PharmacologyTier 1Medical Sciences concept

Mechanisms of action of drugs of addiction/dependence (alcohol-GABA, opioids-mu, stimulants-dopamine)

Core concept

Every drug of dependence converges on dopamine release in the nucleus accumbens (mesolimbic reward pathway from the VTA), by one of three routes
- Directly increase dopamine - stimulants
- Disinhibit VTA dopamine neurons by removing GABAergic tone - opioids, alcohol, benzodiazepines, cannabinoids
- Act on the reward pathway indirectly - nicotine via alpha4beta2 nicotinic receptors on VTA neurons

Drug	Primary molecular target
Alcohol	GABA-A positive allosteric modulator + NMDA antagonist
Opioids	mu receptor (Gi) on GABA interneurons -> disinhibition of VTA
Cocaine	Dopamine (and NA/5-HT) reuptake transporter blockade
Amphetamine/methamphetamine	Reverses DAT/VMAT -> dopamine efflux, independent of firing
Nicotine	alpha4beta2 nicotinic ACh receptor on VTA dopaminergic neurons
Benzodiazepines	GABA-A (alpha1) positive allosteric modulator
Cannabis	CB1 receptor (THC partial agonist)
MDMA	5-HT release and reuptake blockade
GHB	GHB and GABA-B receptors
Ketamine	NMDA antagonist

Alcohol - the dual mechanism explains the withdrawal
- Chronic GABA-A potentiation -> receptor downregulation; chronic NMDA antagonism -> NMDA upregulation
- Abrupt cessation -> unopposed glutamatergic excitation -> tremor (6-24 h), seizures (12-48 h), hallucinosis (12-48 h), delirium tremens (48-96 h)
- Cross-tolerance with benzodiazepines is why diazepam is the treatment - substitute at the same receptor and taper
- Give thiamine before glucose - Wernicke encephalopathy
Opioid withdrawal is unpleasant but not usually life-threatening; alcohol and benzodiazepine withdrawal can kill
Tolerance from receptor downregulation and desensitisation; dependence from adaptation; addiction is compulsive use despite harm - three different things

Pharmacotherapy - matched to the mechanism

Substance	Agents
Opioid	Methadone (full mu agonist, long t-half, QT), buprenorphine (partial mu agonist, ceiling effect on respiratory depression, precipitates withdrawal if given too early), naltrexone, naloxone for overdose
Alcohol	Naltrexone (dec reward), acamprosate (NMDA modulator, dec craving), disulfiram (aldehyde dehydrogenase inhibition - aversive)
Nicotine	Varenicline (alpha4beta2 partial agonist - dec craving and dec reward), bupropion, NRT
Benzodiazepine	Slow taper via diazepam substitution
Stimulant	No proven pharmacotherapy - psychosocial

Buprenorphine's partial agonism gives a respiratory ceiling - safer in overdose, but high affinity means it displaces full agonists and precipitates withdrawal; wait for objective withdrawal (COWS) before induction
Naloxone half-life (~1 h) is shorter than most opioids - always observe or infuse after reversal
Long-acting injectable buprenorphine has changed opioid agonist treatment delivery in Australia
Alcohol withdrawal management is symptom-triggered diazepam by CIWA-Ar, plus parenteral thiamine 300 mg daily before any glucose
Prescribed drugs cause the same problem - benzodiazepines, gabapentinoids, opioids for chronic non-cancer pain, quetiapine
Screen for and treat comorbid mental illness; naltrexone is contraindicated with ongoing opioid use

3 more sections, plus exam facts

Premium unlocks every note across every specialty, and the full exam fact library behind it.