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Cocaine and Amphetamines: Historical Use, Effects, and Pharmacodynamics, Study notes of Psychology

University of Memphis (U of M)Psychology

Historical facts, effects, and pharmacodynamics of cocaine and amphetamines. It covers their social use, isolation of active alkaloids, medicinal uses, and the rise and fall of their popularity. The document also discusses their distribution, elimination, and pharmacological actions, including their effects on the brain and behavior.

Typology: Study notes

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Uploaded on 07/28/2009

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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.
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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- 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- 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

of smell... intravenous - diseases transmitted by needle (hepatitis and AIDS) and infectious endocarditis (infections of heart valves)... smoking crack - pulmonary difficulties and black sputum.

Cocaine Side Effects of Long-Term, High-Dose Use

  • Toxic symptoms : anxiety, sleep deprivation, hyper-vigilance, suspiciousness, paranoia ( toxic paranoid psychosis ).
  • Other high-dose, long-term effects: sexual dysfunction, interpersonal conflicts, severe depressive conditions, dysphoria, and bizarre and violent psychotic disorders that last days or weeks after quitting
  • Acute toxic dose: ~1-2 mgs/kg...thus, 70-150mgs of cocaine is a toxic, one-time dose for a 150- pound person...physiological toxicity follows higher doses.
  • Cardiovascular and neurovascular sequelae: strokes in healthy, young individuals, persistent alterations in blood perfusion of brain, heart oxygen deprivation, cardiac arrhythmias, and seizures.
  • Chronic cocaine-induced psychiatric syndrome : affective disorders, schizophrenia syndromes, personality disorders, etc.
  • Cocaine addicts personality profiles : reckless, rebellious, and low tolerance for frustration and craving for excitement.
  • Cocaine addicts typically abuse opiates and alcohol either to enhance effects of cocaine or to medicate themselves for unwanted side effects : calming jitters, dulling perceptions, and reducing paranoia.
  • Intravenous drug users often take cocaine and heroin together in mixture “ speedball ”.

Cocaine Fetal Effects

  • Fetal cocaine syndrome (jittery baby syndrome) and infants known as " crack babies ."
  • Not well defined , since most fetal effects related to vasoconstriction, hypertension, and infarcts at any time during gestation and in any structure.
  • To determine possible effects on fetus, must examine not only indirect maternal effects on fetal development but also direct teratogenic effects.
  • Indirect effects on fetus result from vasoconstrictive action in mother, which decreases blood flow to uterus and reduces fetal oxygenation.
  • Results of fetal hypoxia : placental detachment, placental insufficiency, preterm or precipitous labour, fetal death (stillbirths), and low birth weight...and can lead to intrauterine growth retardation, small head size (microcephaly), and aberrations in brain development.
  • Unborn is exposed to cocaine even before fertilization, because cocaine can bind to sperm.
  • Cocaine promotes destructive lesions , leading to Neonatal Neurological Syndrome typified by: abnormal sleep patterns, tremors, poor feeding, irritability, seizures, and increased risk/incidence of sudden infant death syndrome ( SIDS ).
  • 50,000-100,000 babies born each year to mothers who have used cocaine during pregnancy
  • Crack babies show difficulty with unstructured play and low tolerance for frustration; also structure input and information poorly...and show high incidence of ADHD.

Treatment Problems of Cocaine Abuse

  • Variety of psychological, behavioral, and pharmacological approaches tried with major complications to overcome: 1. Intensity of both drug effect and behavior-reinforcing action of cocaine. 2. Pronounced tendency toward relapse, with cocaine acting as cue to increase craving for drug. 3. Virtually all cocaine addicts have additional drug dependencies and/or psychiatric disorders, including affective disorders, bipolar disorder, borderline personality disorder, antisocial

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
    1. 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.

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- Time to peak plasma 1-3 1-5 3- 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. mg/day 10-60 38-113 5-

  • 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

drug abuse and without concomitant development of tolerance.

  • New drugs (fenfluramine, fluoxetine, and sertraline) related to amphetamine but act to potentiate serotonin neurotransmission rather than dopamine.
  • Fenfluramine (Pondimin), partially inhibit serotonin reuptake and facilitate its release.
  • Fenfluramine combined with phentermine (dopamine releaser) enhanced weight loss over what could be achieved with behavior modification, exercise, and nutrition program, and effect sustained over 4 yrs (discontinued)
  • Fluoxetine and sertraline are serotonin reuptake inhibitors that are clinical antidepressants ...both drugs produce satiety and reduce food intake; tolerance to anorectic effect after several weeks

Nasal Decongestants (ND)

  • Structurally related to amphetamine , they alter synaptic actions of norepinephrine both in brain (minor effects) and in peripheral nervous system (more potent in PNS).
  • ephedrine, tetrahydrozoline (Tyzine), metaraminol (Aramine), phenylephrine (Neo-Synephrine), pseudo-ephedrine (Sudafed), xylometazoline (Otrivin), nylidrin (Arlidin), propylhexedrine (Benzedrex), phenmetrazine (Preludin), naphazoline (Privine), oxymetazoline (Afrin).
  • After use, compensatory rebound increases nasal stuffiness, similar to cocaine stuffy nose
  • Ephedrine is active ingredient in illicit preparations alleged to be amphetamine.

"ICE" a Free Base Form of Methamphetamine (crank, crystal, and speed)

  • More potent than amphetamine and easily synthesized in clandestine labs from inexpensive chemicals (ephedrine), making large amounts available at low cost.
  • In animals, implicated as a neurotoxic agent ; such toxicity not yet demonstrated in humans
  • When converted to base form ( ICE ) methamphetamine can be vaporized and inhaled in smoke.
  • Abuse of ICE began in Hawaii, spread to Japan (where it is called shabu ), then to California, and dispersed everywhere.
  • Since not injected, smoking removes guilt feelings, needle marks, infection risk, evidence of drug use, and heavy drug impressions associated with injection of illegal drugs.

Methamphetamine Pharmacokinetics

  • Rapid absorption into plasma which abates over 4 hrs and then progressively declines in plasma levels thereafter...~90% eventually reaches plasma.
  • Biological half-life over 11 hrs ....after distribution ~60% slowly metabolized in liver and excreted through kidneys, along with unmetabolized methamphetamine (~40% excreted unchanged).
  • Thus, long action follows from slow and incomplete metabolism ; in contrast, cocaine is rapidly and completely detoxified by enzymes found in both plasma and liver.

Methamphetamine Effects and Toxicity

  • Indistinguishable from cocaine ...potent psychomotor stimulant and positive reinforcer.
  • Repeated high doses associated with violent behavior and paranoid psychosis ...such doses cause long-lasting decreases in brain dopamine and serotonin.
  • Changes are irreversible , since chemical effects persist for >year
  • Permanent neurochemical changes: alterations in sleep, sexual function, depression, movement and/or schizophrenia.
  • Acute delusional and psychotic behavior occurs after smoking ICE...however, unlike cocaine, ICE- induced psychosis persists for days or weeks
  • Fatalities result from cardiac toxicity manifested as pulmonary edema or heart failure.