Psychostimulants: Cocaine and Amphetamines - Lecture Notes | PSYC 7705, Study notes of Pharmacology

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PSYCHOSTIMULANTS: COCAINE AND AMPHETAMINES Classification of some CNS stimulants Class Mechanism of action Examples Behavioral stimulants Augmentation of Cocaine norepinephrine and dopamine Amphetamines Methylphenidate (Ritalin Pemoline (Cylert) Phenmetrazine (Preludin) Clinical antidepressants Blockade of norepinephrine reuptake Imipramine (Tofranil) Amitriptyline (Elavil) Increased norepinephrine, Tranylcypromine (Parnate) secondary to MAO inhibition Blockade of serotonin reuptake Fluoxetine (Prozac) Legal recreational drugs Blockade of adenosine receptors Caffeine Stimulation of acetylcholine receptors Nicotine • Psychostimulant Effects: elevated mood, euphoria, and alertness, reduced fatigue, increased energy, decreased appetite, improved task performance, relief of boredom, increased motor activity. • Examples of psychostimulants: 1. cocaine 2. amphetamines (dextroamphetamine and methamphetamine) 3. amphetamine derivatives used to treat ADHD (methylphenidate; pemoline; Cylert) 4. variety of drugs formerly used to treat obesity (fenfluramine; Pondimin, phentermine; under trade names as lonamin, Obe-Nix, Adipex-P, Oby-Trim, and Fastin, and phenmetrazine; Preludin) 5. caffeine and theophylline (psychoactive drug in coffee and other caffeinated beverages) and nicotine (ingredient in tobacco). • All stimulants subject to compulsive abuse, and have limited therapeutic use, significant side effects and toxicity. • Common side effects (cocaine and amphetamines): anxiety, insomnia, and irritability • High doses: intense irritability and anxiety and psychotic behaviors • Low doses: alerting, arousing response not unlike normal reaction to an emergency or to stress (e.g. increase blood pressure and heart rate, pupils dilate, skin to internal organ blood flow shifts, and rise in blood oxygen and glucose levels) Cocaine - Historical Facts • Erythroxylon coca leaves (Peru and Bolivia) • Social use: religious, mystical, stimulant, and medicinal purposes-to increase endurance, promote sense of well-being, and alleviate hunger (usual total daily dose ~ 200 mgs) • 1859: active alkaloid in coca isolated and named cocaine. • 1884: Freud advocated use of cocaine to treat depression and alleviate chronic fatigue. He described cocaine as a “magical drug" and even wrote a "Song of Praise" to it. • 1884: Koller demonstrated cocaine's local anesthetic properties and for ophthalmologic surgery. • 1885: cocaine incorporated (along with caffeine) in popular patent medicine later known as beverage Coca-Cola, until 1903 (~60 mgs/8 ounce serving) • 1891: at least 200 reports of cocaine intoxication and 13 deaths reported. • 1914: Harrison Narcotic Act banned cocaine in medicines and beverages. • 1924: American Medical Association reviewed 43 deaths of patients who had been under local cocaine anesthesia and attributed 26 of those deaths to cocaine toxicity. • 1920s: Use of cocaine rose then decreased during 1930s, when amphetamines became available, presumably because cost less and produced longer-lasting effects. • 1960s: cocaine not used much until federal restrictions on amphetamine distribution raised cost of amphetamines, making cocaine attractive once again. • Net effects indistinguishable as euphoriants …availability, price, and sociocultural considerations now largely determine comparative popularity of the two. • 1970s: cocaine again became popular; in mid-1980s, smoking of concentrated preparations of cocaine (free base and crack cocaine) opened new era in cocaine abuse characterized by high- dose, rapid-onset effects with rapid development of dependence. • 20-30 million in U.S. have used cocaine; ~ 4 million people use it regularly, and ~ 2 million are "hard core" cocaine users. • At peak use, ~ 800,000 Americans had cocaine daily; today a number closer to 300,000 is likely (result of intensive antidrug campaign?)