CHAPTER 3 Uppers

Behavioral Stimulants Cocaine/Amphetamines Psychostimulants Tranquilizer Augment synaptic action Dopamine Norepinephrine Serotonin Stimulate the nucleus accumbens Behavioral reinforcement Compulsive abuse Attention-deficit/hyperactivity

Behavioral Stimulants Cocaine From leaves of the plant Erythroxylon coca Originally chewed by natives of Central and South America Mid-19 th century - incorporated into many products including wine and Coca-Cola Replaced by amphetamines – longer acting Revived when amphetamine prices rose and ‘crack’ cocaine became widespread

Behavioral Stimulants Cocaine Most users: years old 75% male Polypharmacy Co-existing psychological problem Insufflate Alcohol dependent

Behavioral Stimulants Cocaine One of the most reinforcing/addictive of drugs High dose Rapid onset Rapid toxicity Rapid dependence

Behavioral Stimulants Cocaine Extracted from leaves Generally produced as hydrochloride Average dose – 25 mg Cocaine base = crack Crack will volatilize allowing it to be smoked for more rapid delivery Average dose – 250mg – 1 g High doses of crack lead to high plasma level, and fast but short lived ‘high’

Behavioral Stimulants Cocaine – Pharmacokinetics - Absorption Absorbed from any mucous membrane, stomach, lungs Strong vasoconstrictor, so insufflation is not very effective Hydrochloride is MUCH less lipid soluble, so does not absorb as well as base Smoked, onset of symptoms in seconds, lasting ~30min Injected – 100% bioavailability

Behavioral Stimulants Cocaine-Pharmacokinetics-Distribution Freely crosses all barriers High lipid solubility Brain concentrations >> plasma Fetal levels equal to maternal

Behavioral Stimulants Cocaine – Phramacokinetics - Metabolism and Excretion t1/2 of min. Metabolized by enzymes in liver and plasma to benzoylecgonine, ecgonine methyl ester and other inactive metabolites Metabolized to cocaethylene in the presence of EtOH – highly toxic Mostly eliminated in urine

Behavioral Stimulants Cocaine – Mechanism of Action Local anesthetic Vasoconstrictor Psychostimulant

Behavioral Stimulants Cocaine – Dopaminergic Actions Potentiates synaptic actions to dopamine, norepinephrine, serotonin due to re-uptake blockage Dopamine reuptake blockage may be crucial to reinforcing and stimulant properties High levels of dopamine in reward system may account for addictive/euphoric effects Decrease discharge rate in limbic system – inhibits post- synaptic receptors

Behavioral Stimulants Cocaine – Serotoninergic Actions Studies show cocaine is a reinforcer in the absence of dopamine transporter Serotonin may be another reinforcement mechanism One serotonin receptor may antagonize reinforcing effects of cocaine

Behavioral Stimulants Cocaine – short term, low dose Physiological responses Increased alertness, mental activity – then depression Motor hyperactivity Tachycardia Vasoconstriction Hypertension Bronchodilation Hyperthermia Pupil dilation Increased glucose availability Increased blood flow to muscles, hyperactivity Rapid speech – incoherent Appetite suppressed

Behavioral Stimulants Cocaine – short term, low dose Psychological effects Euphoria Giddiness Enhanced self-consciousness Forceful boastfulness Euphoria/anxiety, progressing to Anxiety Promotes desire for more cocaine Tolerance quickly develops

Behavioral Stimulants Cocaine Reinforcement Strong craving for more Tolerance starts quickly leading to cyclic dependence Rebound depression Isolation Sexual dysfunction

Behavioral Stimulants Toxic effects Huge effects on most organ systems CNS – Strokes, seizures, etc Cardiovascular – MI, Arrhythmias, cardiac arrest, major vessel failure, etc. Pulmonary – nasal septal perforations, pulmonary edema, bronchitis, etc GI – Ulcers, perforations, GI infarcts, etc. Kidney – failure, etc. Maternal – spontaneous abortion, placenta previa, etc. Fetal – demise, premature, defects, etc Neonatal – withdrawal, seizures, defects, etc.

