Pharm: Alcohol and Drugs of Abuse Flashcards
psychological dependence
dependency of the mind - cravings, irritability, insomnia, depression, anorexia
= “addiction”
sensitization
i) An increase in response with repetition of the same dose of the drug (also known as reverse tolerance)
ii) Conditioning is a form of sensitization
iii) The dose-response curve shifts to the left
iv) Example drug: cocaine (repeated daily administration of cocaine to rats produces an increase in motor activity that increases over several days even though the dose remains constant)
mesolimbic DA system
a) Mesolimbic DA system
i) Prime target of addictive drugs
ii) Originates in the ventral tegmental area (VTA), a tiny structure at the tip of the brainstem, which projects to the nucleus accumbens, the amygdala, the hippocampus, and the prefrontal cortex
iii) Most projections of the VTA are DA-producing neurons: large quantities of DA are released in the nucleus accumbens and the prefrontal cortex when the DA neurons of the VTA are activated
iv) As a general rule, all addictive drugs activate the mesolimbic DA system
Dopamine hypothesis of addiction (DA reward pathway)
i) Dependence-producing drugs activate the mesolimbic DA system, releasing DA
ii) The pleasure-related (hedonic) effect results from activation of this pathway, rather than from a subjective appreciation of the diverse other effects (such as alertness or disinhibition) that the drugs produce
LSD
nonaddictive DOA - targets cortical and thalamic circuits
i) Lysergic acid diethylamine (LSD), mescaline, psilocybin
(1) Repetitive exposure leads to rapid tolerance (tachyphylaxis)
(2) Animals will not self administer hallucinogens, suggesting they are not addictive in nature
** LSD can cause flashbacks of altered perception years after consumption
PCP
nonaddictive DOA - targets cortical and thalamic circuits
Phencyclidine (PCP) and ketamine
(1) Developed as general anesthetics (ketamine is still used for this purpose)
(2) Club drugs sold under names such as angel dust, Special K, Hog
(3) Psychedelic effects last for about 1 hour and also include increased blood pressure, impaired memory function, disorientation, nystagmus, and visual alterations
(4) Classification of these NMDA antagonist as nonaddictive agents has been questioned due to animal research that shows that PCP can increase mesolimbic dopamine concentrations and has some reinforcing properties in rodents
** PCP may lead to irreversible schizophrenia-like psychosis
naloxone
(i) MOA: pure opioid antagonist that reverses effects of a dose of opiates within minutes
(ii) Provokes an acute withdrawal syndrome in situations where a dependent person has opiates in their system
Withdrawal symptoms include intense dysphoria, nausea or vomiting, muscle aches, lacrimation, rhinorrhea, mydriasis, piloerection, sweating, diarrhea, yawning, fever
NOTE: naloxone is rapid acting, naltrexone is longer onset
methadone
- Long-acting opioids used for substitution therapy (half-life 25-52 hrs) for opioid dependence
Tolerance and physical dependence develop more slowly in comparison to other opioids (e.g., morphine)
Abrupt discontinuation precipitates a withdrawal syndrome
buprenorphine
mixed agonist/antagonist (partial agonist at opioid receptors)
used for opioid dependence
methadone
- (i) Long-acting opioids used for substitution therapy (half-life 25-52 hrs)
(ii) Tolerance and physical dependence develop more slowly in comparison to other opioids (e.g., morphine)
(iii) Given with supervised intake
(iv) Abrupt discontinuation precipitates a withdrawal syndrome
opioids
GPCR drugs: cause disinhibition of DA neurons
=Drugs that activate Gio-coupled receptors: cause disinhibition of DA neurons
(2) In the VTA, µ opioids cause an inhibition of GABAergic inhibitory interneurons, which leads to a disinhibition of dopamine neurons (see figure below)
(3) µ receptors cause euphoria when activated and are implicated in the reward effects of opiates (commonly abused µ opioids are morphine, heroin, codeine, oxycodone, and meperidine)
Withdrawal symptoms include intense dysphoria, nausea or vomiting, muscle aches, lacrimation, rhinorrhea, mydriasis, piloerection, sweating, diarrhea, yawning, fever
tx for OD: naloxone
tx for substitution therapy: methadone, buprenorphine
buprenorphine
- (i) Long-acting opioids used for substitution therapy (half-life 25-52 hrs)
(ii) Tolerance and physical dependence develop more slowly in comparison to other opioids (e.g., morphine)
(iii) Given with supervised intake
(iv) Abrupt discontinuation precipitates a withdrawal syndrome
cannabinoids
GPCR drugs: cause disinhibition of DA neurons
(3) The exogenous cannabinoid Δ9-tetrahydrocannabinol (THC) causes disinhibition of DA neurons by presynaptic inhibition of GABA neurons in the VTA (similar to opioids)
(4) Effects of THC include euphoria, relaxation, feelings of well-being, grandiosity, and altered perception of passage of time
(5) The THC-induced effects of increased appetite, attenuation of nausea, decreased intraocular pressure, and relief of chronic pain have led to the use of cannabinoids in medical therapy
