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DRUG_ABUSE-2011-C-lecture-publishkey - Drug Addiction and...

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Unformatted text preview: Drug Addiction and Drug Abuse PMY 406 / 512 / 516 Spring 2011 Reading Golan, Chapter 17 Goodman and Gilman, Chapter 23* Recommended reading Volkow and Li (2004) “Drug addiction: The neurobiology of behaviour gone awry,” Nat. Revs Neurosci, 5, 963-970. Hyman, Malenka, and Nestler (2006) “Neural mechanisms of addiciton: The role of reward-related learning and memory,” Ann. Rev. Neurosci, 29, 565-598. Specific Drugs of Abuse • Opioids • CNS depressants – Barbiturates – Alcohol • CNS stimulants – Amphetamines – Methamphetamine – Cocaine • • • • • Nicotine and tobacco Cannabinoids Hallucinogens PCP Inhalant anesthetic gases, and volatile solvents ANRV278-NE29-20 ARI 9 May 2006 14:29 Cingulate gyrus Striatum Prefrontal cortex Figure 2 Substantia nigra Nucleus accumbens Ventral tegmental area Neurosci. 2006.29:565-598. Downloaded from arjournals.annualreviews.org te University of New York - Buffalo on 12/28/09. For personal use only. Dopamine projections to the forebrain. Illustrated are projections from the ventral tegmental area to the nucleus accumbens, and prefrontal cerebral cortex, and projections from the substantia nigra to the dorsal striatum (caudate and putamen and related structures). responses (pleasure), desire or “wanting,” and increase synaptic dopamine in the nucleus acrapid learning of both predictive cues and effi- cumbens (NAc), the major component of the cient behavioral sequences aimed at obtaining ventral striatum (Wise & Bozarth 1987, Koob the reward. Two major differences between & Bloom 1988, Di Chiara 1998, Wise 1998) natural rewards and addictive drugs conspire (Figure 2). Whether acting directly or indito make addiction remarkably harmful. First, rectly (Johnson & North 1992, Jones et al. drug rewards tend to become overvalued at 1998, Tapper et al. 2004, Waldhoer et al. 2004, Hyman, Malenka, and Nestler (2006) Ann. Rev. Neurosci, 29, 565-598. the expense of other rewards, contributing Justinova et al. 2005), all addictive drugs into compulsion and to a marked narrowing of crease levels of synaptic dopamine within the life goals to obtaining and using drugs. Sec- NAc. The source of dopamine to the NAc ondly, unlike natural rewards, addictive drugs (as well as to the amygdala, hippocampus, and do not serve any beneficial homeostatic or re- PFC) is the ventral tegmental area (VTA) of productive purpose but instead often prove the midbrain (Figures 2 and 4). The NAc Substance dependence (addiction) is a “maladaptive pattern of substance use, leading to clinically significant impairment or distress, as manifested by three (or more) of the following symptoms ....” Golan, p. 285 “ ..... substance dependence (addiction) as a cluster of symptoms indicating that the individual continues use of the substance despite significant substance-related problems.” APA as cited in Goodman-Gilman, p. 607 Definitions Tolerance Pharmacokinetic tolerance Pharmacodynamic tolerance Learned tolerance Cross-tolerance Dependence Physical dependence Psychological dependence Cross-dependence Effects of tolerance and sensitization in the dose-response curve Golan, Figure 17.1 Induction of tolerance by increased metabolism of the drug Barbiturates Alcohol Tobacco smoke St. John’s wort Carbamazepine Golan, Figure 17.2 Pharmacodynamic mechanisms of tolerance Golan, Figure 17.3 Induction of tolerance to morphine ↓ ↓ activation cAMP response element-binding protein ↑ ↑ regulation Golan, Figure 17.4 Importance of the route of administration on PK and PD drug PK PD Golan, Figure 17.5 Role of opioid in the brain reward pathway Golan, Figure 17.6 Opioids - Heroin • Development of tolerance depends on pattern of use: – Intermittent use ⇒ can obtain analgesic and sedative actions for an indefinite period. – Continuous use ⇒ significant tolerance – Thus, user in search of high ⇒ requires