Drugs Of Abuse

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      • Drugs of abuse
        • Commonly abused drugs include
          • opioid (narcotic)
          • analgesics (e.g., heroin),
          • general CNS depressants (e.g., ethanol, barbiturates such as pentobarbital)
          • inhalants (e.g., toluene, nitrous oxide, amyl nitrate)
          • sedative–hypnotics (e.g., alprazolam, diazepam)
          • CNS stimulants (e.g., cocaine, amphetamines, nicotine)
          • hallucinogens (e.g., LSD, mescaline, phencyclidine)
          • marijuana (cannabis).
        • Drug addiction
          • drug abuser’s overwhelming preoccupation with the procurement and use of a drug.
        • Tolerance
          • decreased intensity of a response to a drug following its continued administration
          • A larger dose often can produce the same initial effect.
        • Metabolic tolerance(pharmacokinetic tolerance):
          • rate of drug elimination increases with long-term use
          • it is due to stimulation of its own metabolism (autometabolism). (MCQ)
        • Cellular tolerance(pharmacodynamic tolerance):
          • Biochemical adaptation or homeostatic adjustment of cells to the continued presence of a drug.
          • It is due to a compensatory change in the activity of specific neurotransmitters in the CNS (MCQ)
          • It is caused by a
            • change in their levels, storage, or release
            • changes in the number or activity of their receptors.
        • Cross-tolerance.
          • Tolerance to one drug confers at least partial tolerance to other drugs in the same drug class
            • between heroin and methadone (MCQ)
            • between ethanol and diazepam (MCQ)
        • Tolerance is often,but not always , associated with the development of physical dependence. (MCQ)
      • Dependence
        • refers to the biologic need to continue to take a drug.
        • Psychologic dependence
          • Overwhelming compulsive need to take a drug (drug-seeking behavior) to maintain a sense of well-being.
          • Psychologic dependence may be related to increased dopamine activity in the ‘‘brain reward system’’ (MCQ)
          • brain reward system’’ includes(MCQ)
            • mesolimbic dopaminergic pathway
            • from the ventral midbrain to the nucleus accumbens and other limbic structures including the prefrontal cortex and limbic and motor systems).
          • Development of psychologic dependence generally precedes development of physical dependence (MCQ)
          • psychologic dependence does not necessarily lead to physical dependence(MCQ)
        • Physical dependence
          • ‘‘Abstinent withdrawal’’
            • A latent hyperexcitability that is revealed when administration of a drug of abuse is discontinued after its long-term use).
            • Continued drug use is necessary to avoid the abstinent withdrawal syndrome.
            • It is characterized by effects that are often opposite to the short-term effects of the abused drug
            • It often include activation of the sympathetic nervous system. (MCQ)
            • The severity of the withdrawal syndrome is directly related to the
              • dose of the drug
              • how long it is used,
              • its rate of elimination
          • ‘‘Precipitated withdrawal’’
            • follows administration of an antagonist (e.g., naloxone, flumazenil) (MCQ)
            • has a more explosive onset and shorter duration than abstinent withdrawal.
          • The development of physical dependence is always associated with the development of tolerance. (MCQ)
          • Cross-dependence
            • Ability of one drug to substitute for another drug in the same drug class to maintain a dependent state or to prevent withdrawal
              • diazepamfor ethanol
              • methadonefor heroin
      • Barbiturates (secobarbital, pentobarbital, g-hydroxybutyric acid) and benzodiazepines
        • Barbiturates
          • produce drowsiness at hypnotic doses
          • interfere with motor and mental performance.
          • potentiate the depressant effects of other CNS depressants or antidepressants.
          • produce dose-related respiratory depression with cerebral hypoxia, coma or death.
          • Treatment includes
            • ventilation, gastric lavage
            • hemodialysis, osmotic diuretics
            • alkalinization of urine for phenobarbital. (MCQ)
        • g-Hydroxybutyric acid (GHB) has been used as a ‘‘date rape’’ drug(MCQ)
          • Abuse and psychologic dependence are more likely with the shorter-acting, more rapidly eliminated drugs (pentobarbital, amobarbital, secobarbital). (MCQ)
          • The abuse potential of the barbiturates exceeds that of the benzodiazepines.
          • Tolerance develops less readily to the potentially lethal respiratory depression.
          • Withdrawal symptoms include
            • restlessness, anxiety, and insomnia
            • tremor, autonomic hyperactivity, delirium,
            • potentially life-threatening tonic-clonic seizures.