(6) Chronic exposure leads to dependence with a mild and short-lived withdrawal syndrome (includes restlessness, irritability, mild agitation, insomnia, nausea, cramping)
dronabinol
(a) FDA-approved THC analog used for anorexia and weight loss in AIDS patients and cancer-chemotherapy induced nausea and vomiting
Nabilone
(a) THC analog used for the treatment of refractory nausea and vomiting associated with cancer chemotherapy and as an adjunct in chronic pain management
Gamma-hydroxybutyric Acid (GHB)
GPCR drugs: cause disinhibition of DA neurons
(1) GHB is produced during the metabolism of GABA, but the endogenous function is unknown
(2) Activates the GABAB receptor with low affinity and produces euphoria, enhanced sensory perceptions, feelings of social closeness, and amnesia before causing sedation and coma (originally introduced as a general anesthetic)
(3) Also known as liquid ecstasy or the date rape drug (has been used in date rapes because it is odorless, readily dissolved in beverages, reaches maximal plasma concentration 20-30 minutes after ingestion, and has an elimination half-life of 30 minutes)
(4) Recreational use only inhibits GABA neurons but at higher doses GHB hyperpolarizes DA neurons and inhibits DA release
(5) GHB targets GABAB receptors on both GABA and DA neurons, but those on GABA neurons are more sensitive to GHB and lead to disinhibition of DA neurons when activated
nicotine
(a) MOA: selective agonist of the nicotinic acetylcholine receptor (nAChR)
(b) Neuronal nAChRs are expressed on DA neurons in the VTA; activation fulfills the DA requirement of addictive drugs
(c) Though highly addictive, withdrawal is mild compared with opioid withdrawal and involves irritability and sleeplessness
buproprion
(i) Antidepressant with unknown mechanism of action
(ii) Used alone or in combination with nicotine-replacement therapy and/or behavioral therapy
varenicline
“chantix”
(i) Derivative of the plant-extract cytisine
(ii) Partial neuronal nAChR agonist
(iii) Only approved for treating smoking cessation
(iv) Prevents nicotine stimulation of mesolimbic dopamine system associated with nicotine addiction
cocaine
- MOA:
- peripheral nervous system, cocaine inhibits voltage-gated sodium channels and can be used as a local anesthetic
- CNS: Blocks the DAT and increases the DA concentrations in the nucleus accumbens (rewarding effects)
- CNS: Blocks the NET and activates the sympathetic nervous system, which leads to an acute increase in arterial pressure, tachycardia, ventricular arrhythmias, and pupil dilation
Sx: of use include loss of appetite, hyperactivity, and lack of sleep while overdose may lead to hyperthermia, coma, and death
Caution: !! Exposure increases risk for intracranial hemorrhage, ischemic stroke, myocardial infarction, and seizures !!
Withdrawal syndrome not as strong as that observed with opioids
(7) Reverse tolerance can occur (sensitization to small doses of cocaine)
(8) Susceptible individuals may become dependent and addicted after only a few exposures
(9) No antidote; intoxication management remains supportive with agents to control heart rate/rhythm (β-adrenergic receptor antagonist propranolol) and seizures (sedative-hypnotic diazepam)
amphetamines
(1) MOA: cause the release of endogenous biogenic amines by reversing the action of biogenic amine transporters at the plasma membrane
- Amphetamines are taken up into the cell by the DAT
- Amphetamines block the intracellular VMAT and deplete synaptic vesicles of their neurotransmitter content, which causes levels of DA and other amines (serotonin, norepinephrine) to increase in the cytoplasm
- Increasing levels of amines in the cytoplasm cause the DAT, SERT, and NET to work in reverse and release amines into the synapse!
Amphetamines are neurotoxic (dependent on the NMDA receptor and affects mainly serotonin and DA neurons)
Withdrawal consists of dysphoria, drowsiness (insomnia in some cases), and general irritability
Ecstasy
(MDMA; methylenedioxymethamphetamine)
MOA: similar to amphetamines (reverses the action of biogenic amine transporters)
- Preferential affinity for the SERT and strongly increases the extracellular concentration of serotonin
- Heavy users of MDMA report long-term cognitive impairment due
Acute toxic effects include hyperthermia, dehydration, serotonin syndrome (mental status change, autonomic hyperactivity, neuromuscular abnormalities), and seizures
Withdrawal consists of a mood “offset” characterized by depression lasting up to several weeks, possible increased aggression
schedule I
The drug or other substance has a high potential for abuse.
The drug or other substance has no currently accepted medical use in treatment in the United States.
There is a lack of accepted safety for use of the drug or other substance under medical supervision.
All research use is illegal under federal law
Examples = heroin, lysergic acid diethylamide (LSD), marijuana, and methaqualone.
