Pharmacology of Psychostimulant Misuse Flashcards
Describe the current trends in stimulant overdose deaths
Psychostimulants activate the CNS resulting in alertness, excitation, and elevated mood
in 2018, there were 27,342 stimulant overdose deaths (40%)
we have a drug abuse crisis in which stimulants play a major role: synthetic opioids other than methadone (primarily fentanyl), psychostimulants with abuse potential (primarily methamphetamine) and cocaine are all going up
Differentiate between psychostimulants based upon the neurotransmitter effected by their administration
Mesolimbic dopamine system: dopaminergic neurons feed from the ventral tegmental area and go to the nucleus accumbens (reward)
Nicotine MOA
- Nicotine activates nicotinic acetylcholinergic receptor
- Na+ enters cell, K+ exits the cell => action potential
- Heterogeneity of subunits determines how many molecules of Ach bind to receptor
- Variation in receptor composition at different sites may influence physiological response
Acetylcholine vs nicotine
- Similarities between nicotine and ACh are charged amino groups and hydrogen bond acceptor groups
- Nicotine is membrane penetrable at physiological pH (weak base)
- Nicotine is not degraded by acetylcholinesterase
What is the significance that nicotine is not metabolized by AChe?: longer duration of half life because of the longer half-life, more potent than ACh
Cocaine MOA
- Antagonist of amine transporters
1. Dopamine Transporter (DAT)
2. Serotonin transporter (SERT)
3. Norepinephrine transporter (NERT) - DAT≥SERT>NERT (completely blocks DAT, less potent for NE, 5HT)
- Prevents DA reuptake
- Increases DA concentration
- Increase duration of DA action
Methamphetamie ecstasy and bath salts MOA
- Amphetamines/XTC/bath salts compete for reuptake: Resemble endogenous DA, NE –> Block DA reuptake –> Push out DA from vesicles –> ↑ extra-vesicular DA –> reverse transportl amphetamines are MAOis; causes more DA to be released and reduces its reuptake
- Activate Trace amine- associated receptor (TAAR1): Phosphorylates DAT, Induces reverse transport function, now an efflux transporter, forces more DA out
Why do a minority of people become addicted if the pharmacology of the drug drives addiction?
data suggests its not the pharmacology, but how it is used and who is using it
Partial Agonist Therapy
- Causes release of dopamine
- Highly addictive
- Nicotine replacement
therapy relatively
ineffective alone - Varenicline partial agonist increases quit rate success - drug blocks receptors yet still triggers DA release, gives enough DA to stimulate DA receptors that you prevent withdrawal sx but not enough to reward taking it
Describe the primary clinical effects of psychostimulants with escalating dose
Neurologic, psych, ENT, cardiovascular, pulmonary, GI, renal, musculoskeletal, skin
Neurologic
delirium, tremor
Psych
anxiety, paranoia, hallucinations, delusions, repetitive behavior
ENT
tachycardia, HTN/vasospasm
Skin
diaphoresis
Discuss the effect of chronic psychostimulant use on the CNS dopaminergic system
- DA receptor changes argued as support for dopamine hypothesis and brain disease model
- Similar changes occur with NE and 5-HT with antidepressant therapy
- Receptor downregulation believed to mediate withdrawal symptoms
- DA downregulation is not evidence of a broken brain - if you overstimulate receptors, you get downregulation
- Recovery of DA receptors shows ability to return to homeostasis
- Might substitution therapy prevent return to homeostasis and full recovery?
Do addictive drugs increase brain dopamine?
the role of DA in addiction is far more complex and unclear than commonly presented
