BehV Science 3 Flashcards
Dopamine hypothesis of addiction
‣ As a general rule, all addictive drugs activate the mesolimbic dopamine system
‣ Mesolimbic dopamine codes for the difference between expected and actual reward and thus
constitutes a strong learning signal
‣ The mesolimbic system continuously scans for reward, increasing its activity when reward is larger than
expected, and shutting down when reward does not occur
‣ By directly increasing dopamine, addictive drugs generate a strong but inappropriate learning signal,
thus hijacking the reward system and leading to pathologic reinforcement
Opioids
◦MOA — agonist at mu-opioid receptor (Gi) —> disinhibition on dopamine neurons ◦Signs and symptoms of intoxication
‣ Pupil constriction, decreased body temp, decreased HR and BP
‣ Sleepiness, droopy eyelids, soft low voice, euphoria ◦Signs and symptoms of withdrawal
‣ Dysphoria, N/V/D, myalgias, lacrimation, rhinorrhea, mydriasis, piloerection, sweating, yawning, fever ◦Treatment for withdrawal
‣ Naloxone
• Reverses effects of morphine or heroin in minutes
• Provokes an acute withdrawal syndrome in a dependent pt who has recently taken an opioid
‣ Methadone, buprenorphine, morphine sulfate
• Longer acting opioids that act as substitution therapy
Cannabinoids
◦MOA — agonist at cannabinoid-1 (Gi) receptor —> disinhibition on dopamine neurons ◦Signs and symptoms of intoxication
‣ Euphoria and relaxation, feelings of well-being, grandiosity, and altered perception of time passage
‣ Increased appetite, attenuation of nausea, decreased IOP, relief of chronic pain ◦Signs and symptoms of withdrawal
‣ Restlessness, irritability, mild agitation, insomnia, nausea, and cramping
‣ Mild and short-lived
Y-hydroxybutyric acid GHB
◦MOA —weak agonist at GABA-B (Gi) receptors —> disinhibition on dopamine neurons ◦Signs and symptoms of intoxication
‣ Before causing sedation and coma, causes euphoria, enhanced sensory perceptions, feeling of social closeness, and amnesia
LSD
◦MOA — ergot alkaloid; partial agonist at 5-HT2A (Gq) receptor ◦Signs and symptoms of intoxication
‣ Induce perceptual symptoms including shape and color distortion
‣ Can induce abortion via stimulation of uterine contractions
Nicotine
◦MOA — agonist at nAChR —> excitation on dopamine neurons (direct stimulation) ◦Signs and symptoms of intoxication
‣ Increased pulse and BP, odor on breath, stained fingers or teeth ◦Signs and symptoms of withdrawal
‣ Irritability and sleep problems ◦Treatment for withdrawal
‣ Nicotine in slowly absorbing forms — gum, inhaled, transdermal
‣ Varenicline, plant-extract cytisine
• Occupy nAChRs on dopamine neurons of the VTA, preventing nicotine from exerting its action ‣ Buproprion
• Weak inhibitor of neuronal uptake of NE and DA
Alcohol
◦MOA — acts at GABA-A, 5-HT3, nAChR, NMDA, and Kir3 channels —> excitation, disinhibition on DA
neurons
◦Signs and symptoms of intoxication
‣ Increased HR and BP, odor on breath, slurred speech, lack of coordination ◦Signs and symptoms of withdrawal
‣ 6-12 hours after cessation — tremor, N/V, excess sweating, agitation, anxiety
‣ 12-24 hours after cessation — visual, tactile, auditory hallucinations
‣ 24-48 hours after cessation — generalized seizures
‣ 48-72 hours after cessation — alcohol withdrawal delirium (delirium tremens): hallucinations,
disorientation, autonomic instability; 5-15% mortality ◦Treatment for withdrawal
‣ Benzodiazepines that rely less on oxidative hepatic metabolism: oxazepam, lorazepam
Benzodiazepines
◦MOA — positive modulator at GABA-A receptors —> disinhibition on dopamine neurons ◦Signs and symptoms of intoxication
‣ Disoriented, drowsy, uncoordinated, slow slurred speech, reduced HR and BP ◦Signs and symptoms of withdrawal
‣ Irritability, insomnia, phonophobia, photophobia, depression, muscle cramps, seizures
Phencyclidine ketamine
◦MOA — Antagonist at NMDA receptors ◦Signs and symptoms of intoxication
‣ Unpleasant vivid dreams, hallucinations, psychedelic effects, increased blood pressure, impaired memory function, visual alterations, out-of-body experiences
Cocaine
◦MOA — inhibitor at dopamine transporter (DAT), SERT, NET —> blocks dopamine uptake ◦Signs and symptoms of intoxication
‣ Acute increase in arterial pressure, tachycardia, ventricular arrhythmias
‣ Loss of appetite, hyperactivity, little sleep ◦Signs and symptoms of withdrawal
‣ Apathy, irritability, increased sleep time, disorientation, depression ◦Treatment for withdrawal
‣ Supportive
Amphetamine
◦MOA — reverses transport at DAT, NET, SERT, and vesicular monoamine transporter (VMAT) —> blocks DA uptake, synaptic depletion
