Study Worksheet 2

Transcript

Drug Drug of abuse used to treat Receptor(s) acted upon Modafinil Cocaine, postchemotherapy cognitive impairment, methamphetamine , other stimulants Catecholamines, serotonin, glutamate, histamine, GABA, orexin, hypocretin Mechanism of action (full/partial direct/indirect agonist, antagonist, etc) full indirect agonist (DA reuptake inhib. & catecholamine reuptake inhib.) Notes (What aspects of drug use does it treat? Side effects, etc) Methadone Heroin, morphine, & similar drugs. Treatment for opioid dependence; however, also highly addictive. Glutamate, Partial agonists. Nicotine replacement Nicotine Full direct agonists Stimulant dependent. Improves cognitive performance in healthy participants. Improves performance of MA-dependant subjects in reversal learning task. Boosts brain activity in executive cntrl regions. Double-blind, placebo-controlled trial of modafinil (400 mg/da) for MA-dependence = no sig. improvements in treatment retention/abstinence from MA in full sample (one size does not fit all!). Better retention/abstinence for subjects w/ high (>18da/mo) MA-dependence before beginning treatment. Opioid dependence. The Dole-Nyswander Legacy (methadone maintenance therapy MMT): view heroin addiction as a medically treatable disease; use the synthetic opioid agonist methadone to treat heroin addiction. Longer ½-life than heroin (thus, less withdrawal), can be admin. daily, prevents withdrawal/craving, produces tolerance, allows relatively normal life. MMT is controversial (trading one addiction for another?): heavily regulated, by law a physician CANNOT prescribe methadone to tx opioid withdrawal fr. office, any M.D. with DEA# can prescribe “for pain”. Analgesic & maintenance therapy for opioid dependence – long action. Developed in Germany in 1937. Acts on same opioid receptors as morphine, w/ many the same effects. Intro. into US IN 1947. Cross-tolerance w/ other opioids, including heroin & morphine. Oral doses can mitigate (lessen) opioid withdrawal syndrome. Higher doses block euphoric effects of heroin, morphine, & similar drugs. Cigarette smoking. Ex: the nicotinic patch (Murray E. Jarvik, Jed E. Rose, & K. Daniel Rose). Nicotine Replacement Therapy: transdermal=nicotine patches, oral=gum, nasal= spray, inhaler. Methylphenidate Buproprion (aka. Wellbutrin, Zyban) nicotine NE, DA Full indirect agonist Full indirect agonist (NE & DA reuptake inhib.), nAChR antagonist. Stimulant dependence, cigarette smoking. 3cholor-N-tert-butyl-β-ketoamphetamine, a substituted amphetamine. Binds selectively to DA transporter (but behave. effects b/c inhib. NE reuptake). Initially marked as antidepressant. Later found to be effective as a smoking cessation aid. Buprenorphine Opioids, treatment for opioid dependence. (However, also produces dependence). Partial agonist: ↓ likelihood of overdose/respiratory depression (like methadone) suppresses opioid craving & withdrawal, blocks effects of selfadmin opioids, treatment retention, ↓ illicit (not permitted) opioid use. α4β2, α3β4, α3β2, α7, & α6 nAChRs Partial agonist (at α4β2 nAchR), Full agonist (at α7-receptors) Varenicline nicotine More effective than NRT’s (nicotinic replacement therapies) for smoking cessation. Aripiprazole Naloxone Heroin/morphine OD. Note: treatment of heroin OD = O2 & naloxone (IV) & monitoring vital signs. Extremely ↑ affinity for µ receptors (in ventrolateral medulla), ↓ affinity for κ- & δ-opioid receptors. Partial agonist (D2 & 5HT1A receptors) Commonly called receptor antagonists, actually inverse agonists. Opioid dependence. (discovered in 1966) First marketed in 1980s as an analgesic. Used to cntrl moderate-acute pain (low dosages approx. 200µg). Used to cntrl moderate chronic pain (20-70 µg/h). In 2002, FDA approved high-dose sublingual buprenorphine for detox & long-term replacement therapy in opioid dependency (now used mainly for this purpose, >2mg). B/c is a partial agonist, maintains patients in a mild degree of physical dependence & is associated w/ mild withdrawal syndrome following cessation (stopping drug abuse). Cigarette smoking. Weak action on α3β2 & α6containing nAChRs. Stimulates the α4β2 receptor but does not produce a full effect like nicotine. Does not greatly incr. the downstream release of DA. Blocks the ability of nicotine to bind/stimulate the mesolimbic DA system (akin to action of buprenorphine in treatment of opioid addiction). Also acts as agonist at 5-HT3 receptors (may contribute to mood altering effect of varenicline). Stimulant dependence. (aka. Narcan, Nalone, Narcanti) Devoloped in 1960s. Naloxone IV begins acting within a minute. Distributed in emergency OD response kits to heroin & other opioid drug users (↓ the rates of fatal OD). CDC estimates take-home naloxone & training on using it reversed 10,000 opioid OD deaths. -Experimental use to treat: Congenital insensitivity to pain w/ anhydrosis: extremely rare (1:125 million), person does not feel pain. Depersonalization disorder (dissociative disorder): subjective experience of “unreality in one’s sense of self”. -In combination w/ opioid agonist drugs: 1. with oxycodone to prevent opioid-induced constipation in patients requiring opioid therapy. 