Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Drug design wikipedia , lookup
Drug discovery wikipedia , lookup
Pharmacogenomics wikipedia , lookup
Neuropsychopharmacology wikipedia , lookup
Pharmacognosy wikipedia , lookup
Pharmaceutical industry wikipedia , lookup
Prescription costs wikipedia , lookup
Pharmacokinetics wikipedia , lookup
Drug interaction wikipedia , lookup
Polysubstance dependence wikipedia , lookup
Drug Abuse: Outline Why do people do drugs? Reward System Common features of drug addiction – Tolerance, withdrawal, craving & relapse Therapy for drug abuse Abused Drugs – Opiates, Cocaine & Amphetamine, Alcohol, Benzodiazepines, Nicotine, Cannabis Models of Addiction: Why do people use drugs? Because they are sinners! (Moral model) – Drug addicts lack will power (moral fiber) – Predominant until middle of 19th century – Treatment: Punishment; Spiritual reawakening Because ‘they have a problem’ (Disease Model) – There is a biological component to addiction A constitutional factor: once and alcoholic, always an alcoholic – Predominant in late 19th century, in ‘60s, and in AA – Treatment: decriminalize; total abstinence – Weakness of the model: Addiction is not a ‘single’ disease Models of Addiction: Why do people use drugs? Because it feels bad not to. Dependence Model Drugs triggers pleasure after a while tolerance develops absence of drug leads to withdrawal People take drug to prevent withdrawal symptoms Weaknesses of this model: – withdrawal & dependence are often uncorrelated (e.g, cocaine) – "No doc, craving is when you want it—want it so bad you can almost taste it ...but you ain’t sick ...sick is, well sick" (Childress et al.1988). Models of Addiction: Why do people use drugs? Because its use is rewarded Reinforcement Model – Drug addiction is a learned pattern of behavior (maladaptive) – Addictive drugs have reinforcing effects – the reward system is activated by Natural reinforcers (sex, food) and artificial reinforcers (drugs of abuse) Dopamine The Reward System: Dopamine Activities of survival (sex, feed) activate the reward system Drugs of abuse similarly activate the reward system Electrical stimulation of the reward system is also addictive Electrical intracranial self-stimulation stimulation Olds & Milner (1954) n. accumbens The mind is its own place, and in itself, can make heaven of Hell, and a hell of Heaven. dopamine (Satan, in John Milton’s Paradise Lost, book 1, ll. 254–5) Quoted by R. Cardinal VTA ‘drug addiction is a learned pattern of behavior’ Brief detour on ‘Learning’: operant conditioning Operant conditioning (aka instrumental learning) Reinforcing stimulus (dopamine release) follows a particular behavior (lever press, injecting heroin) and thus makes the behavior become more frequent Skinner’s box ‘drug addiction is a learned pattern of behavior’ Brief detour on ‘Learning’: Classical conditioning Pavlov’s dog: US UR (meat -> salivate) CS + US (bell + meat) CS UR (bell -> salivate) Cue-induced Craving: Images of drugs (CS) become associated with the effect of the drug. Dopamine activation (UR) shifts from US (drug) to CS (context, friends, drug stimuli) • Drugs with fast absorption are most CS & US are in close temporal proximity addictive (close temporal link between behavior and drug effect) Animals work for reinforcement for several reasons, including... operant conditioning Classical conditioning Dopamine release in the nucleus accumbens during Intracranial self stimulation - during sexual behavior - in anticipation of sex -during ingestion of a preferred food - to a cue associated with food (CS) -during IV cocaine self-administration -to a cue associated with cocaine (CS) Common features of drug addiction Tolerance: – the need of larger doses to obtain the same effect Withdrawal: – Usually starts hours after stopping drug use – Different drugs produce different withdrawal symptoms from the very mild (cocaine) to the very severe (alcohol) Craving & Relapse: – During abstinence, prefrontal cortex and the anterior cingulate cortex (ACC) of cocaine abusers is hypoactive – Context previously associated with cocaine leads to increased activation of ACC – In rats, one injection activates dopaminergic neurons in reward system of the abstinent rat (‘the first one is free’) – Stressful stimuli (e.g, non-dominant male, isolated rat) increases animal’s susceptibility to relapse Sexual stimuli activate nodes of this limbic circuit (see note) (Dr. Anna Rose Childress, Penn) Cue-induced cocaine craving activates limbic structures correlated with subjective reports of craving Treatment ‘Cold turkey’ method: Unnecessarily painful Mimic the effect of the drug of addiction – The goal is to Minimize Withdrawal Methadone (opioid) for heroin Nicotine