constant increase in dose . • Lethal dose may be increased. • But there is a dose at which respiratory depression ⇒ death. Opioids • In clinical practice, care is taken to avoid establishment of tolerance: – Give minimum dose sufficient to achieve analgesia. – Keep interval between doses as long as possible. • Since most opioids not completely selective for a single sub-type, extent of cross-tolerance is variable among opioids. CNS Depressants: Extent and pattern of use • Barbiturates – Use exceeds opioids. – Use includes • Short-acting barbiturates are preferred to long-acting agents (phenobarbital). – Pentobarbital = "yellow jackets” – Secobarbital = "red devils" • Benzodiazepines are uncommon for deliberate abuse. – Except the short-acting agents (e.g., triazolam) which have high street value. • Dependence not readily recognized. CNS Depressants - Withdrawal syndrome Alcohol - Sedative-Hypnotics - Gaseous Anesthetics • Marked similarities seen with all sedative-hypnotic agents • Not identical, but reasonable to describe a general depressant withdrawal syndrome • Mildest form – Paroxysmal EEG abnormalities – Rebound increases in REM sleep, insomnia, anxiety – Tremulousness and weakness General depressant withdrawal syndrome has all the components of ethanol-induced delirium tremens. • In severe dependence, withdrawal can lead to – Tonic-clonic grand mal seizures – Status epilepticus • In contrast to opioid withdrawal, the withdrawal syndrome with these agents can be a lifethreatening emergency CNS Depressants • While there may be considerable tolerance to the sedative and intoxicating effects, the lethal dose is not much greater in addicts than in normal individuals. • Cross-tolerance between various agents in this group is common. • Babies born to mothers physically dependent on general CNS depressants will manifest withdrawal syndromes of varying severity. – Signs similar to opioid withdrawal in newborn – Treatment: Administer CNS depressant or benzodiazepine. Two types of tolerance develop with respect to barbiturates • Pharmacokinetic (or metabolic) tolerance – This is due to induction of the hepatic drug metabolizing enzymes. Pharmacodynamic (adaptive) tolerance: Illustration • Naive individual takes phenobarbital to achieve 5 µg/cc plasma concentration ⇒ drowsiness • After 12 days use there are no subjective impressions of drowsiness or sedation even though the plasma concentration approaches 25 µg/cc. • YET – tolerance does not develop to the life-threatening medullary respiratory depression. • There is no difference in concentration required to depress respiration ! Pharmacodynamic tolerance • An important characteristic of the pharmacodynamic tolerance in this class of agent: – Tolerance develops to sedative effects. – Yet the lethal dose is not increased. – Acute barbiturate poisoning with marked respiratory depression may be accidentally superimposed on chronic intoxication at any time (same as for alcohol; see below). Psychological dependence • Minor abstinence syndrome • Feelings of anxiety, apprehension, insomnia. • That is, there is a re-emergence of the state for which the drug was originally prescribed. Alcohol 1. 2. 3. 4. Pharmacokinetic ⇐ increased metabolism. • • Only seen in severely alcoholic subjects Higher blood concentrations are needed to produce intoxication in tolerant than in normal individuals Pharmacodynamic tolerance due to adaptation. BUT - there is no marked elevation in lethal dose Thus - acute intoxication with marked respiratory depression may be super-imposed on chronic alcoholic intoxication at any time (similar to case for barbiturates). Cross-tolerance to other agents • Alcohol with sedatives-hypnotics – Barbiturates and benzodiazepines – Due to pharmacodynamic tolerance and metabolic tolerance Cross-tolerance • Cross-tolerance is seen only in sober alcoholic. • When blood ethanol concentrations are high, the synergistic actions of the “cross-tolerant” drugs remain. – Combined effect ⇒ profound depression • No