2. with buprenorphine (Suboxone) in maintenance therapy for opioid dependence. The “unnatural” enantiomer of (-)-naloxone. Unline (-), (+) has no sig. affinity for opioid receptors. Selective antagonist of TLR-4. TLR-4: involved in immune-sys response. Activation of TLR-4 induces glial activation & release of inflammatory mediators (e.g. TNF-α & Interleukin-1). (+) used to block addiction via immune sys of the brain, w/o targeting brain’s wiring; prevents cravings for opioid drugs. Opioid drugs bind to TLR4 in similar way to normal immune response to (+) Naloxone (aka. Dextronaloxone) Morpoine/heroin & other opioid drugs TLR4 Selective antagonist of Toll-like receptor 4 (TLR-4). bacteria (problem is TLR4 acts as amplifier for addiction). (+) suppresses opioid-induced CPP and reduced opioid self-adim in rats. Note: (-)-Naloxone: Naltrexone Prevent relapse. Blocks heroin effects. Treatment for alcohol dependence. Commonly called receptor antagonists, actually inverse agonists. or Dosage Forms: naltrexone tablets – may drop out early, craving can be alleviated w/ opiate. ↓ dropout w/ supervised tablet taking, incentives, sustained-release naltrexone. Can also take naltrexone via injection (higher dosage, less likely to drop out. (Maintenance after detox.). Long-acting inverse agonist, used to prevent relapse of opioid dependence. Works best for highly motivated people. Used in rapid detox: - principle: to induce opioid-receptor blockade while patient is in state of impaired consciousness, to attenuate withdrawal symptoms. - Under general anesthesia (“ultra-rapid detox”): requires intubation & ext. ventilation. - Also possible under light sedation. Rapid detox followed by oral nealtrexone daily for up to 12 mo. (also can use naltrexone implant in lower abdomen). Scientific disagreement to safety of procedure, as well as if should be performed under light sedation/general anesthesia due to rapid & severe withdrawal that occurs. Often misrepresented as a “cure” for opioid dependence. Rapid detox criticized for questionable efficacy in long-term opioiddependence management. CONS: no clear evidence of efficacy of maintenance treatment, poor complienece, receptor sensitization may ↑ risk of death from opiate OD w/ cessation of naltrexone treatment & relapse into addiction. In Russia, substitution therapy forbidden, only option is naltrexone. Due ot lack of alternative & stronger family cntrl of compliance (adherence), naltrexone more effective for relapse prevention & abstinence stabilization in Russia than in Western countries. Naloxone + Buprenophine = Suboxone/Subutex (sublingual/sublingual tablet): discourages i.v. abuse & diversion in patients dependent on full µ-opioid agonists. Suboxone Precipitates withdrawal in opiate-dependent users. Also treats alcohol dependence: in animals, opiate antagonists ↓ alcohol preference (particularly in strains bred for excessive alcohol/after envir. Stressors that elicit excessive drinking). In humans, naltrexone may ↓ reinforcing or pleasurable effects o f alcohol in social drinkers & in alcoholdependent subjects who slip. Thus, data suggests opioid antagonism may have important pharmacological effects of ↓ the reinforcing effects of alcohol & ↓ likelihood of returning to clinically sig. drinking. Mech: (Opioids can induce DA release via disinhib. of inhib GABAergic tone). Naltrexone blocks pleasant & reinforcing effects of alcohol by preventing stimulation of opioid receptors, ↓ DA release in VTA. Naloxone + Buprenophine = Suboxone/Subutex (sublingual/sublingual tablet): discourages i.v. abuse & diversion in patients dependent on full µ-opioid agonists. Precipitates withdrawal in opiate-dependent users. BZ OD. GABA-A receptors GABA antagonist (only benzodiazepine (BZ) receptor antagonist on the market) Antidote in treatment of BZ OD. Reverses effects of BZs by competitive inhib at BZ binding site on GABA-A receptor. Is one of the ingredients of Prometa (a controversial treatment protocol used primarily for METH addiction, claimed to be