Psychostimulants

Lesson 19

Psychostimulants Cocaine

alkaloid from coca plant Amphetamines (synthetics)

similar fx & mechanismsall related to ephedrine (ephedra)dl-amphetamine: methamphetamineMDMA (Ecstasy) ~

Cocaine: Local Anesthetic

Pharmacokinetics Inject SC

Half-life: 1 hr Numbing < 2 min Peak effects: 15-20 minutes

Pharmacodynamics Blocks Na+ channels Constricts blood vessels ~

Cocaine: Psychostimulant Pharmacokinetics p.o.

ineffective for cocaine effective for amphetamine analogs onset: 30 minutes / peak 2-3 hrs

Intranasal onset 3-4 minutes peak effects: 15-20 minutes ~

CocainePharmacokinetics

Inhalation (smoking) & IV injection Onset: < 2 min

For both routes Euphoria Crash Craving

Powerful positive RFT short delay high magnitude ~

Pharmacokinetics: Metabolism

Cocaine By cholinesterases Blood & Liver Half-life: 1 hr

Amphetamines In liver, much excreted unchanged Half-life: 7-30 hrs ~

Tachyphylaxis brief & transient tolerance reuse within minutes - hours

Tolerance Lower doses

Sensitization repeated use over days ~

Psychostimulant Pharmacokinetics

Psychostimulant Pharmacology

Indirect agonists: DA, NE, 5-HT

DA - reinforcing effects in nucleus accumbens Euphoria

Rate of change of blood levels Amphetamine

Primary effects on reuptake Also NT & MAO function ~

Physiological Effects

Sympathomimetic Heart

Low doses: decrease HR Moderate: HR & BP High: cardiac arrhythmia, failure

Body temperature Low doses: decrease moderate & high: increase ~

Physiological Effects

Restlessness Sleep: interferes with REM Vomiting Breathing is facilitated Depresses cortical activity ~

Psychostimulant Neurotoxicity

DA neurotoxicity; DA transporters amphetamine methamphetamine

5-HT neurotoxicity methamphetamine MDA MDMA (Ecstasy)

Single high dose ~

Psychotomimetic Effects

Prolonged use Schizophrenia-like psychosis

Paranoia Hallucinations: parasitosis delusions

Methamphetamine earlier developing may persist for days, weeks ~

Lethality

Cocaine Oral: 500 mg Nasal: 150-300 mg

Amphetamine/Methamphetamine toxic effects: 15 mg in novices lethal 500-1700 mg

Inhalation (smoked): much lower ~

Early•Agitation•Depression•Anorexia•High Craving

Middle•Depression •Fatigue•Insomnia•No craving

Late•Exhaustion•Hypersomnolence•Hyperphagia•No Craving

Phase 1: Crash9 hrs - 4 days

Phase 2: Withdrawal1 - 10 weeks

Early•Normal sleep•Normal mood•Low anxiety•Low craving

Middle & Late•Anhedonia•Anergia•Anxiety•High Craving & conditioned cues

Phase 3: Extinctionindefinite

•Normal hedonic response•Normal mood•Episodic craving•Conditioned cues trigger craving

AbstinenceBinge

Relapse

Cocaine Abstinence Syndrome

Gawin & Kleber (1986)

Cocaine Abuse: Animals

Self-administration Will work hard to get

progressive FR6400

Continuous access: Weight loss Self-mutilation

parasitosis? Death within 2 weeks ~