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Morphine
- Opioids: activate opioid GPCR, disinhibition of DA neurons
- increases DA accumulation in cleft -> euphoria, and blocks GABA release.
- extracted from opium = opiate, 10x more potent than opium
- converted to M6G (potent metabolite, excreted via urine), some to M3G (accumulation = sz)
- dose needs to be titrated to individual pt needs...no ceiling effect for analgesia
- Use: relieve pain of MI, chronic pain mx, CV effects ass'd with pulm edema, post-op pain
- SE: N/V, sedation, chronic HA, ab pain, peripheral neuropathy, resp depression
- Tx acute morphine poisoning: restore respiration, naloxone narc antag 0.4mg prn slowly to avoid causing withdrawal symptoms
- withdrawal: restlessness, increased sensitivity to pain, tachy, N, cramps, muscle aches, dysphoria, insomnia, anxiety. Unpleasant, 7-10 days. NOT life threatening. Dependence on short-acting narcs more intense but shorter withdrawal syndrome.
- maintenance tx of withdrawal: methadone, clonidine, activation of endog opioid system using other drugs
- Routes of Admin: Oral or IV
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Heroin
- Opioids: activate opioid GPCR, disinhibition of DA neurons
- increases DA accumulation in cleft -> euphoria, and blocks GABA release.
- semi-synthetic congener of opium = opiate
- diacetyl morphine
- rapidly converted to 6-acetyl morphine, then to morphine. heroin does not bind to opioid receptors, high lipid solub, enters CNS rapidly "rush"
- addicts prefer heroin over morphine
- Tx acute morphine poisoning: restore respiration, naloxone narc antag 0.4mg prn slowly to avoid causing withdrawal symptoms
- withdrawal: restlessness, increased sensitivity to pain, tachy, N, cramps, muscle aches, dysphoria, insomnia, anxiety. Unpleasant, 7-10 days. NOT life threatening. Dependence on short-acting narcs more intense but shorter withdrawal syndrome.
- maintenance tx of withdrawal: methadone, clonidine, activation of endog opioid system using other drugs
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Methadone
- long-acting opioid for tx of opioid withdrawal
- used for detoxification...has cross-tolerance with abused agonist, but reduced euphoria (normal range)
- safe, does not interfere with daily activity
- dose gradually reduced every 5-7 days
- orally active
- harm reduction: no needles, stable, pregnancy outcomes
- problems with IV: rush, euphoria
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Clonidine
- alpha-adrenergic agonist, used for maintenance tx of opioid withdrawal
- reduces NA firing and hyperexcitability of NA neurons in locus coeruleus, therefore relieves NV, sweating, autonomic sx.
- does not relieve generalized aches and cravings
- SE: insomnia, dry mouth, sedation, joint pain, dizziness.
- 0.2mg daily
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Meperidine
- Opioids: activate opioid GPCR, disinhibition of DA neurons
- increases DA accumulation in cleft -> euphoria, and blocks GABA release.
- faster onset and shorter DoA than morphine, used to treat acute pain ONLY.
- metab'd to toxic normeperidine: accumulates, precipitates Sz and tremors
- CI in pts with impaired renal fxn, pts receiving MAOIs (potentiation, serotonin syndrome)
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Fentanyl
- Opioids: activate opioid GPCR, disinhibition of DA neurons
- increases DA accumulation in cleft -> euphoria, and blocks GABA release.
- 5-10x more potent than morphine, high lipid solub
- treat cancer pain for convenience or when oral not option
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Tramadol
- weak u receptor agonst (1/6000 affinity vs mrphine)
- also blocks 5-HT and NE reuptake in synaptic cleft
- potentiates action of MAOIs on increasing 5-HT or NE levels in synaptic cleft
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Codeine
- Opioids: activate opioid GPCR, disinhibition of DA neurons
- increases DA accumulation in cleft -> euphoria, and blocks GABA release.
- extracted from opium = opiate
- weak opioid, not generally used as an effective analgesic, 5-10% converted to morphine via CYP2D6
- CYP2D6 affected by genetics. Anttussive properties not involving opioid receptors
- SE: NV, Dizziness, dry mouth, sedation, resp depression less than morphine (reversed by naloxone), can cause serotonin syndrome
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Cocaine
- psychomotor stimulants: bind to transporter of DA, SE, NE...blocks DA uptake, accumulation of DA in synapses, "high"
- most potent drug of natural origin
- hydrochloride salt (neutralized via acid) is powder, dissolves in waer, IV or intranasal
- freebase has not been neuralized, smokable
- Routes of admin: oral, inhalation/intranasal, intravenous, smoking ----> all cause RUSH
- Rush - IV > smoking > intranasal > oral
- SE: overdose is fatal - cardiac failure, sz, resp depression
- Short-term effects: increased energy, decreased appetite, mental alertness, inc heart rate & BP, constricted BV, inc Tep, dilated pupils
- Long-term: addiction, mood disturbances, restlessness, paranoia, auditory & disturbing hallucinations "bugs"
- Med consequences of abuse: CVD effects (MI), resp effects (chest pain, resp failure), neurological effects (strokes, sz & ha, intracranial hemorrhage), GI complications (ab pain, nausea)
- Tx toxicity: need to dec DA in synaptic cleft - IV admin diazepam, propranolol, Ca channel blocker; atypical antipsychotic, antidepressants.