cross-tolerance between ethanol and opioids. • Chronic high-dose use of ethanol ⇒ physical dependence • Withdrawal syndrome similar—but not identical—to barbiturates. • Three distinct withdrawal stages. Signs of ethanol withdrawal: 3 phases (Detail) A. W ithdrawal with mild-to-moderate dependence Onset of withdrawal occurs 8-24 hours after cessation of ethanol intake. (previous ethanol load already cleared by this time) 1. feeling of nervousness; 2. apprehension; 3. muscle weakness; 4. tremor and nausea; 5. retching and anorexia 6. abdominal quivering ("butterflies in the stomach") is a common feeling 7. experienced on awakening; controlled by ingestion of ethanol B. W ithdrawal with moderate-to-severe dependence If abstinence continues for 12-24 hours in the 1st phase, leads to this second phase characterized by: 1. marked tremor and muscle cramps 2. rise in body temperature; sweating; diarrhea 3. nausea and vomiting 4. tachycardia and rise in blood pressure 5. hyperpnea; accompanied by a swing from the previous metabolic acidosis to respiratory alkalosis; 6. insomnia; any sleep is of only REM-type sleep; full of nightmares; 7. agitation becomes more pronounced as this phase progresses. C. W ithdrawal with third phase reactions: Delirium tremens 1. Begins 2-4 days after start of abstinence ! 2. "Muttering delirium"; confusion, disorientation; marked agitation and panic reactions; paranoid reactions; hallucinations ("pink elephants"). 3. Clonic muscle jerks may progress to grand mal seizures and then to status epilepticus. 4. Mortality rate in the fully developed untreated state of delirium tremens is high (range: 15-to-greater-than-50 % of cases). a. Treatment with benzodiazepines CNS Sympathomimetics Amphetamine, Cocaine 1. 2. 3. 4. 5. Euphoric effects of amphetamine (i.v.) and cocaine very similar Reduced sense of fatigue ⇓ Decrement in performance caused by lack of sleep Subjective effects are indistinguishable. Duration of effects a. b. c. Cocaine ...............50 minutes Amphetamine ......10 hours Methamphetamine 5 hours • Cocaine: Inhibits dopamine re-uptake in – Ventral tegmental area – Nucleus accumbens – Frontal cortex • Amphetamine: Promotes release of newly synthesized dopamine from intraneuronal stores – Ventral tegmental area – Nucleus accumbens – Frontal cortex Golan, Figure 17.9 Mechanisms of action of amphetamine and cocaine Golan, Figure 17.8 Annu. R by Figure 3 Psychostimulant action. The psychostimulant drugs cocaine and amphetamine increase synaptic dopamine. (Upper panel) Cocaine blocks the dopamine reuptake transporter located on the presynaptic membrane, thus acutely increasing synaptic dopamine. (Right panel) Amphetamines enter dopamine neurons via their reuptake transporters and interact intracellularly with the vesicular monoamine transporter (VMAT) to release dopamine into the presynaptic terminal. Dopamine (DA) is then “reverse transported” out of the neuron into the synapse. 572 Hyman · Malenka · Nestler Annu. Rev. Neurosci. 2006.29:565-598. Downloaded from arjournals.annualreviews.org by State University of New York - Buffalo on 12/28/09. For personal use only. neurons, for example, do not abolish intravenous heroin self-administration. Moreover, animals will self-administer opiates directly into the NAc, where µ opioid receptors exa pressed on NAc neurons appear to bypass dopamine inputs from the VTA (Pettit et al. Cocaine inhibits monoamine reuptake 1984, Bardo 1998). Cannabinoids, ethanol, and nicotine are also thought to produce Cocaine DAT reward partly via nondopaminergic mechaDA Dopamine nisms. Further, mice in which TH has been VMAT genetically inactivated not only continue to show hedonic responses to food rewards (liking), but can also still learn relevant cues. Animals without dopamine cannot, however, use b Amphetamines cause monoamine release Amphetamines DA Dopamine Hyman, Malenka, and Nestler (2006) Ann. Rev. Neurosci, 29, 565-598. Figure 3 Psychostimulant action. The psychostimulant drugs cocaine and amphetamine