...number of users has not decreased. • Cocaine addicts: typically young (12 to 39 yrs), poly drug-dependent, and male (75%); tend to have coexisting psychopathology (30% anxiety disorders, 67% clinical depression, and 25% paranoia); 85-90% are alcohol dependent. • Associated with violent premature deaths, including homicides, suicides, and accidents. Cocaine Chemistry • Extracted as coca paste (60-80% cocaine), each leaf contains 0.5-1.0% C. • Coca paste converted to hydrochloride salt before exportation and sold as cocaine hydrochloride ("crystal" or "snow"). • Inhaled, cocaine hydrochloride provides ~10-25 mgs into each nostril; • Hydrochloride salt form not suitable for smoking, because it decomposes at temperatures required to vaporize it....thus • Hydrochloride form altered to base form, by extraction in ether ("free base") • Cocaine base or "crack," from cracking sound it makes when heated • Absorbed from: mucous membranes, gastrointestinal tract, and lungs. • Detoxified in plasma and liver...only small amounts excreted unchanged Cocaine Absorption • Routes: oral (chewing), intranasal (snorting), intravenous (mainlining), and inhalation (smoking or free-basing). • Orally: absorption over ~I hour, with ~75% metabolized in liver on first pass...thus, only ~25% reaches brain, eliminating feeling of "rush" that follows other routes. • Intranasally: poorly absorbed, as hydrochloride salt poorly crosses mucosal membranes....vasoconstriction limits absorption....20-30% absorbed, with peak levels in 30-60 min. • Inhalation: (smoked base), particles trapped in nose while others pass into trachea and lung, from which absorption is rapid and complete…onset of effects: seconds, and persist for 5-10 minutes…~6-32% of initial amount reaches plasma, remainder undergoes pyrolysis before inhalation. • Intravenous injection bypasses all barriers to absorption, placing drug immediately into the bloodstream....30-60 second delay in onset of action Cocaine Distribution and Elimination • Into brain rapidly; brain concentrations far exceed plasma concentrations personality disorder, and eating disorders. • Given these complications, needs of cocaine addict are at least 5-fold: 1. immediate abstinence 2. diagnosis of any coexisting disorders 3. determination if addiction is primary disorder or secondary to other disorders 4. maintenance of abstinence long enough to diagnose and begin treatment of coexisting disorders 5. prevention of relapse Treatment Approaches of Cocaine Abuse • Treatment approaches are many, from classical "12-step" recovery programs (AA) to psychopharmacotherapy, psychotherapy, or cognitive-behavioral approaches. • Abstinence essential and must be monitored by frequent, unannounced urine tests to screen for drugs. • 3-phase cocaine abstinence model: phases called crash, withdrawal, and extinction • Crash (9 hrs-4 days); user is uninterested in using cocaine, appearing quite depressed and somnolent. • Withdrawal (1-10 wks); max relapse potential/drug craving. • Extinction continued monitoring required since conditioned cues can trigger craving and result in relapse. • Psychopharmacotherapy to treat cocaine abuse: 1. antagonize the effects of cocaine at its receptors 2. produce an aversive (Antabuse-like) reaction 3. treat the coexisting psychiatric disorder 4. reduce cocaine craving and withdrawal • To date, no successful antagonists are available, nor are any aversive drugs; thus, psychopharmacotherapy aimed at utilizing drugs to attenuate drug craving. • Most popular drug for reducing craving is antidepressant desipramine. • Desipiramine relieves craving and withdrawal; effect is not predictable; positive effects short-lived • Other agents include: antiparkinsonian dopamine receptor agonist bromocriptine, the amino acid tyrosine, phenothiazines, (antipsychotics-antidopaminergics), other antidepressants, the mood stabilizer lithium, and the anticonvulsant carbamazepine. AMPHETAMINES AND RELATED DRUGS Amphetamine - Historical Facts • Amphetamines: methyl derivative methamphetamine, and several other derivatives (methylphenidate, fenfluramine, pemoline) exert stimulant effects resembling cocaine. • 1888: synthesized, but not used for medicinal purposes until 1930s, when found to increase blood pressure and stimulate CNS, and cause bronchodilatation. • 1935: treat narcolepsy; thought not to pose threat to health • 1935-1946: list of 39 conditions for which drug could be used: schizophrenia, morphine addiction, tobacco smoking, heart block, head injury, radiation sickness, hypotension, seasickness, severe hiccups, and caffeine dependence. • World War II: to fight fatigue and enhance battle performance • 1940s: large-scale abuse (usually oral ingestion) and continued to be used (and abused) as diet aid. • 1960s: abuse pattern changed with advent of injectable forms. Amphetamine Mechanism of Action • Indirect-acting catecholamine agonists: CNS effects exerted by causing release of newly synthesized catecholamines (especially dopamine) from nerve terminals. • Behavioral stimulation and increased psychomotor activity due to stimulation of dopamine receptors in mesolimbic system (including nucleus accumbens). • High-dose stereotypical behavior (constant repetition of meaningless acts) involves dopamine neurons in caudate nucleus and putamen of basal ganglia. • Increase in aggressive behavior complex...seen primarily in adults; in children they reduce aggressive behavior and activities characteristic of ADHD. • Potent anorectics: decrease appetite but tolerance to satiating effects develop rapidly; Involves lateral hypothalamus but may also involve serotonin neurons, which, when activated, produce satiety. Amphetamine Pharmacology • Psychomotor stimulant in the CNS: increased alertness, euphoria, excitement, wakefulness, reduced fatigue, loss of appetite, mood elevation, increased motor and speech activity, and improved task performance, dexterity loss. • Excreted in urine and detectable up to 48 hrs after use. • Low oral doses: (2.5-20 mgs) increase in blood pressure, with reflex slowing of heart rate, relaxation of bronchial muscle • Moderate doses (20-50 mgs): stimulation of respiration, slight tremors, restlessness, a greater increase in motor activity, insomnia, agitation, appetite suppression, wakefulness, and causes sleep deprivation (recovery takes many weeks). • High dose (>50 mgs): stereotypical behaviors (continual, purposeless, repetitive acts), aggression and violence, paranoid delusions, severe anorexia, and state of amphetamine psychosis, indistinguishable from acute schizophrenia attack. • Chronic amphetamine in animals, associated with: persistent depletion of both dopamine and enzyme tyrosine hvdroxylase (synthesis of dopamine)...thus, toxic to dopamine-releasing neurons. • Loss of responsiveness to "natural reinforcers" develops… dopamine neurons lose their sensitivity to dopamine. • Other harmful high-dose effects: psychosis and abnormal mental conditions, weight loss, skin sores, infections resulting from neglected health care, poor eating habits, and lack of sleep...including deterioration in social and occupational affairs. • Toxic doses vary widely...severe reactions can occur from low doses (20-30 mgs) whereas persons who do not have tolerance have survived doses of 400-500 mgs. Amphetamine Dependence and Tolerance • Prone to compulsive abuse (induces psychological dependence). • Dependence follows classical positive conditioning model; positive reward leads to further use. • Tolerance rapidly develops and accompanied by dysphoria, sedation, lassitude, and drug craving...solution to this state is taking more drug in higher and higher doses, which starts a vicious cycle of drug use and withdrawal. • At this point, tolerance to euphoriant effects develop, and periods of "binging" begin. • Tolerance leads to further drug intake, social withdrawal, and a focus on procuring drugs. Amphetamine Therapeutic Uses and Status • Medical uses are restricted and often controversial and include treatment of: 1. narcolepsy (application is now rare.) 2. attention deficit hyperactivity disorder 3. obesity • Note: amphetamines are not of much value in treating major depression (because of great potential for addiction and general lack of therapeutic efficacy). Amphetamines and Attention Deficit Hyperactivity Disorder • Since 1936 started with amphetamine and has progressed to use of methylphenidate (Ritalin), pemoline (Cylert), and, more recently, the antidepressant nortriptyline. • Evolution of terminology for the disorder: "minimal brain dysfunction" to "minimal brain disorder" to "hyperactivity syndrome" to "attention deficit disorder" to