- Chronically, may need to give DA agonists because long term cocaine can deplete DA
- Withdrawal: ravenous appetite, exhaustion, mental depression: persists for few days after withdrawal
- Other uses: high doses can inhibit Na+ channels to have local anesthetic properties (like procaine, lidocaine)
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Amphetamines
- psychomotor stimulants: bind to transporters of DA, SE, NE, VMA...blocks DA uptake, synaptic depletion
- synthetic psychostimulant; metab'd by liver, excreted in urine
- blocks NE reuptake & promotes NE release from vesicles
- blocks DA reuptake, promotes DA release from vesicles, and causes reversal of reuptake transporters to extrude DA
- SE: schizophrenic states, delusion, excoriations, exhaustion, lack of sleep & food
- toxicity: paranoid psychosis (due to DA depletion), necrotizing areteritis, brain hemorrhage, renal failure, neurotox (reduction in DA, tyrosine hydrolase, DA transporter)
- Tx toxicity: sedate pts with BZDs
- "Run....inhaled/IV gives "rush" (feeling of mental alertness and euphoria), more when snorted.
- plasma half-life is short.
- Withdrawal: ravenous appetite, exhaustion, mental depression: persists for few days after withdrawal
- Other uses: narcolepsy, ADHD
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Methcathinone
- another stimulant
- structural analog of methampethamine and cathinone
- oral, IV admin or snorted
- amphetamine like effects
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Alcohol
- sedative/hypnotics:
- methyl, ethyl, isopropyl...most commonly abused drug in world, main effects on CNS
- alcohol -alc dehydrog-> acetaldehyde (toxic) -acetaldehyde dehydrog-> acetic acid -ox-> CO2 + H2O
- 95% metabolized by liver in above mech to excrete in urine, remaining 5% goes to lungs
- absorbed well from GI (10% stomach, 90% intestine) -> diffusion -> blood. faster you drink, faster diffusion because greater concentration gradient. males have 60% higher alc dehydrog than females
- MoA:
- enhance DA release, 5-HT action at 5-HT3R, GABA action, Ach action at nicotinic
- inhibit Glu at NMDA, AMPA kainate receptors, and voltage sens Ca2+ channels
- effect on neuronal memb - change lipid composition, relationship of protein in membrane, bind at NT binding site, change gating mechanism, direct interaction with channel protein, stimulates Gs to increase adenylyl cyclase
- Effects of acute alcoholism: CNS(sedation, relief of anxiety, slurred speech, ataxia, disoriented behavior), CV(depression of myocardium contrxns), SM(direct SM relaxation, relax UT muscles (pee a lot)
- Effects of chronic alcoholism: dysfunction of vital organs (liver, heart, NS, GI, immune)
- Tolerance (high consumption), psychological dependence (desire rewarding effects)
- Chronic alcoholism can lead to both tolerance and physiological dependence
- Tolerance: acute, drug disposition (ADH & CYP450 increased), PD, behavioral
- Withdrawal sx: hyper-excitability, Sz, toxic psychosis, delirium, insomnia
- Tx withdrawal: prevent Sz/arrhythmias/delirium, balance K+/Mg2+/PO4, thiamine (required for glucose metab. when lacking, neurons die in thalamus/hypothalamus, get Wernicke-Korsakoff syndrome)
- Tx alcoholism: detox by substituting with long-acting sedative (BZD>barb), taper + rehab programs.
- Fetal alcohol syndrome: don't see effects until decade...embryos more susceptible...mental retard, low birth weight, neurological problems, craniofacial malfunction, physical abnorms
- *Alcohol abuse: depends on 3 factor vulnerability: psychological fx, biological fx, sociocultural fx
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Barbiturates
- sedative/hypnotic: bind to ionotropic receptors/ion channels GABA-A, cause disinhibition of DA neurons.
- short-acting, intermediate-acting, long-acting
- Initial overdose: slurred speech, ataxia, lethargy, nystagmus, headache, confusion
- Progress: depth of coma increases (loss of neurologic fxn, EEG mimic brain death), resp dep, peripheral VD (hypotension, hypothermia), blisters on skin
- Early deaths due to resp arrest & CV collapse; Delayed deaths due to acute renal failure, pneumonia, pulm edema, ceebral edema
- Overdose management: secure airway, O2 support, IV with lactate ringer/NS, px heat loss, alkalinize urine with bicarbonate
- Withdrawal: LIFE-THREATENING. Sx apprehensiveness, anxiety, tremulousness, DNV, Sz
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BZDs
- sedative/hypnotic: bind to ionotropic receptors/ion channels GABA-A, cause disinhibition of DA neurons.
- most widley used...HIGH hypnotic, MODERATE anxiolytic, LOW sedative
- MoA: BZD bind to gamma-subunit of GABA-A, structural mods, activate receptor, increase in Cl- channel conduction, decrease action potential.
