DRUGS USED IN DISORDERS OF THE CENTRAL NERVOUS SYSTEM AND TREATMENT OF PAIN Lecture 9:
Brain Reward Circuit and Drugs of Abuse Marc Imhotep Cray, M.D.
Learning Objectives:
CNS Pharmacology Lecture 9
DRUGS OF ABUSE AND DRUG DEPENDENCY 1. The underlying biological basis of addiction as a disease. 2. The differential diagnostic criteria for drug abuse vs dependence and the difference between them 3. The MOA within the central nervous system of the major drugs of abuse 4. The signs and symptoms of overdose caused by the major drugs of abuse including alcohol, heroin and cocaine. 5. The signs and symptoms of opioid withdrawal 6. The pharmacotherapeutic options for the treatment of opioid abuse and dependence and their relative benefits and side effects. 7. The signs and symptoms of alcohol withdrawal 8. The pharmacotherapeutic options for the treatment of alcohol abuse and their relative benefits and side effects. Marc Imhotep Cray, M.D.
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Drugs of Abuse (select): Topical Outline
CNS Pharmacology Lecture 9
I. Brain Reward Circuit II. General Features of Substance Abuse Drug abuse (addiction) terms and concepts III. Sedative-Hypnotics Ethanol: Deleterious Effects Ethanol Abuse: Treatment Withdrawal: Opioids, Benzodiazepines, and Barbiturates IV. Cigarettes V. CNS Stimulants (sympathomimetics) Cocaine Khat & Synthetic Cathinones VI. Hallucinogens (psychotomimetics) marijuana (cannabis) dronabinol (marinol) Marc Imhotep Cray, M.D.
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CNS Pharmacology Lecture 9
I. Brain Reward Circuit Drug abuse involves 2 components: psychosocial (e.g., family situation, peer pressure) and endogenous (e.g., genetics, enzyme levels) Pharmacologic mechanisms of drug abuse involve CNS neurotransmitter systems that operate for therapeutic drug effects An endogenous pleasure or reward pathway in the brain is important for motivation and learning (survival) and is thought to be excessively active—because of genetics, overuse, or other factors—in drug abuse
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CNS Pharmacology Lecture 9
I. Brain Reward Circuit (2) Brain reward circuit consists of neuronal pathways, cortical sites, and subcortical nuclei, especially within limbic region Primary among these are dopaminergic neurons in the ventral tegmentum that project to the nucleus accumbens and then to the cortex and other centers Also, norepinephrine-containing neurons from the locus ceruleus project to the ventral tegmentum Stimulation or disinhibition of dopaminergic neurons within the ventral tegmentum may be common to abuse of different substances Marc Imhotep Cray, M.D.
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Brain reward circuits
Marc Imhotep Cray, M.D.
CNS Pharmacology Lecture 9
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Potential sites of drug action
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II. General Features of Substance Abuse
CNS Pharmacology Lecture 9
Drug abuse (addiction) is a multifaceted problem, involving a complex combination of biological and psychosocial contributing factors Hereditary predisposition is also suspected to play a role in some cases Many, perhaps most, drug addicts abuse more than 1 drug Hence, list of abused drugs is extensive and includes some substances that are thought of primarily as mood or physique enhancers or as “recreational” drugs (e.g., anabolic steroids, mushrooms, designer drugs, hallucinogens, inhalants, marijuana, nicotine) This presentation focuses on some of the major classes of therapeutic and non-therapeutic drugs that are abused Marc Imhotep Cray, M.D.
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Drug abuse (dependence and addiction)
CNS Pharmacology Lecture 9
Abuse is misuse of a drug (e.g., taking it in ways not medically approved) Abuse of a drug is often, but not always, associated with kinetic, dynamic, homeostatic or learned tolerance o An acute tolerance (with first dose) has been described for ethanol o Cross-tolerance occurs between drugs with same mechanism of action
Drugs are abused for a variety of reasons:
To induce a feeling of euphoria To alter perception As a means of escape Due to peer pressure in young people
Abusers of drugs usually derive more pleasure from a drug with a rapid onset of action than from a drug with a slow onset of action within same class Marc Imhotep Cray, M.D.