increase synaptic dopamine. (Upper panel) Cocaine blocks the dopamine reuptake transporter located on the presynaptic membrane, thus acutely increasing synaptic dopamine. (Right panel) Amphetamines enter dopamine neurons via their reuptake transporters and interact intracellularly with the vesicular monoamine transporter (VMAT) to 2005), whic stantia nigr within the m Despite dopamine, what inform release in t thought to tation of a has been sh imals can s sponses in t ies in which pharmacolo Robinson 1 tyrosine hy enzyme in d Palmiter 20 mals contin Because an defect in th and thus ca be placed in test prefere blocked or (liking) for or nonnutri alternatives substances. Dopami be required or for learn ministration antagonists neurons, fo venous hero animals wil into the NA pressed on dopamine i 1984, Bard and nicotin reward part nisms. Furt genetically show hedon • Cocaine – Tolerance develops toward euphorigenic, anorectic effects. – Psychological dependence – No physical dependence. • That is, there is no characteristic withdrawal syndrome. • Amphetamine – Tolerance develops toward some of the central effects (euphorigenic; anorectic effects; hyperthermic; lethal actions). – Psychological dependence – No physical dependence (??) – Cross-tolerance among amphetamine-like agents. • Tolerance does not develop to psycho-toxic effects of cocaine and amphetamine; I.e., schizophrenic-like symptoms (toxic psychosis). • • • • Suspiciousness; paranoia; paranoid ideations; visual hallucinations; Tactile hallucinations ("cocaine bugs" in the skin) and visual hallucinations ("snow lights"). Bruxism; touching-picking the face-andextremities; feeling of being watched. Stereotypical repetitious behaviour. • Withdrawal signs? 1. There are no grossly observable disturbances or disruptions that necessitate gradual withdrawal of cocaine or amphetamine-like agents. 2. Withdrawal syndrome for both includes drug craving, prolonged sleep, general fatigue, depression. Ephedrine, Ψ-Ephedrine and Methamphetamine 1 2 Methamphetamine Meth and the Brain • • • • Meth releases a surge of dopamine, causing an intense rush of pleasure or prolonged sense of euphoria. Over time, meth destroys dopamine receptors, making it impossible to feel pleasure. Although these pleasure centers can heal over time, research suggests that damage to users' cognitive abilities may be permanent. Chronic abuse can lead to psychotic behavior, including paranoia, insomnia, anxiety, extreme aggression, delusions and hallucinations, and even death. Visible Signs • • • Meth abuse causes the destruction of tissues and blood vessels, inhibiting the body's ability to repair itself. Acne appears, sores take longer to heal, and the skin loses its luster and elasticity, making the user appear years, even decades older. Poor diet, tooth grinding and oral hygiene results in tooth decay and loss. Meth Mouth • • • "Meth mouth" is characterized by broken, discolored and rotting teeth. The drug causes the salivary glands to dry out, which allows the mouth's acids to eat away at the tooth enamel, causing cavities. Teeth are further damaged when users obsessively grind their teeth, binge on sugary food and drinks, and neglect to brush or floss for long periods of time. Sex and Meth • • Meth heightens the libido and impairs judgment, which can lead to risky sexual behavior. Many users take the drug intravenously, increasing their chances of contracting diseases such as Hepatitis B or C and HIV/AIDS. http://www.pbs.org/wgbh/pages/frontline/meth/body/methbrainflash.html 2.5 years later Cigarettes and Tobacco 5000 CIGARETTE CONSUMPTION 4000 3000 2000 1000 0 1900 1920 1940 1960 1980 2000 YEAR Cigarette consumption (Billions) Cigarette consumption per capita BRITISH MEDICAL LONDON SATURDAY SEPTEMBER 30 JOURNAL 1950 SMOKINGAND CARCINOMAOF THE LUNG PRELIMINARY BY RICHARD Member of the Statistical REPORT 3VLR.C.P. the Medical Research Council DOLL, Unit AND M.D., of Research A. Professor of Medical Statistics, BRADFORD HILL, Ph.D., D.Sc. Director