Amphetamines - PMCOL Midterm 2 PDF
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This document provides an overview of amphetamines, including their learning objectives, potency, synthesis, neurotransmitter effects, adverse effects, and mechanisms of action. It also discusses tolerance and withdrawal symptoms.
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Amphetamines Learning objectives: Ma huang hinese medicine herb from which amphetamines C are derived Edeleanu erson who synthesized alpha...
Amphetamines Learning objectives: Ma huang hinese medicine herb from which amphetamines C are derived Edeleanu erson who synthesized alpha P methylphenethylamine (AMPH) to treat asthma Potency of Amphetamines Least potent → most potene 1) L-amphetamine 2) D-amphetamine 3) methamphetamine AMPHs vs neurotransmitter chemistry ETH = phenyl M DA = phenol AMPH = phenylethylamine NE = catecholamine Structural similarity allows amphetamines to bind nt transporters How is meth synthesized Nagai or Leuckart synthesis AMPH ADME :ingested (70%), injected, snorted (80%), or A smoked (70-99%) (smoking is the fastest onset) Ice (HCl salt smokable form) has a 12 hour t1/2, Longer lasting high than cocaine D:30-120 min M:Slower metabolism,CYP2D6metabolizes METH (12+ h t1/2, 10-20 h duration) and AMPH (~11 h t1/2, 3-12 h duration) E:kidney, sweat, saliva → eliminate active metabolites (Norephedrine and 4-HA) Acute & Adverse effects of AMPH cute: A Increased NE release → Sympathomimetic Increased 5HT release → delusional parasitosis and perceptual disturbances Increased DA → locomotor activity ie. punding Adverse: Poisoning from contaminants Polypharmacy → enhance stimulatory effects Cellular mechanisms of AMPH levate DA, NE, 5HT availability E Doesnotrequire DA-ergic neuron firing Enter via DAT or diffusion 1) Block reuptake via DATs, NETs, & SERTs a) AMPH-TAAR complex and cytoplasmic DA build-up reverse the DAT b) Can leak into synapse c) DA spike can cause post-synaptic cell activation ) Increase release into synapse 2 3) Inhibit MAOs at high concentrations Cause DA surge in basal ganglia Small which allows transporter to complete transport → doesn’t lock the transporter Tolerance of AMPH epletion via displacement (5HT, DA, NE) D Inhibition of tyrosine hydroxylase (reduced NE and DA synthesis) Acute dosing reduces DAT function Reverse tolerance targets motor function ganglia Withdrawal of AMPH Physical and psychological withdrawal - Craving, depression, lethargy, muscle pain, abnormal sleep - Anhedonia, emotional volatility - Degree and duration depends on dosing Dependence of AMPH hronic dosing causes reduced cell-surface C expression of DA and NE transporters - Upstream TAAR activation - TAAR1 knockout mice = more sensitive to DA activation - TAAR1 agonists reduce effects of AMPHS ow do long-term brain effects of AMPH H - eight loss W effects other conditions - Skin breakdown - Sores, picking - Meth mouth - Exaggerated psych effects → sensitization → unprovoked aggression, anxiety, homi/suicidal thoughts - DA depletion in movement (BG), memory (Hippo), and decision making (PFC) - Damage to DA, NE, 5HT terminals → excitotoxicity stresses neurons and induces cell death → brain damage - Measured by reduced volume - DAT levels may recover, but function may not → impacts anticipation and craving - Most significant loss incingulate gyrus - Loss of DA-ergic neurons predisposes METH addicts to developing Parkinsons - AMPH may triggernAChRs→ allows CA influx → form ROS and cellular stress - Blocked by nAChR antagonists Meth mouth and toxic mechanisms ooth decay, jaw grinding tic T Activate α1 receptors on vessels→ vessel constriction Activate presynaptic α2 receptors on salivary glands → reduced saliva production Keywords: Ma huang hinese medicine herb from which amphetamines C are derived Edeleanu erson who synthesized alpha P methylphenethylamine (AMPH) to treat asthma stereochemistry 1) L -amphetamine = decongestant, raise BP, cause headache 2) D-amphetamine = elevate mood and enhance energy, same effects as L-amph 3) Meth = has methyl group which increases lipophilicity = increased potency and psychoactivity a) Crosses BBB, enters NAc, increase DA release Nagai ynthesis of METH from pseudoephedrine or S ephedrine Leuckart eductive amination to make METH from R phenylacetone TAAR Intracellular GPCR, activated by 4-HA, stimulates NE release, inhibits MAO (MAO degrades monoamines) Activates phosphorylation dependent signalling that targets the DAT to reverse transport Regulatory role regarding DA activation parasitosis eeling of bugs under skin as a result of increased F 5HT release influences perceptions punding epetitive meaningless behaviours as a result of R too much DA leading to decreased selectivity of basal ganglia activity DAT Brings meth into nerve terminals VMAT esicular monoamine transporter: pump meth into V storage vesicles MAO onoamine oxidase: degrade monoamine NTs M such as DA, NE, and 5HT anhedonia inability to feel pleasure – psychological effect of withdrawal Meth mouth Tooth decay, jaw grinding tic nAChRs icotinic acetylcholine receptors N May be triggered by AMPH, lead to ROS production and cellular stress