present ADHD. • No definitive CNS pathology has been demonstrated, however a dopamine hypothesis of ADHD, has evolved invoking a disorder of polysynaptic dopaminergic circuits, between prefrontal and striate centers. • Affects 6% of school-age children, characterized by: inattentiveness, impulsivity, and hyperactivity that are persistent and severe to cause functional impairment at school, home, and with peers....evidence that disorder may be inherited. • Symptoms may persist into adulthood • Effective intervention early in childhood may alter course of ADHD, decreasing conduct disorder as an adolescent and antisocial personality disorder with its various complications (e.g., alcohol and drug abuse, criminality) as an adult. • Pharmacological treatment usually discontinued when a child reaches puberty, because adolescents presumably are more prone to abuse amphetamine-like drugs. • Growth-reducing effects blunt adolescent growth spurt (even with "summer holiday" from drug). • Drugs improve behavior and learning ability in 50-75% of ADHD children Psychostimulants used to treat ADHD Feature Methylphenidate Pemoline d-amphetamine Elimination half-life 2-3 2-12 6-7 Time to peak plasma 1-3 1-5 3-4 Onset of behavioral effect 1 week 3-4 weeks 1 week Duration of behavioral effect 3-4 not available 4 Dailv dose range mg/kg/day 0.6-0.7 0.5-3.0 0.3-1.25 mg/day 10-60 38-113 5-40 • Methylphenidate has rapid onset and short duration; thus must be administered at both breakfast and lunchtime • Pemoline has longer but variable half-life; disadvantages: slow onset and reduced level of therapeutic efficacy. • Dextroamphetamine rarely used for ADHD...however can be useful in non-respondents to methylphenidate or pemoline. • Antidepressants not widely used for ADHD, but one, nortriptyiine, has been studied Amphetamines and Obesity • Impediments: side effects, dependency, addiction, and rapid tolerance. • Small amounts of weight loss (<1 pnd/wk) accompany use; effects lost after only few weeks • Anorexics: benzphetamine (Didrex), phendimetrazine (Anorex, Oblan, Phendiet, Wehless), diethylpropion (Tenuate, Tepanol), mazindol (Mazenor, Sanorex), phentermine (Fastin, lonamin, Phentrol, Adipex-P, ObyTrim), phenylpropanolamine (Dexatrim), and d- amphetamine/amphetamine combination (Obcontrol). • Search continues for amphetamine-related derivatives that suppress appetite without potential for and amnesia; PNS effects: tachycardia, blurred vision, urinary retention, and dry mouth. Catecholamine-like Psychedelic Drugs (C-PD’s) • Methoxylated amphetamine derivatives: mescaline, DOM (also as STP), TMA, MDA, MDMA (ecstasy), MMDA, DMA, and drugs from nutmeg (myristin and elemicin). • Compared to amphetamines/cocaine: more intense psychedelic action and less intense behavioral stimulant action. • C-PD’s produce similar effects: sensory perceptual (time) distortion; altered color perception, sounds, shapes; complex hallucinations and synesthesia; dreamlike feelings; depersonalization; altered affect (depression or elation); and somatic effects (tingling skin, weakness, tremor, etc.). Mescaline • Peyote (Lophophora williamsii) common plant in southwestern U.S. and Mexico; spineless cactus with small crown, or "button," and long root. When used for psychedelic purposes, crown is cut from cactus and dried into hard brown discs (mescal button); active compound is mescaline. Mescaline - Historical Background • Pre-Columbian times, when cactus was used in religious rites of Aztecs and other Mexican Indians. • Legally available for religious practice of Native American Church of North America-an organization that claims some 250,000 members from Indian tribes throughout North America. 