Question 15

College answer

Most candidates did not know mechanism of MDMA toxicity, and many answers were generic and did not address specific therapies. Many candidates listed the features but failed to subsequently address these in the management section.

Discussion

"Mechanism of action" is different to "mechanism of toxicity" for many drugs,  though the Venn diagrams do overlap. For instance, it is not inconceivable that MDMA may be consumed in a dose that has effects that are not necessarily toxic per se, a stance that may vary individually depending on one's level of moral Puritanism. What is presented below hopefully answers the original question as it was asked, as well as the question that wasn't asked but which was clearly still expected to be answered.  

Mechanism of action:

• Blockade of monoamine reuptake transporters (5HTT more than DAT and NET)
• Displacement of monoamines from presynaptic vesicles by acting a substrate for VMAT
• Displacement of monoamines from neurone cytosol by changing cytosolic pH
• Reversal of 5HTT reuptake transporter effect, producing serotonin exocytosis
• Minor contribution from interfering with the activity of CNS monoamine oxidase

Mechanism of toxicity:

• Serotonergic hyperthermia partly due to change in hypothalamic thermopreferendum and to increased muscle activity
• Serotonergic neurotoxicity (excitotoxicity) due to increased excitatory neurotransmitter release and increased neuronal intracellular calcium, leading to mitochondrial damage and apoptosis (plus also the hyperthermia)
• Rhabdomyolysis due to increased locomotor activity as well as the uncoupling of oxidative phosphorylation in skeletal muscle (Rusinyak et al, 2005)
• Cardiovascular toxicity due to sympathomimetic effects (increased afterload, increased myocardial oxygen consumption, subendocardial ischaemia and Takotsubo-like phenomena)

Common features of toxicity:

• Respiratory
  • Tachypnoea, increased minute volume
  • Irregular respiratory pattern
• Circulatory
  • Tachycardia
  • Hypertension (with severe overdose, hypotension)
  • ECG changes suggestive of coronary ischaemia
  • Raised troponin
  • Flushing, brisk capillary refill
• Neurological
  • Agitation, anxiety
  • Hallucinations
  • Psychosis
  • Seizures
  • Hyperthermia
  • Mydriasis
  • Piloerection
  • Hyper-reflexia
• Fluid, electrolyte and endocrine-related
  • Diaphoresis
  • Increased insensate fluid loss though tachypnoea and diaphoresis
  • Hyponatremia through psychogenic increase in water intake
  • Hyperkalemia
  • Metabolic acidosis
• Renal
  • Rhabdomyolysis-induced myoglobinuria
  • Concomitant acute pre-renal failure due to dehydration

Management:

• Decontamination
  • Activated charcoal (if with 1-2 hrs)
  • Laparotomy for body packers
• Control of agitation
  • Benzodiazepines, haloperidol, dexmedetomidine
  • Intubation may be required if there is respiratory depression or if therapeutic cooling must be instituted
• Control hypertension
  • Alpha-antagonist drugs such as phentolamine, or vasodilators such as GTN or sodium nitroprusside.
  • nonselective β-blockers such as labetalol
• Seizure management
  • Benzodiazepines would be first-line.
  • Phenytoin should be avoided
• Temperature management
  • Maintain normothermia
  • Active cooling may need to take place
  • Local guidelines recommend intubation and active cooling with paralysis if the temperature exceeds 39.5°C
  • Antipyretics such as paracetamol are not effective
  • Dantrolene is suggested by some authors
• Electrolyte control
  • Investigate for hyponatremia (i.e. from polydipsia)
  • Investigate for consequences of rhabdomyolysis