Behavioral Stimulants Cocaine – High Dose Hyperactivity Paranoia Impulsive, repetitive, compulsive behavior Altered perception of reality Aggressive/homicidal – persecution complex Toxic paranoid psychosis

Behavioral Stimulants Cocaine – Comorbidity “virtually every psychiatric syndrome, affective disorders (mania and depression), schizophrenia-like syndromes, personality disorders and so on.” High percentage dependent on multiple drugs

Behavioral Stimulants Cocaine – Pregnancy Crack babies Vasoconstriction - Insufficient blood flow Placental detachment Preterm labor Fetal demise Low birth weight Growth retardation Microcephaly CNS and PNS development Many congenital physical and mental defects 50,000 to 100,000 babies per year ADHD Too diverse to specify a ‘Fetal cocaine syndrome’

Behavioral Stimulants Cocaine - Pharmacological Treatment Problems Intensity of drug effect Intensity of behavior reinforcement Relapse Co-existing disorder

Behavioral Stimulants Cocaine - Pharmacological Treatment Antiwithdrawal agents – none to date Anticraving agents - ecopipan Treatment of comorbid disorders – difficult but the most promising Pharmacological treatment not yet very successful

Behavioral Stimulants Cocaine – Psychosocial Interventions Sometimes work: AA-like Individual/group counseling Cognitive-behavioral therapy Supportive-expressive therapy Behavioral reinforcement

Behavioral Stimulants Amphetamines Sympathomimetic amines Mimic epinephrine Vasoconstriction Hypertension Tachycardia Alerting response

Behavioral Stimulants Amphetamines Phenylethylamine Amphetamine Methamphetamine Resemble dopamine Uses Narcolepsy ADHD Appetite suppression – but… Abuse Wakefulness Appetite suppression

Behavioral Stimulants Amphetamines Mechanism Release norepinephrine and dopamine Dopamine stimulation of limbic system Constant repetitive behavior associated with dopamine neurons in brain stem

Behavioral Stimulants Amphetamines Pharmacological effects Release of norepinephrine and dopamine from presynaptic neurons Similar response as cocaine

Behavioral Stimulants Amphetamines Pharmacological effects Low dose (methamp more potent than amp) Increase bp Slow pulse Relax bronchial muscles Psychomotor stimulant Increases alertness Euphoria Dexterity deteriorated Loss of appetite Wakefulness Mood elevation Alertness Feeling of power Etc.

Behavioral Stimulants Amphetamines Pharmacological effects Moderate dose Stimulates respiration Tremors Restlessness Greater increase in motor activity Agitation Prevent fatigue Sleep deprivation

Behavioral Stimulants Amphetamines Pharmacological effects High dose Continual purposelessness Repetitive behavior Aggression Violence Paranoid delusions Severe anorexia Psychosis, abnormal mental conditions Weight loss Skin sores and infections from poor hygiene/neglect Pregnancy Little data, but some correlation to a variety of congenital problems

Behavioral Stimulants Amphetamines Dependence and Tolerance Potent stimulant and behavior reinforcer Typical dependence cycle use/reward/more use Withdrawal – increase appetite, weight gain, decreased energy, increased sleep, severe depression Does not require de-tox, but other symptoms must be closely monitored Tolerance develops quickly – binge behavior, isolation

Behavioral Stimulants Amphetamines ICE Free base methamphetamine - smokable

Behavioral Stimulants Amphetamines Pharmacokinetics Absorption – up to 4 hr t1/2 >11hr 60% metabolized by liver Amphetamine is primary active metabolite Excreted by kidneys

Behavioral Stimulants Effects and Toxicity Very similar to cocaine Psychomotor stimulant Positive reinforcer Self administration difficult to control Violent/aggressive behavior High doses may lead to IRREVERSIBLE decreases of dopamine and serotonin and a large number of serious sequelae (paranoia, schizophrenia, delusional/psychotic behavior) Cardiac toxicity

Behavioral Stimulants Other drugs Ritalin – amphetamine relative Pemoline – non-amphetamine, lower abuse potential Sibutramine – weight loss - similar to amphetamines. Alternate: Orlistat – weight loss inhibits pancreatic lipase in gut. Fat not absorbed; excreted in feces Modafinil – narcolepsy – potentiates glutamate neurotransmission

Behavioral Stimulants Treatment of ADHD Ritalin – 90% of prescribed cases Amphetamines – similar response Pemoline Buspirone Bupropion Antidepressants – nortriptyline, fluoxetine, etc Long-term efficacy of drug treatment of ADHD unknown

Caffeine Most commonly used psychoactive drug Coffee – caffeine mg Tea –theophylline- 25–90 mg Cola – caffeine mg Chocolate - theobromine – 25mg/oz Cocoa

Caffeine Enhanced mental alertness Increased energy Sense of well-being Dopaminergic? Reinforcing?