- New info on how NTs work together in VTA:
- No BZD: low glutamate activity and continued GABA interneuron inhibition = low DA neuron activity
- W/ BZD: GABA interneuron inhibited, increase glutamate (also increases eating), therefore increase in DA neuron activity, increase DA release to nucleus accumbens -> euphoria
- Tx effects: induce sleep, anxiolytic, anesthesia, anticonvulsant, muscle relaxation
- Clinical effects: high doses cause resp depression, miosis, anesthesia, coma, death due to cerebral anoxia
- Tx toxicity: flumazenil...but death from BZD overdose is rare?
- Tolerance: develop several weeks after
- Withdrawal: anxiety, muscle cramps, sleep disturbances, paresthesias, photo/phonophobia, Sz and delirium
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Gamma-hydroxy butyrate (GHB)
- closely related to GABA inhibitory neurotransmitters, CNS depressant, and behaviorally sedating drugs.
- LOW alcohol-like experiences. HIGH lethargy, ataxia, dizziness, NV.
- VERY HIGH VERY DANGEROUS resp dep, unconsciousness, comatose, Sz
- MoA:
- 1) activation of pre/post-syn GABA-B receptor b/c some effects blocked by GABA antag
- 2) GHB receptor binding in brain...so that mediates effects.
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Marijuana
- Cannabis: activate GPCR, disinhibition of DA neurons
- grown indoors, genetically mod'd with 10x more efficiency
- marijuana obtained by crushing leaves & flower tops of Cannabis sativa
- used by 200-300 mil people
- Routes of admin: smoking/inhalation (rapidly absorbed to circulation, PPB), oral (slower abs, lower peak)
- active ingredient: delta9-tetrahydrocannabinol
- total clearance take days because cannabis deposits in fat
- MoA:
- 1)endocannabinoids released when inc. Ca2+ at postsynaptic cells
- 2)endocannabinoids activate CB1 receptors (GPCRs), inhibit Ca2+ med'd release from presynaptic bouton. CB1 activation = inhibition of Na+, N/P/Q Ca2+ channels, cAMP and protein kinase. activation of inwardly rectifying K+ channels.
- 3)endocannabinoids diffuse to GABA interneurons - disinhibition, firing of pyramidal cells increase
- delta9-THC: binds to CB1 receptors on pre-synaptic nerve terminals, same as endocannabinoids
- Therapeutic effects of cannabinoids:BD, antiemetic, appetite stim, analgesia, dec spasticity/ataxia/muscle weakness, dec IOP
- PK: inhalation (effects after 2-3 inhales, increase after 20 mins, vanish after 3 hours). oral (peak at 3-4 hours, persist for 6-8 hours)
- Clinical effects: early "high", euphoria, laughter, depersonalization. late relaxation, dream, lack of concentration
- Toxicity: excess pulsation, red conjunctiva, dec BP, muscle weakness, tremors, unsteadiness
- Physical dependence: develops if take high doses for several weeks (moderate use no dependence)
- Withdrawal sx at abrupt cessation: mild abstinence syndrome, insomnia, irritability, anorexia, increased sweating, mild nausea.
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Hashish
- Cannabis: activate GPCR, disinhibition of DA neurons
- grown indoors, genetically mod'd with 10x more efficiency
- contains THC rich material from cannabis plant
- collected, dried, cmpressed, smoked in pipes
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Lysergic acid Diethylamide (LSD), mescaline, psilocybin
- Hallucinogens: activate GPCR, partial agonist at serotonin receptor
- Clinical Effects: somatic (dizzines, weakness, remors, nausea, paresthesia), perceptual (blurred vision, distortion of perception, hallucination, hearing disability, altered sense of change of time), psychological (memory, mood, thinking difficulty)...3 effects overlap.
- Physiological effects: CNS stim, sympathomimetic effects (dilation of pupils, inc HR/BP, tremor and alertness)
- LSD is most potent (1-2ug/kg)...given orally or IV.
- Tx toxicity: BZDs, constant monitoring, acidification of urine (if pH greater than 8)
- Methadone?
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Nitrous Oxide, Amyl Nitrite, Toluene steroids
- inhalants
- volatile solvents, anesthetic gases, organic nitrites, aerosol propellants
- anesthetic gases (nitrous oxide): euphoria, dreaminess, numbness, visual/auditory disturance, unconsciousness
- industrial solvents (gasoline, toluene, benzene): euphoria, relaxation, disorientation, hallucinations
- organic nitrites: dizziness, giddiness, low BP, rapid HR, flushing of skin
- Toxicity: liver/renal damage, resp disorder, memory impairment, deaths due to cardiac failure
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Nicotine
- Tobacco: greatest single preventable cause of death in NA
- Women are 2x more prone to lung cancer in smokers (3x more likely to get cancer than males in non-smokers?)
- (women have gene for gastrin releasing peptide receptor..stimulates cell growth and cancer)
- Lung Cancer risk:
- non-smokers: women 55%, men 0%
- smokers: women 75%, men 20%
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