1896 mescaline identified as active ingredient in peyote. • Variety of mescaline derivatives synthesized; all have methoxy (OCH3) groups or additions on benzene ring • Methoxylation results in high affinity for presynaptic serotonin receptors and exert LSD-like psychedelic effects. Mescaline Pharmacology • Orally: Transport to brain in 30-90 mins...effects persist for ~10 hrs...not metabolized before it is excreted. • Low doses: (2-3 mgs/kg) produce amphetamine-like behavioral effects and include: pupil dilatation, increased blood pressure and heart rate, increase body temperature, EEG and behavioral stimulation. • Usual oral dose: (5 mg/kg) causes: anxiety, sympathomimetic effects, hyper-reflexia of limbs, static tremors, and vivid hallucinations of brightly colored lights, geometric designs. Synthetic Amphetamine Derivatives • DOM, MDA, TMA, MDMA, MMDA, and DMA structurally related to mescaline and methamphetamine and more potent and toxic than mescaline • Produce similar effects: low doses amphetamine-like effects, high doses LSD-like serotonin-mediated effects DOM (or STP for "serenity, tranquillity, and peace") • Effects similar to mescaline: doses 1-6 mgs produce euphoria, followed by 6-8 hr period of hallucinations. • 100x more potent than mescaline but less potent than LSD. • High incidence of overdose; acute toxic reactions; tremors leading to convulsive movements, followed by death. MDA, MMDA, TMA • Effects resemble mescaline and LSD: reflect mix of catecholamine and serotonin interactions. • MDMA ("ecstasy") resembles MDA but less hallucinogenic, with less sense of disembodiment and visual distortion • MDMA releases serotonin and cause acute depletion of forebrain serotonin and destruction of serotonin neurons...serotonergic systems are implicated in control of sleep, food intake, sexual behavior, anxiety, and mood, disruption due to cell loss could have major consequences. Myristin and Elemicin • Active ligand in nutmeg and mace related to mescaline • From dried seed and seed coat of East Indian nutmeg tree (Myristica fragrans) • Ingestion of large amounts (I-2 teaspoons, usually brewed in tea), after 2-5 hr delay, induce euphoria and changes in sensory perception, visual hallucinations, acute psychotic reactions, and feelings of depersonalization and unreality. • Unpleasant side effects: vomiting, nausea, and tremors. Serotonin-like Psychedelic Drugs (S-PD’s) • S-PD’s include: 1. lysergic acid diethylamide (LSD) 2. psilocybin and psilocin (mushroom Psilocybe mexicana), 3. dimethyltryptamine (DMT), and 4. bufotenine • LSD is partial serotonin2 (5-HT2) receptor agonist: triggers responses involving other neurotransmitter systems (hence, overlap between serotonin and catecholamine psychedelics). • S-PD’s alter mood and perception via activation of serotonin cells in pontine raphe (a neuronal filter for sensations and perceptions, eliminating those that are unimportant, irrelevant, or commonplace). • Adverse reactions: paranoid ideation, depression, undesirable hallucinations, and/or a confusional state resembling a drug-induced dementia. • Serotonin receptor blockers are useful in antagonizing psychedelic effects "bad trip". • Antipsychotic drugs with antiserotonergic properties used to treat LSD-induced psychosis...however, not routinely used because neuroleptics evoke motoric side effects LSD - Historical Background • 1938 synthesized by Albert Hoffman, Swiss chemist, as part of an organized research program to investigate therapeutic uses of compounds obtained from ergot. • Ergot: natural product from fungus (Claviceps purpurea), which grows on rye in grain fields of Europe and North America...active agents are derivatives of lysergic acid. • Pharmacological actions of ergots: constriction of blood vessels and increased contractions of uterus (at least at low doses). • Ergot alkaloids used for migraine headaches and control postpartum hemorrhaging. • From 1938 until 1943 LSD remained on laboratory shelf unnoticed, when Doctor Hoffman had an unusual experience: In the afternoon of 16 April 1943...I was seized by a peculiar sensation of vertigo and restlessness. Objects, as well as the shape of my associates, appeared to undergo optical changes. I was unable to concentrate on my work. In a dreamlike state I left for home, where an irresistible urge to lie down overcame me. I drew the curtains and immediately fell into a peculiar state similar to drunkenness, characterized by an exaggerated imagination. With my eyes closed, fantastic pictures of extraordinary plasticity and intensive color seemed to surge toward me. After 2 hours this state gradually wore off. " Hoffman ingested compound under controlled conditions and described experience with a dose now known as ~10x the