Caffeine Pharmacokinetics Absorption – 90 min Distribution – throughout total body water Crosses blood-brain and maternal-placental barriers, present at high conc in breast milk Metabolized in liver t1/2 of hr (extended in infants and pregnant women) SSRIs may cause blockage of caffeine metabolism and toxicity

Caffeine Pharmacological effects Psychostimulant Rewarding effect: alertness Reduced fatigue Sustained intellectual effort Fine muscle control, timing, arithmetic skills may be adversely affected’

Caffeine Pharmacological effects Heavy consumption (12 cup or more/day) Agitation Anxiety Tremors Increased respiration Insomnia Caffeinism – serious combination of the above

Caffeine Pharmacological effects Outside CNS Cardiac stimulant Hypertension Dilates coronary arteries Constricts cerebral vessels Relieves headache (migraines)

Caffeine Mechanism of action Adenosine (depressant neurotransmitter – facilitates GABA binding) antagonist Stimulates dopaminergic activity, due to above, in cerebral cortex rather than limbic system

Caffeine Reproductive effects Unknown High dose may cause spontaneous abortion FDA suggests pregnant women limit caffeine

Caffeine Tolerance and Dependence Habituation Tolerance Withdrawal syndrome – headache, drowsiness, fatigue, impaired intellect, motor skills, craving

Nicotine Primary active ingredient in tobacco 4000 compounds in tobacco smoke Nicotine causes pharmacologic effects, but other compound cause most of the long-term deleterious health effects – emphysema, cancer, etc.

Nicotine Pharmacokinetics Absorbed from all sites in or on body Peak levels reached in minutes Distribution – brain first t1/2 about min. Major metabolite cotinine Similar to caffeine – some SSRIs can inhibit metabolism leading to toxicity

Nicotine Pharmacological effects Brain Spinal cord PNS Heart Nausea, vomiting Stimulates hypothalamus to release ADH – fluid retention Reduces muscle tone Reduces appetite ADHD Potent behavior reinforcer

Nicotine Pharmacological effects Increased Psychomotor activity Cognition Sensorimotor performance Attention Memory Anxiolytic Antidepressant Higher doses Nervousness Tremors Seizures Panic attacks

Nicotine Mechanism of action Activates acetylcholine receptors Increased bp, pulse Releases epinephrine from adrenals Increases GI activity Stimulates presynatptic release of dopamine, acetylcholine, glutamate Increases dopamine in limbic system Increased acetylcholine, glutamate responsible for improved mental functions

Nicotine Tolerance and dependence Does not induce biological tolerance Physiological and psychological dependence in most smokers Nicotine is highly addictive Withdrawal – abstinence syndrome – craving. Irritability, increased appetite, weight gain, insomnia – can last many months More difficult to quit smoking than stop taking many other drugs

Nicotine Toxicity Most mortality/morbidity due to other compound in smoke Cardiovascular CO – decreases O2 Nicotine – heart rate, bp, atherosclerosis, thrombosis Pulmonary Emphysema Cancer Nicotine probably not carcinogenic Other compounds definitely ARE carcinogenic Lung, mouth, voice box, throat, bladder, pancreas, cervical Passive inhalation Matter of degree – all of the above

Nicotine Pregnancy Spontaneous abortion Fetal demise Premature delivery, early postpartum death Growth retardation, Low birth weight Fetal hypoxia – leads to a number of brain/behavior problems Predisposition to addiction?

Nicotine Therapy for dependence Replacement – gum, patch, sprays, etc. All equally efficacious Antidepressants About 10-30% of those who try to quit can make it a year.