Topic 21: Amphetamines Flashcards
What are amphetamines?
amphetamines are a large class of stimulants originally based on the naturally occurring ephedrine
quest for alternatives to ephedrine resulted from concerns over stability of supply
amphetamine first synthesized in 1887, brought to market in 1930s as Benzedrine as a decongestant
What are the historical impacts of stimulant effects?
Benzedrine came into regular use in WWII for it’s stimulant and performance enhancing effects
popular in post-war era with truck drivers, students, and the military
use became regulated in the 60s and 70s as addictive potential emerged
remain in use in military
What are the pharmacokinetics of amphetamines?
typically taken orally: also IV or smoking in cases of abuse
amphetamine and methamphetamine are used interchangeably in clinical context
methamphetamine is more potent and has higher BBB permeability and is preferred for illicit use
methamphetamine HCl is preferred for smoking (crystal meth)
as with cocaine - oral route is slowest, least susceptible for abuse: most common therapeutic route
liver metabolism
much longer half-life than cocaine: 7-30 hours
susceptible to binge use - typically IV or inhalant: often combined with depressants to limit anxiety
What are the behavioral effects of amphetamines?
euphoria or exhilaration
heightened alertness
increased confidence
reduced fatigue: insomnia
improved performance on repetitive motor tasks: stereotyped behavior
enhanced athletic performance: banned in many professional leagues
What are the psychosis effects of amphetamines?
drug-induced, particularly in chronic users
indistinguishable from schizophrenia
use precipitates psychosis in schizophrenia
can persist beyond periods of intoxication
What are the punding effects of amphetamines?
stereotyped behaviors
useless repetitive tasks
abstain from eating, drinking, bathroom breaks
irritated or angry if interrupted
What are the formication effects of amphetamines?
feeling of insects crawling on skin
common to pick at skin as a result
What is the mechanism of action of amphetamines?
amphetamines act at catecholaminergic nerve terminals: dopamine, norepinephrine, lesser effects on 5-HT (exception being the enactogenic amphetamines)
like cocaine, amphetamines are reinforcing through effects on dopamine and are stimulant and sympathomimetic through effects on norepinephrine
What are the four mechanisms through which amphetamines increase catecholamine release?
competitive inhibition of DAT/NET
exchange transport at VMAT
altered catecholamine transport via TAAR1 signaling
MAO inhibition
What is the competitive inhibition of DAT/NET caused by amphetamines?
dopamine and amphetamine are both substrates for the dopamine transporter
at dopaminergic terminals amphetamine transport competes with dopamine transport leading to elevated synaptic dopamine
What is the changes to the exchange transport at VMAT caused by amphetamines?
once inside the cell, amphetamines is a substrate for the vesicular monoamine transporters (VMAT1/VMAT2)
amphetamines are transported through VMAT by exchange with intravesicular dopamine, resulting in transport of dopamine out of vesicles into the synaptic terminal
What is the change in the activation of TAAR1 caused by amphetamines?
amphetamines bind an intracellular receptor (GPCR coupled to Gs/Gq) involved in monoamine regulation - trace amino-associated receptor 1 (TAAR1)
TAAR1 signaling activates protein kinase C (PKC) which phosphorylates DAT
phosphorylated DAT reverses the direction of dopamine transport (dopamine efflux transport) and is internalized (non-competitive reuptake inhibition)
How do amphetamines impact DAT, VMAT, TAAR1, and MAO all together?
amphetamine competitively inhibits reuptake through DAT
amphetamine increases cytosolic dopamine levels by exchange transport at VMAT
amphetamine increases DAT internalization and induces dopamine efflux by activating TAAR1
additionally at higher doses amphetamines inhibit MAO, decreasing intracellular dopamine breakdown
What are the persistent effects of amphetamine abuse?
prolonged amphetamine use can lead to psychosis: hallucinations and paranoia resembling schizophrenia, can occur outside of intoxication in chronic users
in animals, methamphetamines doses result in long-lasting decreases in DA, tyrosine hydroxylase, and DAT in the striatum: histology shows degeneration of DA fibers, damage to 5-HT fibers in neocortex, hippocampus, and striatum
What are the adverse effects of methamphetamines?
formication: feeling of insects crawling on/under skin
increases with chronic use and seen as a strong hallucination with psychosis
results in picking at bugs and lesions on skin and face
methamphetamine HCl (crystal meth) is highly acidic
smoking causes degradation of tooth enamel: “meth mouth”
exacerbated by sympathomimetic and stereotypic effects: decreased salivation, dehydration, teeth grinding
reduced self-care in heavy abusers
What are the clinical uses of amphetamines?
largely discontinued as decongestants after abuse potential was discovered: pseudoephedrine in common use
still can be used to treat narcolepsy
amphetamines most common treatment for ADHD
widely used (illicit) as nootropic drugs: high use among university students to improve studying
What is ADHD?
ADHD characterized by increased locomotor activity and distractibility
inattentive subtype: characterized by extreme difficulty in sustained attention
impulsive-hyperactive subtype: characterized by high impulsivity and excessive motor activity
combined subtype incorporates both inattentiveness and impulsive-hyperactivity
What are psychomotor stimulants effective in treating ADHD?
ADHD is dominated by an attentional deficit: hyperactivity manifests from distractibility
ADHD may occur through excessive DAT activity resulting in dopamine insufficiency: DAT density increased in ADHD adults, genetic evidence links some cases with a polymorphism in the DAT gene
What are enactogenic amphetamines?
MDMA developed in 1912 by Merck as a precursor to a coagulant drug
Alexander Shulgin synthesized MDMA in 1965 while at Dow and first tested the psychoactive effects in 1976 after hearing about recreational use from a grad student
MDMA became popular among psychotherapists in the late 70s and early 80s: MDMA cause clients to become more communicative, introspective, and empathic
criminalized in 1985 as a schedule I drug (meaning no recognized medical use)
What are the pharmacokinetics of enactogens?
readily absorbed from GI
plasma levels peak after 2 hours
half-life of 8 hours
liver metabolism by CYP450 2D6
What are the drug effects of enactogens?
euphoria
increased wakefulness
increased endurance
sense of well-being, sociability, and extraversion
sense of closeness, tolerance, and empathy to others
sexual arousal
What is the mechanism of action of enactogens?
MDMA functions as amphetamines but has increased activity at serotonergic neurons
entactogenic effects are modulated by effects on 5-HT
sympathomimetic and stimulant effected modulated by NE
reinforcing effects modulated by DA
high affinity for TAAR1 and VMAT
affects 5-HT, NE, and DA levels at synapses
weak agonist at postsynaptic 5-HT1 and 5-HT2 receptors: MDA has more potent effects at 5-HTR
MDMA found to increase oxytocin levels in healthy volunteers: oxytocin increase correlated with subjective social effects
What are the adverse effects of enactogens?
increased heart rate
tremors
sweating
hyperthermia: potentially fatal, exacerbated by physical activity (i.e. dancing)
trismus (tightening of jaw muscles)
bruxism (grinding teeth): considered a stereotyped behavior
What is withdrawal of enactogens?
no medically serious withdrawal syndrome
some effects persist briefly after cessation (crash similar to cocaine)
trismus, depression, anxiety or paranoia, irritability, impulsiveness, restlessness, insomnia, memory impairment, anhedonia