dose required to induce psychedelic effects...as a result: After 40 minutes, I noted the following symptoms: slight giddiness, restlessness, difficulty in concentration, visual disturbances, laughing.... Later, I lost all count of time. I noticed with dismay that my environment was undergoing progressive changes. My visual field wavered and everything appeared deformed as in a faulty mirror. Space and time became more and more disorganized and I was overcome by a fear that I was going out of my mind. The worst part of it being that I was clearly aware of my condition. My power of observation was unimpaired.... Occasionally, I felt as if I were out of my body. I thought I had died. My ego seemed suspended somewhere in space, from where I saw my dead body lying on the sofa.... It was particularly striking how acoustic perceptions, such as the noise of water gushing from a tap or the spoken word, were transformed into optical illusions. I then fell asleep and awakened the next morning somewhat tired but otherwise feeling perfectly well. • 1949 first study of LSD in humans conducted in U.S., and during 50s large quantities of LSD distributed to pharmacologists and physicians worldwide for research • LSD tried as adjunct to psychotherapy to help patients verbalize problems; this has not proven to be effective. • Early work on human volunteers introduced LSD to college campuses, from there, to a wider audience...reached peak in popularity in late 60s, after which use has decreased LSD Pharmacokinetics • LSD often added to other substances, such as squares of paper, backs of stamps, or sugar cubes and taken orally...usual doses range 25-300 micrograms and absorbed in ~1hr reaching peak in 3hrs and subsiding in 6-8 hrs. • Distributed rapidly in body, brain and crosses placenta; liver metabolized; detected in urine by radioimmunoassay LSD Physiological Effects • Slight increase in body temperature, pupil dilatation, increased heart rate and blood pressure, increased blood glucose levels, dizziness, drowsiness, and nausea. • Low level of toxicity...effective dose 50 microgms and lethal dose of 14 milligms...therapeutic ratio of 280 LSD Psychological Effects • Unpredictable and influenced by variety of factors: personality, expectations, previous experience with LSD and other psychoactive drugs, motivations for using drug, drug setting, and persons with whom user interacts • Predictable responses: alterations in mood and emotion, laughter or sorrow evoked easily; euphoria and dysphoria • Principal psychological effects: perceptual changes, especially visual hallucinations and perceptual distortions...true auditory hallucinations rare. • Psychedelic experience can be divided into three phases: 1. Somatic phase consists of CNS stimulation and autonomic changes predominantly sympathomimetic. 2. Sensory phase characterized by sensory distortions and pseudo-hallucinations, effects desired by user. 3. Psychic phase signals maximum drug effect where changes in mood, disruption of thought processes, altered perception of time, depersonalization, true hallucinations, and psychotic episodes (bad trip) occur. LSD Tolerance and Dependence • Tolerance develops rapidly, and cross-tolerance occurs between LSD and other C-PD’s and S-PD’s. • Physical dependence does not develop, even when drug is used repeatedly or for prolonged period of time...no withdrawal signs exhibited...animals do not self-administer. LSD Adverse Reactions and Toxicity • Fall into four categories: 1. effects on the psychological state of the user 2. possibility of permanent damage to the brain 3. possible effects on the fetus when the drug is taken by a pregnant woman, and 4. deleterious effects on society if use of drug were widespread. • LSD eliminates normal defence mechanisms, and thus precipitates psychotic episodes. • Persistent flashbacks occur weeks/months after last drug use...mechanism unknown (15% of users)...precipitated by use of marihuana, anxiety, fatigue, or movement into a dark environment, flashbacks persist intermittently for several years. • Psychedelics can precipitate serious depressions, paranoid behavior, or prolonged psychotic episodes. LSD-like Tryptamine Derivatives Dimethyltryptamine (DMT)