1. Amphetamine Toxicity AM Report 8/10/09 Mike Contarino

2. Learning Points 1. Hyperthermia has a broad differential, and drugs of abuse should be kept in mind. 2. Watch for rhabdomyolysis, DIC, and multiorgan failure after hyperpyrexia. 3. Amphetamines result in dopamine, NE, and serotonin release, catecholamine surge!

3. Hyperthermia Differential Sepsis Encephalitis Meningitis/Brain Abscess NMS Malignant hyperthermia Pheochromocytoma Thyroid storm Tetanus EtOH/Benzo withdrawal Salicylate/Li toxicity Sympathomimetic toxicity Serotonin syndrome Anticholinergic Toxicity Hypothalamic Stroke/ Cerebral hemorrhage Status Epilepticus Typhoid fever Catatonia

4. Amphetamines Used and abused since 1930’s after reports of enhanced intellectual performance. Schedule I: MDMA (ecstasy), MDA, MDEA Schedule II: Adderall, Ritalin, etc. OTC: Ma Huang (ephedra), Sudafed

5. Amphetamines Mechanism: Enter neurons via serotonin/dopamine transporters, displace storage vesicles leading to NE, serotonin, and dopamine efflux. Catacholamine release leads to tachycardia, inc SVR, mydriasis, and hyperthermia.

6. Amphetamine increases the concentration of dopamine in the synaptic cleft in 3 ways: (1) bind to the pre-synaptic membrane of dopaminergic neurones and induce the release of dopamine from the nerve terminal (2) interact with dopamine containing synaptic vesicles, releasing free dopamine into the nerve terminal (3) bind to the dopamine re-uptake transporter, causing it to act in reverse and transport free dopamine out of the nerve terminal. Amphetamine can also cause an increased release of noradrenaline into the synaptic cleft.

7. Acute Toxicity May present w/ AMS, agitation, seizures, palpatations, chest pain, n/v/d. Severe Hyperpyrexia Hyponatremia Secondary Conditions:  Rhabdomyolysis  DIC  Renal Failure  Hepatic Necrosis  GI Bleeding  Diarrhea

8. Acute Toxicity Thermoregulatory: up to 43 deg, which leads to rhabdo, DIC, multiorgan failure CV: tachy, inc SVR, HTN, dysrhythmia, late- hypotension Neuro: stimulant effects to coma Electrolyte: Severe hyponatremia, acidosis and rhabdo changes GI: Hepatotoxicity and GI Bleeding MSK: rhabdomyolysis Renal: ARF from rhabdo, DIC, shock Heme: DIC

9. Chronic Toxicity Risk of vasculitis Neuropsychiatric abnormalities  Damage to dopaminergic and serotonergic neurons Cardiomyopathy

10. Learning Points 1. Hyperthermia has a broad differential, and drugs of abuse should be kept in mind. 2. Watch for rhabdomyolysis, DIC, and multiorgan failure after hyperpyrexia. 3. Amphetamines result in dopamine, NE, and serotonin release, catecholamine surge!

11. Sources White, S. Amphetamine Toxicity. Seminars in Resp & Critical Care Medicine Vol 23, 2002. Lanken, PN. UpToDate. Hyperthermia. 2008. Stahl S. Drugs of abuse. Essential Psychopharmacology – neuroscientific basis and practical applications. Cambridge University Press: Cambridge. 1996:332–366.

12. THANKS!!