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Drug abuse (2)
CNS Pharmacology Lecture 9
Inappropriate and usually excessive, self-administration of a drug for non-medical purposes Almost all abused drugs exert their effects in CNS
Drugs with high abuse potential have a tendency to induce compulsive drug-seeking behavior Preoccupation with procurement and use of drug may be so demanding as to decrease users productivity Prolonged abuse may cause chronic toxicity
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Physical Dependence:
CNS Pharmacology Lecture 9
Dependence is physical requirement for a drug due to adaptive physiologic changes (tolerance) after multiple exposures If drug is not available, abstinent withdrawal syndrome will occur o Symptoms during withdrawal tend to be opposite of effects due to drug administration o Withdrawal from a drug of abuse is usually less severe with long-acting drugs than, with short-acting drugs within same class This is theoretical basis for replacement therapy (e.g., methadone for heroin addicts) Marc Imhotep Cray, M.D.
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CNS Pharmacology Lecture 9
Addiction: Addiction is psychological requirement for a drug It is characterized by compulsive drug use in spite of associated negative social and biological consequences An addicted person can crave a drug even in absence of physical dependence Addiction is thought to be caused by an increase in CNS dopamine release and/or a decrease in dopamine reuptake that occurs with use of drug Marc Imhotep Cray, M.D.
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CNS Pharmacology Lecture 9
Drug tolerance Normal
Tolerance
After chronic use, same amount of drug is insufficient to cause desired effect and thus, more drug is used A compensatory response Acquired Tolerance Pharmacokinetic or metabolic Pharmacodynamic or functional Learned or behavioral
Drug Dose
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CNS Pharmacology Lecture 9
Drug tolerance(2) Metabolic tolerance (pharmacokinetic tolerance): rate of drug elimination increases with long-term use because of stimulation of its own metabolism (autometabolism) Cellular tolerance (pharmacodynamic tolerance): Biochemical adaptation or homeostatic adjustment of cells to continued presence of a drug o development of cellular tolerance may be due to a compensatory change in activity of specific neurotransmitters in CNS caused by a change in their levels, storage, or release o or to changes in number or activity of their receptors
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CNS Pharmacology Lecture 9
Cross-tolerance When an individual has become tolerant to a drug and requires higher than normal doses of a second drug to have its effects
i.e. Barbiturates BDZ Amphetamine Cocaine BARBs Anesthetics
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CNS Pharmacology Lecture 9
Cross-tolerance(2) In general there is cross-dependence and cross-tolerance between drugs of same class, but not between drugs in different classes There is some cross-tolerance btw sedative-hypnotics and volatile intoxicants; thus a person tolerant to barbiturates will require more anesthesia than a non-tolerant person LSD type drugs (tryptamine group) and phenylethylamines have cross-tolerance for each other but not with other hallucinogens Marc Imhotep Cray, M.D.
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CNS Pharmacology Lecture 9
Cross-dependence When a drug is administered to achieve same outcome as that of another drug
i.e. heroin methadone In a heroin user, methadone can be substituted for heroin in preventing withdrawal syndrome
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CNS Pharmacology Lecture 9
Co-administration/Co-abuse Drugs of abuse are used in combination with other drugs from one or more categories Alcohol is used, for example, with almost everything else Smoking (nicotine intake) is prevalent in patients using other drugs
Be aware of possibility of combination of drugs when treating intoxication, withdrawal or overdose, each drug will require a specific treatment
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CNS Pharmacology Lecture 9
Important Point: Because of the diverse character of these drugs, there is no “single reason” for their use, nor is there an “addictive personality" IT IS NOT NECESSARY TO HAVE A PREEXISTING EMOTIONAL OR PSYCHIATRIC PROBLEM TO BECOME DRUG DEPENDENT!!!