patch Benzodiazepines (GABA) for alcohol – The new drug is less damaging – Problems: side effects, cost, social stigma Block the drug – The goal is to counteract the drug of addiction – Problem: the lack of compliance due to withdrawal, disphoria, etc. Cocaine ‘vaccine’ Reduce addiction (tapping on the reward system) – Most promising approach (but untested) - Commonly abused drugs: Write down as many as you can Opiates: – Endogenous opiates: secreted in response to survival behaviors analgesia positive reinforcement (encourages the survival behavior) – Exogenous opiates; Morphine (opium) Codeine (opium) Heroin (semisynthetic) •1897 – Mail order advertisement from Sears, Roebuck & Co. for opiumbased drink •Early 20th century – mothers encouraged to use opium syrup to soothe teething pain • •Narcotic comes from the Greek word, “narke”, meaning stupor and referred to any drug that induced sleep morphine Diacetyl-morphine (1898) Naloxone: Antagonist Opiate Effects Analgesia Blunted emotion to pain Euphoria Sedation Periaqueductal gray matter amygdala limbic system reticular formation & locus coeruleus Reinforcement VTA and nucleus accumbens hypothermia reduced libido hypothalamus (preoptic area) reduced sexual hormones Autonomic effects brain stem Shallow breathing, Inhibit vomit*, Inhibit coughing Other effects: Small pupils, constipation, vasodilation (warm & flushed face) Opiates: administration & distribution Administration: smoke (Opium, Heroin) intranasal (heroin) intravenous (Heroin) oral, not very good to get high (Codeine, morphine, methadone) Distribution: Heroin is 10 times more liposoluble than morphine, so it reaches brain faster and at larger concentrations, and get transformed into morphine Opiates: tolerance & withdrawal Tolerance Develops rapidly (tenfold increase in 3-4 months) Shift from nasal to IV administration Withdrawal: due to increased noradrenaline by locus coeruleus starts 6-12 hs after last dosis, peaks at 48-72 hs, over after a week restless, agitation, chills, goose bumps (‘going cold turkey’), followed by drowsiness (12 hs), stomach cramps, vomit, diarrhea, sweating & twitching of extremities (‘kicking the habit’) Not as dangerous as alcohol withdrawal Opiates: Side effects Most of the risks are secondary to the status as illegal. – Legal: Jail – Health: HIV, hepatitis C, overdose – Financial: loss of employment, cost of drugs – Few direct problems from chronic use (surprisingly) (constipation, bladder cancer, pregnancy) Opiates: Treatment – Acute overdose: Naloxone (opiate antagonist) – Methadone maintenance (+ social support) Potent opiate, but Slow absorption (Oral administration) and thus – Blunted euphoric effect (No ‘high’) – Less addictive Long-lasting (24hs half life): Blocks effect of heroin – Social support: stable employment predicts clinical outcome – Shortcomings: side effects, stigma, difficult access (6 states don’t have any clinic) Opiates: treatment Medically supervised detoxification Goal: to block opioid receptors – Naltrexone (antagonist) – Buprenorphine: partial agonist (easier to detox than methadone) Problem 1: withdrawal Solution: Clonidine (alpha-2 adrenergic), antagonizes adrenergic response and thus minimizes withdrawal effects Problem 2: Relapses (?) Trainspotting. Screenplay by John Hodge, based on novel by Irvine Welsh Maintenance Therapies Side effects of heroin Reduced libido Withdrawal: Diarrhea (Renton, the main character in the play, has decided to stop his heroin addiction, but wants a last hit) Renton: What the fuck are these? Mickey: Opium suppositories. Ideal for your purpose. Slow release. Bring you down gradually. Custom fucking designed for your needs. Renton: I want a fucking hit! (Renton voice over) Heroin had robbed Renton of his sex drive, but now it returned with a vengeance. And as the impotence of those days faded into memory, grim desperation took hold in his sex-crazed mind. His postjunk libido, fuelled by alcohol and amphetamine, taunted him remorselessly with his own unsatisfied desire dot. (22.00) Heroin makes you constipated. The heroin from my last hit is fading away and the suppositories have yet to melt. I am no longer constipated Trainspotting. Screenplay by John Hodge, based on novel by Irvine Welsh Decision making: short-term vs. long-term reward Reward system Highjacked from natural reinforcers (e.g., sex, food) Choose your future. Choose life. But why would I want to do a thing like that? I chose not to choose life: I chose something else. And the reasons? There are no reasons. Who need reasons when you've got heroin? People think it's all about misery and desperation and death and all that shite, which is not to be ignored, but what they forget - is the pleasure of it. Otherwise we