Drugs of Abuse
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- Alcohol belongs to which group of compounds?
- Sedative-hypnotics & anxiolytics
- Elimination and excretion pathway of alcohol
- Alcohol -> Acetaldehyde -> Acetic Acid -> Carbon Dioxide + Water + Energy
- What enzyme converts alcohol into acetaldehyde?
- Alcohol dehydrogenase
- What enzyme converts acetaldehyde into acedic acid?
- Acetaldehyde dehydrogenase
- What causes flushing, nausea, headache, increased heart rate and why?
- Build-up of acetaldehyde when aldehyde dehydrogenase is less active
- Asian Flush??
- 10% of Asians have the gene that codes for the homozygous inactive form of acetaldehyde dehydrogenase- even small amounts of alcohol lead to high concentration of acetaldehyde
- Homozygous for active form of acetaldehyde dehydrogenase
- Effect: mild or no flushing
- Heterozygous form of acetaldehyde dehydrogenase
- Effect: get sick, flushing
- Homozygous for inactive form of acetaldehyde dehydrogenase
- Effect: severe flushing, alcohol is toxic
- Sex differences in metabolism
-
Men have first pass metabolism of alcohol b/c alcohol dehydrogenase is 60% more active in male stomachs- effect is less alcohol gets into the small intestine/ bloodstream.
Women have less active alcohol dehydrogenase in female stomach, so more alcohol goes straight into the intestine/bloodstream- greater health problems for female alcoholics. - Disinhibition- relaxed, more social
- 100-150 mg/100ml
- Sedative effects- slurred speech, falling out of chair, really drunk
- 150-300 mg/100ml
- Stupor- under the table, barfing, can barely talk or stand
- 300 mg/100ml
- (LD50)Lethal- death via respiratory depression
- 400 mg/100ml
- Cognitive effects of alcohol
- decreased memory (especially storage), greyouts (retrieval limited to when person drinks again), blackouts; mood changes- Low BAC= euphoria, friendly & High BAC= greater hostility; expectancy matters
- Acute tolerance of alcohol
- BAC on rising phase = BAC on falling phase, but different effects- rising phase-> increased body sway/impairment/"intoxicated", falling phase-> normal body sway, no impairment, "sober", TOLERANT
- Chronic tolerance of alcohol
- After 7 days of drinking, more rapid decrease in blood alcohol levels, illustrates tolerance. Pharmacokinetic tolerance: inducing enzymes that break down ETOH (you see and increase in both alcohol dehydrogenase and P450 liver enzymes -> more rapid tolerance, blood levels reduced). Shift to the right in curve representing degree of intoxication vs. BAC (expression depends on set and setting, as well as learning).
- Withdrawal: hangover
- low blood sugar levels, dehydration, irritated stomach, decreased REM- stopped by drinking a little more-> hangover is partly a mini-withdrawal- residual acetaldehyde, loss of body fluids, etc.
- Withdrawal: severe, lethal effects
- delirium tremens (DT's) characterized by seizures, hallucinations; cramps, nausea, tremors; treated by administering another sedative hypnotic like diazepam (BZD)
- What increases absorption of alcohol?
- Harder drinks (greater alcohol concentration), carbonated drinks (champagne), empty stomach (nothing blocking the movement of material from the stomach into the small intestine)
- Fetal Alcohol Syndrome
- Blocking of NMDA receptors during development triggers widespread apoptotic neurodegeneration
- Apoptosis
- The controlled destruction of cells.
- Pharmacological treatment of alcoholism
-
Antabuse (disulfiram)- blocks acetaldehyde dehydrogenase -> increased levels of acetaldehyde -> sickness (mixed results).
SSRIs- relieve anxiety, depression (withdrawal effects) - First barbiturate
- Barbital (Veronal)
- Phenobarbital (Luminal)
- long-acting (8-12 hrs), surgery/anxiety treatment, less lipid soluble
- Pentobarbital (Nembutal)
- intermediate-acting (2-8 hrs), helps induce sleep
- Secobarbital (Seconal)
- short-acting (1-4 hrs)
- Thiopental (Pentothal)
- ultra-short-acting (5-30 min.), most lipid soluble, high abuse potential, commonly used on street
- Medical Uses for barbiturates
- sleep induction (short action), anticonvulsants, anaesthetics, sedatives, alcohol withdrawal, anxiolytics (all long action)
- Illicit Use of barbiturates
- used for effects similar to alcohol; often used with other drugs (stimulants or opiates- smoothes the high); rapid tolerance (faster than alcohol); severe withdrawal; low safety margin (50% of drug related suicides)
- Meprobamate (Miltown)
- Anxiolytic, treatment of anxiety and depression, thought to have less aversive effects, actually very dangerous
- Chlordiazepoxide
- Librium
- Diazepam
- Valium
- Oxazepam
- Sevax
- Nitrazepam
- Moyodon
- Flurazepam
- Dalmane
- Medical Uses of anxiolytics
- Pathological anxiety, severe emotional distress, relief from agitation and alcohol withdrawal, sedation(sleep-inducing), pre-surgery sedation & amnesia, anticonvulsants
- Therapeutic Effects of anxiolytics
- Calming & relaxation (desired effects); side effects- motor incoordination, intoxication (like alcohol), memory loss, sedation & sleep, deep sleep and coma, respiratory depression
- BZDs vs. Barbiturates
- BZDs/anxiolytics have less tolerance effects (less dose required, not as dangerous), lower likelihood of abuse (SA), safer drugs
- Date rape cases
- Rohypnol (flunitrazepam, BZD), "Micky Finn" (chloryl hydrate, tasteless pill-barb), GHB (hydroxybutyric acid, neither barb/BZD but same effect)
- BZD Binding
- Neocortex, hippocampus, cerebellum, olfactory bulb- binds to GABAa receptor
- GABA neurotransmission
- Major inhibitory NT, hyperpolarizes neurons
- GABA Synthesis
- Glutamate -glutamate acid decarboxylase(GAD)-> GABA
- What enzyme converts GABA back into glutamate and succinate?