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CNS Pharmacology Lecture 9
Toxicology of Drugs of Abuse: A) Tissue and organ toxicity Usual dose vs overdose Acute use (respiratory depression - narcotics, comabarbiturates; cardiovascular effects and seizures-cocaine; arrhythmias-volatile intoxicants) Chronic use (alcohol, tobacco)
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CNS Pharmacology Lecture 9
Toxicology of Drugs of Abuse (2) B) Psychic toxicity  Acute use (bad trips, flashbacks - hallucinogens; CNS stimulants)  Chronic use (alcohol, hallucinogens, stimulants => reality distortion)
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CNS Pharmacology Lecture 9
Toxicology of Drugs of Abuse (3) C) Behavioral toxicity Amotivational syndrome, loss of productivity loss of psychomotor control, accidents, violence Acute use (alcohol, stimulants, PCP) Chronic use (alcohol, CNS depressants, stimulants, hallucinogens, PCP)
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Toxicology of Drugs of Abuse (4) D) Associated Diseases  Infections, AIDS, venereal diseases, tobaccorelated fires, toxicity due to bad batches of drug (MPTP, PCP congeners), car accidents, big machinery accidents, other accidents, violent death
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Controlled substances:
CNS Pharmacology Lecture 9
A drug deemed to have abuse liability that is listed on governmental Schedules of Controlled Substances* Such schedules categorize illicit drugs, control prescribing practices, and mandate penalties for illegal possession, manufacture, and sale of listed drugs (next slide) Controlled substance schedules are presumed to reflect current attitudes toward substance abuse; therefore, which drugs are regulated depends on a social judgment *An example of such a schedule by US Drug Enforcement Agency (DEA) is shown in next slide. Note that criteria given by an agency do not always reflect actual pharmacologic properties of the drugs. Marc Imhotep Cray, M.D.
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Schedule for controlled substances* Schedule
Criteria
Examples
I
No medical use; high addiction potential
Flunitrazepam, heroin, LSD, mescaline, PCP, MDA, MDMA, STP
II
Medical use; high addiction Amphetamines, cocaine, methylphenidate, short potential barbiturates, strong acting opioids
III
Medical use; moderate abuse Anabolic steroids, barbiturates, dronabinol, potential moderate ketamine opioid agonists
IV
Medical use; low abuse potential
CNS Pharmacology Lecture 9
Benzodiazepines, chloral hydrate, mild stimulants (e.g., Ritalin), most hypnotics (eg, zaleplon, zolpidem), weak opioids
*See http://www.usdoj.gov/dea/pubs/scheduling.html for additional details Marc Imhotep Cray, M.D.
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III: Sedative-Hypnotics: ETHANOL
CNS Pharmacology Lecture 9
ď ąETHANOL is a commonly abused legal substance 1. Due to high lipid solubility and high water solubility, ethanol distributes in total body water 2. Clearance from the body occurs in liver a. Metabolism by alcohol and aldehyde dehydrogenases follows zeroorder kinetics i. Products are acetaldehyde and acetic acid, respectively ii. Two molecules of nicotinamide adenine dinucleotide hydrogenase (NADH) are produced for each molecule of ethanol b. An insignificant amount of ethanol is metabolized by mixed-function oxidases (MFOs), but this can induce the MFOs, particularly in alcoholics
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Sedative-Hypnotics: ETHANOL (2)
CNS Pharmacology Lecture 9
3. Effects of ethanol are related to blood ethanol concentration a. Legal limit for driving in most states is a 0.08% (80 mg EtOH/100 ml blood) blood alcohol concentration (BAC) b. Death due to respiratory depression occurs in the range of 0.4–0.5% BAC, although this is quite variable c. Treatment of an overdose of ethanol is symptomatic  Support ABCs/vital signs Marc Imhotep Cray, M.D.
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CNS Pharmacology Lecture 9
Sedative-Hypnotics: ETHANOL (3) 4. Acute adverse effects develop after a single exposure to ethanol a. b. c. d. e. f.
Behavior is changed due to a loss of inhibitions Effects of other CNS depressants are enhanced Hypothermia results from peripheral vasodilation, which makes person feel warm even though body heat is being lost Hangovers are common after drinking ethanol and may represent symptoms of an acute withdrawal Acute use of alcohol decreases metabolism of other CNS depressants Panic attacks may occur day after alcohol is abused as blood alcohol levels drop
5. A low intake of ethanol (one drink per day) is associated with increased high-density lipoprotein and decreased low-density lipoprotein cholesterol. This may reduce the risk of heart disease Marc Imhotep Cray, M.D.
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CNS Pharmacology Lecture 9
Sedative-Hypnotics: ETHANOL (4) 6. Adverse effects from chronic (repeated) use occur on almost every tissue in body and include: a. Physical and psychological dependence b. Activation of MFOs, which increases metabolism of many other drugs (e.g., phenytoin, warfarin) c. Edema and ascites d. Hypertension e. Cardiomyopathy and arrhythmias f. Liver damage (e.g., cirrhosis, fatty liver) g. Acetaminophen combined with ethanol can cause severe acute liver damage due to production of hepatotoxic metabolites h. Changes in blood glucose due to impaired gluconeogenesis i. Damage to the gastrointestinal tract j. Megaloblastic anemias due to folate or vitamin B12 deficiency, or anemia due to iron deficiency caused by GI bleeding Marc Imhotep Cray, M.D.