of the Statistical School London Research and Tropical Medicine ; Honorary of Hygiene Unit Research Council of the Medical In England number of and Wales deaths the phenomenal to cancer of increase the For lung in the pro whole may attributed explanation, well have and proper although been to no one would As causes. Increase to of and time a deny corollary, that it it is vides one of mortality annual of the most by striking changes the Registrar-General. in the pattern example, of right contributory. seek for other Causes have the from surface of the time dust recorded number out of of in the quarter of a century deaths all between This to 1922 and from of age 1947 the 612 to Two main of Possible causes from recorded increased been put for 9,287, or roughly fifteenfold. course, tion?both proportion in total and, changes, males remarkable the increase in its older increase is, popula groups. ward fumes from former : (1) a general atmospheric cars, gas-works, have has industrial pollution Some more Such than from the exhaust tarred coal and roads, fires ; and particularly, shows the females plants, Stocks these (1947), using population in 1936-9, standardized death rates to allow trend The rise for : rate (2) the smoking of tobacco. become increased. be no more been characteristics prevalent associated in of the the last following 2.5. per 100,000 in 1901-20, males 10.6, 1.1, females 0.7 ; rate per seems 50 years, and there is also no doubt cigarettes in time recently dence. records, male greatly can, however, has there That relates evidence, mainly certainly that the smoking suggestive, little more of 100,000 to have been particularly rapid since the end of the first world war ; between 1921?30 and \94b-4 the death rate of men the at ages 45 and over same ages approximately It has Canada, and Japan. increased sixfold and This of women increase of is still threefold. changes and until direct evi singularly based upon to the use of the of clinical tobacco. and experience For instance, continuing. the U.S.A., from Many whether Turkey too, occurred, and Australia, in Switzerland, Denmark, and has been reported in Germany, M?ller with (1939) found cancer that only 3 out of 86 have studied these considering changes, a real increase in the incidence of the they denote or are due merely to improved disease standards of diag can be regarded nosis. Some believe that the latter factor as wholly, or at least mainly, responsible?for example, writers patients while 56 were smokers, heavy " men of the same age healthy 31 heavy smokers. and only smokers non-smokers, lung were 86 in contrast, among and, " 14 non there were groups Similarly, lung were in America, Schrek 82 male and his co-workers 23.9% of 522 male other In this than the country, patients with cancer (1950) reported of the that 14.6% of non-smokers, against of sites tracts. patients admitted with and cancer Willis (1944). (1948), Clemmesen On the other and Busk (1947), and Steiner and upper Thelwall respiratory Jones digestive (1949?personal “Light” cigarettes Nicotine and tobacco • • Nicotine (1-3 mg/cigarette) absorbed rapidly. Nicotine is selfadministered; a less powerful reinforcer than amphetamine or cocaine. But, nicotine dependence is durable ! • Role of cholinergic neurotransmission in the brain reward pathway β2 α4 β2 α4 β2 Cholinergic (α4)2(β2)3 β2 α4 β2 α4 α4 α7 α7 α7 α7 α7 (α4)3(β2)2 α2βγδ α2βγε Golan, Figure 17.7 α4β2 (α7) Nicotine and tobacco Involve stereospecific receptors for nicotine and DA pathways. Blocked by mecamylamine: not by muscarinic antagonists. Varenicline (Chantix) Antidepressants NRT (patches / gums) • • • • • • Absorption: – Respiratory tract • Reaches brain within 7 seconds !! – Buccal membrane – Skin • Severe acute poisoning through percutaneous absorption • Acute nicotine poisoning: – Nausea, Salivation, Abdominal pain, Vomiting, Diarrhea, Cold sweat, Headache, Dizziness, Disturbed hearing / vision, Mental confu...
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