- GABA aminotransferase
- GABA transporters
-
GAT-1,2,3 (astrocytes)
GAT-1 (on pre-synaptic terminal) - Metabotropic Receptor
- slow-acting; composed of single large protein in cell membrane that activates G proteins (G-protein coupled)
- GABAa receptor
- Ionotropic, Cl- selective(forms chloride channel), composed of 5 subunits (each w/number of isoforms), GABA increases Cl- conductance, hyperpolarization
- Allosteric Modulation
- Change conformation of GABAa receptor complex so that GABA works better -> greater Cl- conductance, hyperpolarization
- How do Barbiturates affect Cl- channel openings?
- Increase long DURATION open states, no change in # of openings- easy to kill yourself b/c channels are stuck open, neurons can't fire and perform normal functions
- How do BZDs affect Cl- channel openings?
- Increase FREQUENCY (# of times the channel opens), do not change duration
- Inverse agonists
- First example were drugs that act at BZD site on GABAa receptor: B-carbolines, negatively modulate: decrease Cl- conductance, reduced inhibition (produce extreme anxiety and panic)
- Which subtypes of the GABAa receptor are sensitive to diazepam?
- alpa-1,2,3,5 (point mutations)
- Alpha-1
- sedative and amnesic effects
- Alpha-2
- anxiolytic effects
- Endogenous ligands ar BDZ site
- steroid metabolites of progesterone and deoxycorticosterone
- Why can't you inject marijuana/cannabinoids?
- b/c they're like an oil- very lipid soluble
- What are cannabinoids?
- Psychoactive compounds of marijuana plant, over 60-vary tremendously in potency (eg. delta-9-tetrahydrocannabinol)
- What is Marijuana?
- mixture of leaves, stems, tops (all contain cannabinoids)- contain up to 8-10% THC (more potent today)
- Hashish
- form of marijuana smoked in a pipe, dried resin from top of female plant, THC usually 2-5% but up to 15% (highest concentration, so can smoke less)
- Hash Oil
- compressed hashish, organic extraction- dissolved in alcohol, filtered, evaporated, left w/dark brown oily substance- THC usually ~10-20%, up to 70% (pure cannabinoid- drop put on cigarette and smoked)
- Synthetic Cannabinoids
- Developed for research, more potent than naturally occurring cannabinoids, but water soluble (can work w/them)- synthetic antagonists, Rimonabant; agonist- WIN 55212
- Cannabinoid Absorption
-
very lipid soluble, good absorption if smoked (20-37%), rapid peak (15 min).
Slow absorption w/oral administration, 1st pass metabolism & degradation in stomach- blunted "high" effect reported - Cannabinoid Routes
- smoked via joint, water pipe (bong-less drug lost)
- Cannabinoid Metabolism and Clearance
-
Rapid initial drop due to redistribution to fats, slow metabolism in liver, metabolites may persist for weeks.
*Major biologically active compound may be metabolite
1) Primary metabolite of delta-9-THC (11-hydroxy-THC) is more potent
2) Delay between peak plasma levels and reported "high" (peak psychoactive effect after metabolism of delta-9-THC) - Cannabinoid Behavioral Effects: Low-Moderate doses
- disinhibition, relaxation, drowsiness, feeling of well being, exhilaration, euphoria, sensory-perceptual changes, STM impairment (very clear lab evidence), balance/stability impaired, decreased muscle strength, small tremor, poor on complex motor tasks, increase hunger (munchies)
- Synesthesias
- melding of senses (eg. sounds have colors)
- Repeated Administration of Cannabinoids
-
Chronic THC -> fairly rapid tolerance, huge down-regulation of cannabinoid receptors in caudate (fewer receptors for drug to bind to).
Tolerance *rats*: BP, HR, Operant responding (mixed)
Tolerance *humans*: "High" (mixed) - Potential Medical Uses of Cannabinoids
- decreases glaucoma, antiemetic (reduces nausea and vomiting- chemotherapy), anticonvulsant, enhances appetite (AIDS patients), analgesic
- pure THC vs. marijuana controversy
- few clinical trials report THC isn't effective medically, users claim marijuana is effective
- Endogenous cannabinoids (endocannabinoids)
- act as retrograde messengers w/in the brain- released from post-synaptic cell and bind to CB-1 receptors on pre-synaptic terminal: decrease calcium conductance, decrease NT release
- Locus of cannabinoid actions
-
*Hippocampus- memory effects
*Mesostriatal DA system- reward
*Basal ganglia, cerebellum- motor activity
*Spinal cord & peripheral tissue- analgesic effects - Reinforcement of cannabinoids
- Self-administration blocked by CB-1 antagonist and naltrexone, preexposure enhances SA and conditioned place preference (mixed), CB-1 knockouts also altered SA of alcohol, opioids, cocaine, and nicotine