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CNS Pharmacology Lecture 9
Sedative-Hypnotics: ETHANOL (5) Adverse effects cont. k. Malnutrition, especially thiamine deficiency, which leads to Wernicke– l. Korsakoff syndrome (paralysis of extraocular muscles, ataxia, and confusion) m. Psychological sequelae Depression and Korsakoff’s psychosis (long-term memory loss) n. Fetal alcohol syndrome Ethanol is a common cause of birth defects and neurologic disorders. o. Impaired visual acuity (blurry vision) p. Immune system effects Increased inflammation of liver and pancreas and increased risk for oropharynx and liver cancers Marc Imhotep Cray, M.D.
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Vitamin B1 (thiamine) and alcoholics
CNS Pharmacology Lecture 9
DEFICIENCY Impaired glucose breakdown ATP depletion worsened by glucose infusion; highly aerobic tissues (e.g., brain, heart) are affected first. Wernicke-Korsakoff syndrome and beriberi Seen in malnutrition and alcoholism (2° to malnutrition and malabsorption) Diagnosis made by in RBC transketolase activity following vitamin B1 administration Wernicke-Korsakoff syndrome—confusion, ophthalmoplegia, ataxia (classic triad) + confabulation, personality change, memory loss (permanent) Damage to medial dorsal nucleus of thalamus, mammillary bodies Dry beriberi —polyneuritis, symmetrical muscle wasting Wet beriberi —high-output cardiac failure (dilated cardiomyopathy), edema Marc Imhotep Cray, M.D.
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CNS Pharmacology Lecture 9
Ethanol: Deleterious Effects Short- and long-term excess ethanol consumption leads to widespread problems for the individual and for society Lifetime prevalence of ethanol dependence is estimated at 10% to 15%, and as many as 30% of male and 10% of female admissions to general hospitals are related to ethanolassociated disorders Ethanol is rapidly absorbed from the GI tract and distributes to all cells in the body It readily passes into fetal circulation Marc Imhotep Cray, M.D.
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CNS Pharmacology Lecture 9
Ethanol: Deleterious Effects (2)
High concentrations saturate this pathway and give rise to toxic byproducts of alternative pathways Because ethanol is so widely distributed throughout body, toxic consequences of excess ethanol consumption involve essentially every organ Marc Imhotep Cray, M.D.
The pathway of ethanol metabolism. ADH = alcohol dehydrogenase; ALDH = acetaldehyde dehydrogenase. Modified from: Lippincott Illustrated Reviews-Pharmacology Sixth Edition. 2015
Low concentrations of ethanol are safely metabolized in a 2-step process: first by alcohol dehydrogenase to acetaldehyde and then by aldehyde dehydrogenase to acetate
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Effects of Alcohol on End Organs:
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CNS Pharmacology Lecture 9
Organ damage Caused by alcohol Marc Imhotep Cray, M.D.
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Cirrhosis of the Liver
Alcoholic Liver Disease:
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CNS Pharmacology Lecture 9
Normal vs Cirrhotic Liver: Normal liver, gross
Cirrhosis, gross
Klatt EC. Robbins and Cotran Atlas of Pathology, 2nd Ed. 2010
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Fetal alcohol spectrum disorder
CNS Pharmacology Lecture 9
ď ą Fetal alcohol spectrum disorder results from maternal abuse of ethanol. ď ą Fetal alcohol syndrome is characterized by retarded growth, microencephaly, poorly developed coordination, mental retardation, and congenital heart abnormalities. ď ą Severe behavioral abnormalities can occur in the absence of dysmorphology. There is also an increased rate of spontaneous abortions.
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Ethanol Abuse: Treatment
CNS Pharmacology Lecture 9
Abrupt withdrawal from ethanol (in persons with physical dependency) is accompanied by excitatory CNS signs such as delirium tremens and potentially lethal seizures Medication management in the past was limited to disulfiram, which inhibits aldehyde dehydrogenase Buildup of acetaldehyde produces an unpleasant reaction when ethanol is consumed and thereby provides a deterrent to excess ethanol use
Naltrexone and acamprosate (in Europe) are newer alternative choices
Naltrexone is an opioid receptor antagonist that seems to have additional (perhaps independent) property of reducing chance of relapse when used in conjunction with psychosocial treatment Acamprosate seems to enhance abstinence by a modulatory effect on NMDA subtype of glutamate receptor Marc Imhotep Cray, M.D.