effective for alcohol & cocaine dependence). - Inhibits ethanol metabolism. Mech: Ethanol is converted into acetaldehyde by alcohol dehydrogenase (ADH). Acetaldehyde is then transformed into acetate by aldehyde dehydrogenase (ALDH). Disulfiram inhibits ALDH (↑ acetaldehyde). Produces “the disulfiram-ethanol rxn” that promotes abstinence from alcohol. - Inclinical trials, disulfiram ↓ both alcohol & cocaine use. Later shown that disulfiram ↓ cocaine use independent of an action on alcohol consumption. Mech: Disulfiram ↑ DA levels. In the catecholamine syn. Pathway, tyrosine converted to 3,4-dihydroxy-L-phenylalanine (L-DOPA) by tyrosine hydroxylase (TH), which is then transformed into DA by aromatic aa decarboxylase (AADC). DA β hydroxylase (DBH) then converts DA into NE. Disulfiram inhibits DBH, ↓ NE production & ↑ ratio of DA:NE. Flumazenil Disulfuram Inhibits ethanol metabolism. Reduces alcohol & cocaine use. Catecholamines, acetaldehyde, DA, NE. Enzyme inhibitor How can DBH inhib. by disulfiram reduce cocaine use? (DA replacement therapy: ↓ rewarding effects of cocaine, ↑ aversive affects of cocaine. Favored hypothesis: Decreased levels of NE mediate relapse prevention. With ↓ NE, ↓ excitatory drive to VTA would result in ↓ extracellular DA despite a higher DA level. Possible mech of Disulfiram effect on cocaine addiction: Vigabatrin Treats stimulant dependence. GABA GABA analogue, enzyme inhibitor. An antiepileptic drug that inhib. the catabolism of GABA by irreversibly inhibiting GABA transaminase. GABA analogue, but not a GABA receptor agonist. Some positive findings in treating stimulant dependence. Produces visual field defects. Galantamine, Rivastigmine, Donepezil. Improved sustained attention in cocaine users (Physostigmine, Rivastigmine). Attenuate subjective effects of amphetamines. Clinical trials have not yet shown reduced use of stimulants. Cholinesterase inhibitors Cognitive Function ACh Enzyme inhibitor. Acomprosate Ondansetron Topiramate Drug Short-term side effects Long-term side effects Nicotine =liquid soluble plant alkaloid, half-life of 2 Blocks withdrawal. Desensitizes nicotinic acetylcholine Receptor(s) acted on, modulation (excitatory = +, inhibitory = -) (+) nAChR Receptor composition and stoichiometry Important subunits and their function Notes: Pentamers, assembled from various nAChR subunits encoded Specific agonist at ion channels normally gated by Ach (called neuronal hrs in bloodstream, reaches brain in 10 sec, metabolism rate: depends on gender, genetic factors, age, ethnicity, mode of ingestion. Come from flower nicotiana tabacum. Principal breakdown product is cotinine. receptors. Addictive & very toxic (LD50 0.1 mg/kg in childen). & other longterm physiological alterations. Induces behave. tolerance, sensitization, dependence, & withdrawal. combinations of proteins encoded by different genes. by 17 different genes. nicotinic Ach receptors, nAChRs). In vertebrates, 17 different genes encode nAChR subunit proteins. 5 subunits, 4 genes: (α1)2βγδ Note: A fxnal receptor of defined composition & stoichiometry = subtype. How nicotine works? Release of NT DA in mesolimbi sys of brain mediates reinforcing properties of several drugs of abuse, including nicotine. When administered systemically incr EC levels of DA in dorsal & ventral NAcc striatum by acting on nAChR located on DA cell bodies and/or nerve terminals. Accordingly, lesionso of mesolimbic DA neurons attenuate nicotine self-admin in rats. Transgeneic mice establish a role for nAChRs in reinforcing properties of nicotine (β2 subunit of nAChRs). β2-/mice extinguish selfadmin behavior when nicotine is substituted for cocaine (compared to WT, or self-admin nicotine after trained to self-admin cocaine). Rewarding effects attenuated thru VTA. α4containing nAChRs mediate rewarding properties of nicotine. Low dose nicotine causes nAChR fxnal up-regulatio in L9’Ala mice. Behav. Test to study motivational properties of nicotine & other drugs is CPP. Based on CPP assay, 0.5 mg/kg nicotine is rewarding for WT mice. Based on CPP assays, α4containing nAChRs are sufficient for the rewarding properties of nicotine. Most adult smokers start smoking during their adolescence. Smoking cessation rates of 7-20%. Smokers who acquire insular damage more likely to quit smoking easily & immediately and to remain abstinent (no longer experience conscious urges to smoke after quitting). Alcohol K+ voltagegated ion channelsm GABAAR, GlyR, P2X. Inhallents – toluene Inhallents – N20 Notes: Running Wheel Exercise Ameliorates METH Damage to DA and 5-HT Terminals (slide 13, 1st lecture of 6th week) -