          • For a smoother withdrawal, chlordiazepoxide or phenobarbitalis substituted for shorter-acting barbiturates. (MCQ)
      • Cocaine and amphetamine
        • Amphetamines include
          • methamphetamine
          • dextroamphetamine
          • amphetamines that also heighten responses to sensory stimulation
            • methylene-dioxymethamphetamine [MDMA, ‘‘Ecstasy’’] (MCQ)
            • 2,5-dimethoxy-4-methyl- amphetamine [DOM, ‘‘STP’’] (MCQ)
            • methylenedioxyamphetamine [MDA]
      • Mechanism of action
        • Cocaine
          • blocks the dopamine transporter which is also norepinephrine and serotonin transporters at higher doses) in the CNS (MCQ)
          • it inhibit uptake of dopamine into nerve terminals in the mesolimbic pathway that includes the ‘‘brain reward’’ center. (MCQ)
        • Amphetamine
          • blocks the uptake of biogenic amines
          • its major effect is to increase the release of prejunctional neuronal catecholamines, including dopamine and norepinephrine
          • also exhibits some direct sympathomimetic action
          • weakly inhibits MAO. (MCQ)
      • What is “crack cocaine’’, ‘‘ice.’’ , ‘‘spree’’ or ‘‘run’’ , ‘rush’’
        • Cocaine
          • inhaled (snorted)
          • smoked (free-base form, ‘‘crack cocaine’’); (MCQ)
        • Amphetamine
          • usually in the form of methamphetamine, is taken orally, IV,
          • smoked in a formreferred to as ‘‘ice.’’ (MCQ)
          • Short-term, repeated IV administration or smoking (referred to as a ‘‘spree’’ or ‘‘run’’) results in intense euphoria (‘‘rush’’) as well as increased wakefulness, alertness, self-con- fidence, and ability to concentrate. (MCQ)
        • Amphetamine use also (MCQ)
          • increases motor activity
          • increases sexual urge
          • decreases appetite
        • Cocainehas a much shorter duration of action than amphetamine.
      • Cocaine Metabolism
        • is metabolized by plasma and liver cholinesterase(MCQ)
        • genetically slow metabolizers are more likely to show severe adverse effects
        • A nonenzymatic metabolite, benzoylecgonine, is measurable for 5 days or more after a spree and is used to detect cocaine use.
      • Therapeutic uses
        • Cocaine is used as a local anesthetic for ear, nose, and throat surgery. (MCQ)
        • It is the only one with inherent vasoconstrictor activity (MCQ)
        • Uses of Methylphenidate , an amphetamine congener
      • Attention-deficit/hyperactivity disorder (ADHD) (MCQ)
        • decreases behavioral problems, aggression, noncompliance, and negativity associ- ated with ADHD.
      • Narcolepsy(MCQ)
        • It causes an increase in wakefulness and sleep latency.
      • Short-term and adverse effects
        • intense euphoria (MCQ)
        • increased wakefulness, alertness, self-confidence, and ability to concentrate.
        • increases motor activity and sexual urge
        • decreases appetite.
        • Adverse effects due to excessive sympathomimetic activity.
          • Anxiety, inability to sleep
          • hyperactivity, sexual dysfunction
          • stereotypic and sometimes dangerous behavior, often followed by exhaustion (‘‘crash’’) with increased appetite and increased sleep with disturbed sleep patterns (the withdrawal pattern) (MCQ)
        • Toxic psychosis
          • marked by paranoia and tactile and auditory hallucinations. (MCQ)
          • This condition is usually reversible, but it may be permanent.
        • Necrotizing arteritis(MCQ)
          • It is produced by amphetamine.
          • results in brain hemorrhage and renal failure.
        • Perforation of the nasal septum (MCQ)
          • Due to vasoconstrictor effects of ‘‘snorting’’ cocaine
        • Cardiac toxicitycaused by cocaethylenethat forms when cocaine and ethanol are taken together(MCQ)
        • ‘‘cocaine babies’’(MCQ)
          • Fetal abnormalitiesand early childhood learning disabilities from the maternal use of cocaine (‘‘cocaine babies’’)
      • Overdose
        • results in tachycardia, hypertension, hyperthermia, and tremor.
        • Overdose, particularly withcocaine, may cause hypertensive crisis with cerebrovascular hemorrhage and MI. (MCQ)
        • occasionally produces seizures, coronary vasospasm, cardiac arrhythmias, shock, and death.
        • Overdose is more likely with ‘‘crack’’ and ‘‘ice.’’
      • Tolerance and dependence
        • Extremely strong psychologic dependence to these drugs develops.
        • Tolerance, which may reach extraordinary levels, can develop.
        • The withdrawal-like syndrome includes long periods of sleep, increased appetite, anergia, depression, and drug craving.
      • Nicotine
        • Nicotine mimics the action of ACh at cholinergic nicotinic receptors of ganglia, in skeletal muscle, and in the CNS. (MCQ)
        • it has a plasma half-life (t1/2) of 1 hour.