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Alcohol Withdrawal Syndrome:
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Alcohol Withdrawal Syndrome(2)
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CNS Pharmacology Lecture 9
Methanol (wood alcohol) poisoning Methanol is metabolized by ADH to formaldehyde, which is then oxidized to formic acid, which is toxic
Methanol produces blurred vision and other visual disturbances (“snowstorm”) when poisoning has occurred In severe poisoning, bradycardia, acidosis, coma, and seizures are common o Treatment of methanol toxicity includes the administration of ethanol to slow the conversion of methanol to formaldehyde (ethanol has a higher affinity for ADH) o In addition to other supportive measures, dialysis is used to remove methanol, and bicarbonate is administered to correct acidosis o Fomepizole, an inhibitor of ADH that reduces the rate of accumulation of formaldehyde, is also used to treat methanol (and ethylene glycol) toxicity
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Withdrawal: Opioids
CNS Pharmacology Lecture 9
Abrupt discontinuation of drugs used for long-term abuse results in withdrawal signs In general, these signs are opposite of those induced by drug: o withdrawal from CNS excitatory drugs is inhibitory, and o withdrawal from CNS depressants is excitatory Rate and severity of withdrawal are lessened by tapered cessation of drug use rather than abrupt cessation Withdrawal that is too rapid, particularly from CNS depressant drugs, such as ethanol and barbiturates, can be life-threatening Marc Imhotep Cray, M.D.
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Opioid Withdrawal(2)
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CNS Pharmacology Lecture 9
Opioid Withdrawal(3)
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Withdrawal: Benzodiazepines, and Barbiturates
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CNS Pharmacology Lecture 9
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IV: Cigarettes:
CNS Pharmacology Lecture 9
A. NICOTINE is active substance and is responsible for addictive nature of cigarettes 1. Nicotine binds to nicotinic acetylcholine receptors, causing dopamine release in ventral tegmental area of brain 2. Stimulation of CNS induces arousal, relaxation, and mild euphoria 3. Activation of sympathetic nervous system induces vasoconstriction and 4. increase blood pressure B. TARS AND CARBON MONOXIDE inhaled in cigarette smoke increase risk of: 1. Chronic obstructive pulmonary disease (COPD) 2. Cancer 3. Heart disease Marc Imhotep Cray, M.D.
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CNS Pharmacology Lecture 9
Cigarettes(2) C. PHYSICAL AND PSYCHOLOGICAL DEPENDENCE occurs. Abstinence leads to anxiety, insomnia, and enhanced appetite that can last for several months D. Many approaches are available that increase the probability of successfully abstaining from cigarettes 1. Physicians should follow the five As when counseling smokers a. Ask patients if they smoke b. Advise patients to quit smoking c. Assess patients’ readiness to quit d. Assist patients who would like to quit e. Arrange for follow-up . Marc Imhotep Cray, M.D.
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CNS Pharmacology Lecture 9
Cigarettes(3) 2. Nicotine is available in a patch, in gum, and in an inhaler  These devices release nicotine more slowly compared with smoking 3. Other aids are available for smoking cessation a. Bupropion (Zyban) is an antidepressant b. Varenicline (Chantix) is a nicotinic receptor partial agonist 4. Behavioral modification programs and telephone quit lines are also helpful
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CNS Pharmacology Lecture 9
V: CNS Stimulants: Sympathomimetics A. COCAINE AND AMPHETAMINES are most commonly abused CNS stimulants in Western society B. Magnitude of euphoria depends on speed of onset: 1. Amphetamines can be taken orally, which results in a slow onset  Can also be injected or crushed and snorted, which results in a much faster onset 2. Cocaine can be ingested, chewed, snorted, injected, or smoked a. Crack is free-base form of cocaine HCl  It is formed by heating cocaine HCl in an alkaline solution b. Smoked crack has most rapid onset and the most pleasurable effects
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CNS Pharmacology Lecture 9
CNS Stimulants Mechanism of action 1. Cocaine blocks the DA transporter (DAT) also norepinephrine and serotonin transporters(NET and SERT) at higher doses in CNS to inhibit uptake of DA into nerve terminals in mesolimbic pathway that includes “brain reward” center Blockade of NET also leads to increased sympathomimetic activity 2. Amphetamine increases release of prejunctional neuronal catecholamines, including DA and norepinephrine Amphetamine also exhibits some direct sympathomimetic action and weakly inhibits MAO
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CNS Stimulants (3)
CNS Pharmacology Lecture 9
C. Stimulants produce euphoria with: 1. Enhanced self-confidence and alertness 2. Increased motor activity 3. Little physical dependence  Fatigue is primary physical symptom during withdrawal 4. Strong psychological dependence D. Period of euphoria varies depending on half-life of drug in body 1. Cocaine induces a very short euphoria (approximately 15 minutes), which is followed by a period of marked dysphoria 2. Euphoria from amphetamines has a much longer duration E. Chronic abusers develop paranoid, psychotic-like symptoms Marc Imhotep Cray, M.D.