wouldn't do it. After all, we're not fucking stupid. At least, we're not that fucking stupid. Take the best orgasm you ever had, multiply it by a thousand and you're still nowhere near it. When you're on junk you have only one worry: scoring. When you're off it you are suddenly obliged to worry about all sorts of other shite. …You have to worry about bills, about food, about some football team that never fucking winds, about human relationships and all the things that really don't matter when you've got a sincere and truthful junk habit. Moral model The only drawback, or at least the principal drawback, is that you have to endure all manner of cunts telling you that … “ Every chance you've ever had, you've blown it, stuffing your veins with that filth” … He's always been lacking in moral fibre. Cocaine and Amphetamine: administration & distribution Administration: intranasal intravenous smoke (‘crack’) Distribution: ‘Crack’: is more liposoluble, thus stronger effect! Cocaine has a very short half life (40 mins) Cocaine and Amphetamine Dopamine agonists – Cocaine blocks dopamine reuptake – Amphetamine also stimulates dopamine release Behavioral effects – – – – – – Euphoria mesolimbic system (reward) reinforce drug-taking behavior Stimulation, Insomnia repetitive motor behaviors nigrostriatal system psychotic behavior: hallucinations, delusions of persecution mood disturbances, Chronic effect – decreased number of dopamine transporters in basal ganglia, despite a three year abstinence from the drug (predisposition to Parkinson’s disease) Cocaine and Amphetamine: Treatment Aimed at reducing ‘craving’ – Agonists on D3 receptors in reward system - GABA agonist to reduce dopamine secretion in reward system Dopamine vaccine (?) Antidepressants (?) – An effect of chronic cocaine use may be depression-like changes – Patients with Parkinson’s disease also have depression Alcohol Alcohol acts on many systems: – Blocks NMDA: that is why memory is impaired, and why alcohol withdrawal can trigger seizures – GABA: That is why at low levels alcohol has an anxiolytic effect, and at higher levels sedative effect – Dopamine (mesolimbic system): increases release of DA in nucleus accumbens, thus the euphoria, addictive power of alcohol Alcohol Fermentation (by yeast) – Sugar + water alcohol + carbon dioxide (COs) Grapes wine grains beer – Yeasts tolerate only low levels of alcohol (10-15%) Distillation – Alcohol + heat vaporized alcohol Wine brandy Fermented grains whisky Alcohol: Pharmacokinetics Absorption is faster: in empty stomach, because alcohol is metabolized in stomach In high concentration (tequila vs. wine) In women (lower levels of enzime in stomach) Metabolization: – in the liver – 0.015% per hour (linear) – Nothing you can do to speed up rate Blood Alcohol Concentration: – – – – 0.08% (80 mg per 100 ml of blood) > .08 illegal to drive > .15 dangerous (black outs, unable to walk) > .35 (1% death due to no gagging reflex) Acute Alcohol Intoxication Blood Alcohol Concentration: 0.08% (80 mg per 100 ml of blood) Fatal Crashes: BAC Increase 0.05-0.09 11X 0.1-0.14 48X >0.15 380X (Zador, 1991) Benzodiazepines Mechanism of action – GABAergic system (major inhibitory system) Effects: – Reduce anxiety – Increase sleep (hypnotic), – Reduce seizures – muscle relaxant Side effects (same as before): – sedation, – drowsiness, – muscle weakness, – impair memory; For treating: phobias insomnia epilepsy, alcohol withdrawal cerebral palsy, pre-surgery Benzodiazepines Withdrawal (opposite of the main effects): – – – – increased anxiety insomnia, tremor, restlessness. Peak in 2-10 days, and most think it abates within 4 weeks (others say it can take years). Barbiturates Mechanism of action – GABAergic system (major inhibitory system) – At higher (anesthetic) concentrations, they directly increase Cl- channel openings, even in the absence of GABA. Rapid tolerance; profound withdrawal; low therapeutic index; synergism with alcohol (Marilyn Monroe) Nicotine Mechanism of action – activates nicotinic receptors of acetylcholine (Ach) – Including those in the mesolimbic system – But unlike Ach, nicotine is not affected by Ach-ase – Steady concentration of nicotine in synapses leads to tolerance by downregulation of receptors Withdrawal: – Restlessness, anxiety, insomnia Nicotine is highly addictive drug Smokers exhibit compulsive behavior typical of drug addiction it accounts for more deaths than the so-called “hard drugs”. Cannabis: THC is the active ingredient in marijuana. THC receptor: CB1 – large concentration in hippocampus (memory effect) THC stimulates release of dopamine in the nucleus accumbens and the ventral tegmental area – Long-term damage: Cognitive impairments from long-term use appear to be subtle.