic Implications:

• Acute intoxication may present as agitation, tachycardia, hypertension, and mydriasis.
• Serotonin syndrome risk when combined with serotonergic drugs.
• Management primarily supportive with benzodiazepines for agitation.
• No significant direct interactions with anaesthetic agents, though anticholinergic agents may exacerbate delirium.

Chronic use rarely causes physiological dependence but psychological effects may complicate consent and cooperation.

Ketamine (Recreational Use)

While a pharmaceutical agent, illicit ketamine use is increasingly common. Chronic recreational use causes:

• Ketamine bladder syndrome: cystitis with ulceration, reduced capacity, and fibrosis
• Hepatotoxicity with elevated transaminases
• Tolerance requiring higher doses for anaesthesia
• Cognitive impairment with chronic use

Gamma-Hydroxybutyrate (GHB)

Mechanism of Action:

• GABA-B receptor agonist and GHB receptor agonist.
• Produces euphoria, sedation, and amnesia.
• Narrow therapeutic window with rapid onset (15-30 minutes) and duration of 3-4 hours.

Clinical Presentation:

• Dose-dependent effects from mild sedation to coma with respiratory depression.
• Characteristic rapid recovery (2-4 hours) with sudden emergence.
• Seizure-like myoclonic movements common but generally not true seizures.

Anaesthetic Management:

• Additive respiratory depression with opioids, benzodiazepines, and volatile anaesthetics.
• No specific reversal agent exists.
• Supportive care with airway protection until emergence.
• Acute withdrawal in chronic users causes severe agitation, delirium, and autonomic instability, requiring benzodiazepine management.

Perioperative Approach to Substance Users

Preoperative Assessment

Focused history should determine:

• Last use (timing and amount)
• Route of administration (infection risk with IV use)
• Duration and frequency of use
• Previous anaesthetic complications
• Current withdrawal symptoms or risk thereof

Laboratory Considerations

Consider checking:

• Electrolytes (particularly sodium in MDMA users)
• Liver function (chronic alcohol, MDMA, cocaine, volatile substance abuse)
• Renal function (cocaine, amphetamines, synthetic cannabinoids)
• ECG (prolonged QT with cocaine, MDMA, methadone)
• Troponin if recent stimulant use with chest pain

Drug Testing

• Urine drug screening detects recent use but doesn't correlate with current intoxication or impairment.
• Cocaine metabolites detectable for 2-4 days, cannabis for days to weeks, amphetamines for 2-3 days, opioids for 1-3 days depending on agent.
• Synthetic drugs may not appear on standard screening.

Elective Surgery Timing

Where possible, delay elective procedures:

• 24-48 hours after stimulant use (cocaine, amphetamines) to allow cardiovascular system stabilisation
• Until acute intoxication resolved for any substance
• Optimise treatment for substance use disorder prior to surgery

Clinical Relevance

Understanding illicit drug pharmacology is crucial for safe anaesthetic practice. Key principles include:

Cardiovascular instability is common with stimulants requiring careful haemodynamic monitoring and judicious use of vasopressors, direct-acting agents preferred over indirect-acting in acute intoxication but both may produce unpredictable responses.

• Analgesic requirements are typically increased in chronic opioid and cannabis users requiring aggressive multimodal analgesia and early pain service involvement.
• Baseline opioid requirements must be maintained to prevent withdrawal.

Withdrawal syndromes particularly from opioids, benzodiazepines, and alcohol require prophylaxis and treatment as they worsen surgical outcomes and may be life-threatening.

Serotonin syndrome risk necessitates caution when combining serotonergic anaesthetic agents in patients using MDMA, LSD, or cocaine.

MAC requirements and sedative drug dosing may be altered bidirectionally depending on acute versus chronic use patterns and specific substance involved.

Regional anaesthesia techniques become particularly valuable in this population by reducing general anaesthetic and opioid requirements while providing superior analgesia.

A non-judgmental approach facilitating honest disclosure optimises patient safety and perioperative care planning.