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CNS Stimulants (4)
CNS Pharmacology Lecture 9
F. OVERDOSES can be dangerous 1. Sympathomimetic actions can lead to tachycardia and arrhythmias 2. Abusers can become aggressive and experience hallucinations Other dangerous effects include hypertension, hyperthermia, coma, and death. 3. Cocaine can also induce: a. Gangrene, due to peripheral vasoconstriction b. Perforation of nasal septum, due to vasoconstriction in nasal mucosa c. Convulsions, due to local anesthetic effects on brain Marc Imhotep Cray, M.D.
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CNS Stimulants (5) Khat and Synthetic Cathinones
CNS Pharmacology Lecture 9
Cathinone is the psychoactive component in an evergreen shrub called Khat native to East Africa and the Arabian Peninsula Synthetic cathinones, also known as “bath salts,” have become increasingly popular products are packaged and labeled in such a way as to circumvent detection, prosecution, and enforcement These are substances that are sold as something else at large profits with an unstated understanding by seller and buyer that they will produce intoxication Synthetic cathinones are not easily detected on urine toxicology screens Marc Imhotep Cray, M.D.
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CNS Stimulants (5) Khat and Synthetic Cathinones
CNS Pharmacology Lecture 9
Methcathinone, butylone, methylene dioxypyrovalerone, and naphyrone are just a few examples of synthetic cathinones These drugs increase the release and inhibit the reuptake of catecholamines (norepinephrine, epinephrine, and dopamine) in a manner very similar to cocaine and amphetamines A rapid onset of amphetamine-like stimulation with psychotomimetic effects of variable duration is common with synthetic cathinones
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See: Kebede Y. Editorial. Should the Silence on Khat Be Allowed to Continue in Ethiopia? Ethiop. J. Health Biomed Sci., 2009. Vol.2, No.1
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CNS Pharmacology Lecture 9
VI: Hallucinogens (psychotomimetics) Marijuana (cannabis) and dronabinol (marinol) Active ingredient in marijuana is Δ-9 tetrahydrocannabinol (THC) MOA: it acts prejunctionally as an agonist to inhibit adenylyl cyclase through G-protein-linked cannabinoid receptors Through disinhibition of DA neurons it inhibits activity of GABA neurons in the ventral tegmentum area (VTA) a. Cannabinol CB1 receptors, which account for most CNS effects, are localized to cognitive and motor areas of the brain b. Cannabinol CB2-receptors are found in immune system among other peripheral organs Marc Imhotep Cray, M.D.
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Cannabinoids
CNS Pharmacology Lecture 9
ď ą Cannabinoids are effective antiemetics and appetite stimulants and have some analgesic actions ď ą Dronabinol is a synthetic, orally active cannabinoid approved for treatment of cachexia in patients with cancer or acquired immunodeficiency syndrome (AIDS) and to treat emesis caused by cancer chemotherapy in patients who do not respond to conventional antiemetics ď ą Many also argue for use of smoked marijuana in treating chronic pain, improving appetite in AIDS patients, and suppressing spasticity in multiple sclerosis and spinal injury
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THE END
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CNS Pharmacology Lecture 9
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CNS Pharmacology Lecture 9
Further study (SDL): MedPharm Digital Guidebook: Unit 3-Drugs Used for CNS Disorders Companion eNotes: CNS- Central Nervous System Pharmacology Textbook Reading: L端scher C. Drugs of Abuse Ch. 32 In: Katzung BG, ed. Basic & Clinical Pharmacology. 12th ed. Pgs. 565-79 Online resource center: Medical Pharmacology Cloud Folder
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