        • Tolerance to the subjective effects of nicotine develops rapidly.
        • Tolerance is primarily cellular; there is some metabolic tolerance.
        • Nicotine produces strong psychologic dependence
        • The withdrawal-like syndrome indicative of physical dependence occurs within 24 hours and persists for weeks or months
        • Medications and replacement therapies
          • Nicotine polacrilexis a nicotine resin contained in a chewing gum that is used as nicotine replacement,
          • A nicotine transdermal patch
          • A nicotine nasal spray
          • Other available pharmacologic therapies
            • varenicline (nicotine)
            • clonidine (a2-adrenoceptor agonist) (MCQ)
            • nortriptyline and bupropion (antidepressant agents) (MCQ)
            • selegiline (MAOI).
      • LSD(d-lysergic acid diethylamide);also mescaline , psilocybin
        • An extremely potent synthetic drug
        • When taken orally,causes
          • altered consciousness, euphoria,
          • increased sensory awareness (‘‘mind expansion’’), (MCQ)
          • perceptual distortions
          • increased introspection.
        • It has action as an agonist at neuronal postjunctional serotonin receptors (5-HT1A- and 5-HT1C).
        • The sympathomimetic activity of LSD includes pupillary dilation,increased blood pressure, and tachycardia. (MCQ)
        • Adverse effectsof LSD include
          • alteration of perception and thoughts with misjudgment
          • changes in sense of time
          • visual hallucinations, dysphoria,
          • panic reactions, suicide (bad trips), (MCQ)
          • ‘‘flashbacks,’’ and psychosis(MCQ)
        • treatment includes benzodiazepines for sedation.
        • A high degree of tolerance to the behavioral effects of LSD develops rapidly.
        • Cross-tolerance develops with mescaline and psilocybin, hallucinogens that are less potent than LSD.
        • Dependence and withdrawal do not occur with these hallucinogens.
      • Phencyclidine (PCP,‘‘angeldust’’) (MCQ)
        • PCP is similar to ketamine
          • Both cause dissociative anesthetia
          • Both have hallucinatory activity
        • PCP is taken orally and IV
        • it is also‘‘snorted’’and smoked. (MCQ)
        • behavioral actions are due ti  antagonist activity at NMDA receptorsfor the excitatory amino acid glutamate. (MCQ)
        • Low doses of PCP produce a state resembling ethanol intoxication
        • High doses cause
          • euphoria, hallucinations
          • changed body image, and an increased sense of isolation and loneliness(MCQ)
          • also impairs judgement and increases aggressiveness. (MCQ)
        • Overdose with PCP may result in seizures,respiratory depression,cardiac arrest,and coma.
      • Marijuana (cannabis),dronabinol
        • active ingredient in marijuana is D-9 tetrahydrocannabinol
        • it acts as an agonist to inhibit adenylyl cyclase through G-protein–linked cannabinoid receptors. (MCQ)
      • Cannabinol CB1-receptors
        • account for most CNS effects
        • localized to cognitive and motor areas of the brain(MCQ)
      • Cannabinol CB2-receptors
        • found in the immune system among other peripheral organs. (MCQ)
      • Anandamide and 2-arachidonylglycerol
        • naturally occurring ligands that are derived from arachidonic acid
        • agonists at CB1-receptors
      • Marijuana is mostly smoked, but can be taken orally
      • It is very lipid soluble.
      • The effects of smoking are immediate and last up to 2–3 hours.
      • The initial phase of marijuana use (the ‘‘high’’) consists of
        • euphoria, uncontrolled laughter, (MCQ)
        • loss of sense of time, and increased introspection.
      • The second phase includes
        • relaxation, a dreamlike state
        • sleepiness, and difficulty in concentration.
      • At extremely high doses, acute psychosis with depersonalization has been observed.
      • The physiologic effects of marijuana include
        • increased pulse rate
        • characteristic reddening of the conjunctiva.
      • Marijuana, and its analogue dronabinol, is used therapeutically to (MCQ)
        • decrease intraocular pressure for the treatment of glaucoma,
        • antiemetic in cancer chemotherapy
        • stimulate appetite in patients with AIDS.
      • Tolerance is not seen  in man
      • Very  mild form of psychologic and physical dependence has been noted among long-term high-dose users
      • Adverse effects of marijuana,
        • Long-term effects similar to those of cigarette smoking, including periodontal disease.
        • Exacerbation of preexisting paranoia or psychosis
        • ‘‘Amotivational syndrome,’’ may be more related to user’s personality type(MCQ)
        • Impairment of short-term memory
        • disturbances of the immune, reproductive, and thermoregulatory systems

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