◦Signs and symptoms of intoxication
‣ Increased arousal, reduced sleep, euphoria, agitation, confusion, bruxism, skin flushing
◦Signs and symptoms of withdrawal
‣ Dysphoria, drowsiness or insomnia, general irritability
Ecstasy
◦MOA — reverses transport at SERT > DAT, NET —> blocks DA uptake, synaptic depletion ◦Signs and symptoms of intoxication
‣ Feelings of intimacy and empathy without intellectual impairment
‣ Hyperthermia, dehydration, serotonin syndrome, seizures ◦Signs and symptoms of withdrawal
‣ Mood “offset” — depression, aggression,
Alcohol intoxication
◦Acute ethanol exposure enhances the action of GABA and GABA-A receptors ◦Ethanol inhibits the ability of glutamate to open NMDA-subtype of glutamate receptors
‣ the NMDA receptor is implicated in aspects of cognitive function including learning and memory ◦Overall metabolism:
‣ Extensive first pass metabolism by gastric and liver alcohol dehydrogenase (ADH) • Followed by aldehyde dehydrogenase
‣ Follows zero-order kinetics
• Rate of biotransformation is independent of time and concentration of ethanol
• Enzymes are almost immediately saturated
• Compare and contrast the drugs used for acute alcohol withdrawal vs alcohol cravings and select appropriate pharmacologic therapy based on presentation and patient medical history
◦Drugs used for acute alcohol withdrawal:
‣ Benzodiazepines (diazepam, lorazepam, oxazepam), electrolytes, thiamine therapy
‣ Goal is to prevet seizures, delirium, and arrhythmias
◦Drugs used in the setting of alcohol cravings:
‣ Naltrexone
• Mu-opioid receptor antagonist (long acting)
• Reduces craving for alcohol and rate of relapse to either drinking or alcohol dependence in the
short-term
• Individuals physically dependent on alcohol and opioids must be opioid free before initiating
therapy bc naltrexone precipitates an acute withdrawal syndrome
‣ Acamprosate
• Weak NMDA receptor antagonist and GABA-A receptor agonist (also affects serotonergic, noradrenergic, and dopaminergic systems)
• Reduces short-term and long-term relapse rates (more than 6 months)
‣ Disulfiram
• Irreversibly inhibits aldehyde dehydrogenase —> accumulation of aldehyde
• Causes extreme discomfort in pts who drink alcohol — flushing, headache, N/V, sweating,
hypotension, confusion
‣ Psychosocial therapy
• Explain the molecular mechanisms behind the combined use of alcohol, benzodiazepines, barbiturates, and sleep aids in order to predict the depressive effects on the
Additive effects
In order to treat toxicity associated with methanol and ethylene glycol, you should be able to diagram the biotransformation pathway, identify toxic metabolites, and select appropriate pharmacotherapy
◦Methanol
‣ Converted to toxic metabolites by alcohol dehydrogenase and aldehyde dehydrogenase—
formaldehyde & formate
‣ Treatment = fomepizole and ethanol —> inhibition of alcohol dehydrogenase —> reduction of toxic
metabolite formation ◦Ethylene glycol
‣ Toxic aldehydes and oxalate; lactate causes respiratory acidosis
‣ Tx with fomepizole, IV ethanol, or hemodialysis
In order to treat signs/symptoms of Wernicke’s encephalopathy and Korsakoff’s psychosis, diagram the time course of events during alcohol withdrawal syndrome and select drugs appropriate for therapy
◦Wernicke’s encephalopathy
‣ Paralysis of the external eye muscles, ataxia, and confusion; can progress to coma and death
◦Korsakoff’s psychosis
‣ Chronic disabling memory disorder following Wernicke’s encephalopathy
◦Drugs for withdrawal
‣ Benzodiazepines + Thiamine
• Compare and contrast the rate of onset and half-lives of benzodiazepines and select an appropriate agent to treat acute anxiety attacks based on presenting symptoms and PMH
◦Onset of action from fastest to slowest:
‣ 1 hr — Triazolam, eszopiclone
‣ 1-2 hrs — Alprazolam, clorazepate (nordiazepam prodrug), diazepam, flurazepam
‣ 2-3 hrs — Temazepam
‣ 2-4 hrs — Chlordiazepoxide, oxazepam
‣ 1-6 hrs — Lorazepam
◦Duration of action from shortest to longest:
‣ 2-3 hrs — Triazolam
‣ 10-20 hrs — Lorazepam, oxazepam
‣ 10-40 hrs — Temazepam
‣ 12-15 hrs — Alprazolam
‣ 15-40 hrs — Chlordiazepoxide
‣ 20-80 hrs — Diazepam
‣ 40-100 hrs — Flurazepam
‣ 50-100 hrs — Chlorazepate (nordiazepam prodrug)
◦Based on Iszard’s slides:
‣ Fastest onset = Diazepam > Alprazolam = flurazepam = clorazepate > chlordiazepoxide = lorazepam =
triazolam = clonazepam
‣ Half lives:
• Intermediate to long acting
◦Diazepam, lorazepam, clonazepam
◦Note: longer half-life agents are more likely to cause cumulative effects (excessive drowsiness,
etc.) with multiple doses
• Short to intermediate acting
◦Alprazolam, oxazepam, temazepam, midazolam, triazolam
