chapter 3 uppers. behavioral stimulants cocaine/amphetamines psychostimulants tranquilizer augment...

CHAPTER 3 Uppers

Behavioral StimulantsCocaine/AmphetaminesPsychostimulantsTranquilizerAugment synaptic action

DopamineNorepinephrineSerotonin

Stimulate the nucleus accumbensBehavioral reinforcementCompulsive abuseAttention-deficit/hyperactivity

Behavioral StimulantsCocaine

From leaves of the plant Erythroxylon cocaOriginally chewed by natives of Central and

South AmericaMid-19th century - incorporated into many

products including wine and Coca-ColaReplaced by amphetamines – longer actingRevived when amphetamine prices rose and

‘crack’ cocaine became widespread

Behavioral StimulantsCocaine

Most users: 12-39 years old 75% male Polypharmacy Co-existing psychological problem Insufflate Alcohol dependent

Behavioral StimulantsCocaine

One of the most reinforcing/addictive of drugsHigh doseRapid onsetRapid toxicityRapid dependence

Behavioral StimulantsCocaine

Extracted from leavesGenerally produced as hydrochloride

Average dose – 25 mgCocaine base = crackCrack 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 StimulantsCocaine – 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 StimulantsCocaine-Pharmacokinetics-Distribution

Freely crosses all barriersHigh lipid solubilityBrain concentrations >> plasmaFetal levels equal to maternal

Behavioral StimulantsCocaine – Phramacokinetics - Metabolism

and Excretiont1/2 of 30-90 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 StimulantsCocaine – Mechanism of Action

Local anestheticVasoconstrictorPsychostimulant

Behavioral StimulantsCocaine – 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 StimulantsCocaine – 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 StimulantsCocaine – 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 StimulantsCocaine – 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 StimulantsCocaine

Reinforcement Strong craving for more Tolerance starts quickly leading to cyclic

dependence Rebound depression Isolation Sexual dysfunction

Behavioral StimulantsToxic 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 StimulantsCocaine – High Dose

HyperactivityParanoiaImpulsive, repetitive, compulsive behaviorAltered perception of realityAggressive/homicidal – persecution complexToxic paranoid psychosis

Behavioral StimulantsCocaine – 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 StimulantsCocaine – 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 StimulantsCocaine - Pharmacological Treatment

Problems Intensity of drug effect Intensity of behavior reinforcement Relapse Co-existing disorder

Behavioral StimulantsCocaine - Pharmacological Treatment

Antiwithdrawal agents – none to dateAnticraving agents - ecopipanTreatment of comorbid disorders – difficult but

the most promisingPharmacological treatment not yet very

successful

Behavioral StimulantsCocaine – Psychosocial Interventions

Sometimes work: AA-like Individual/group counseling Cognitive-behavioral therapy Supportive-expressive therapy Behavioral reinforcement

Behavioral StimulantsAmphetamines

Sympathomimetic amines Mimic epinephrine

VasoconstrictionHypertensionTachycardiaAlerting response

Behavioral StimulantsAmphetamines

PhenylethylamineAmphetamineMethamphetamineResemble dopamine

UsesNarcolepsyADHDAppetite suppression – but…

AbuseWakefulnessAppetite suppression

Behavioral StimulantsAmphetamines

Mechanism Release norepinephrine and dopamine Dopamine stimulation of limbic system Constant repetitive behavior associated with

dopamine neurons in brain stem

Behavioral StimulantsAmphetamines

Pharmacological effects Release of norepinephrine and dopamine from

presynaptic neurons Similar response as cocaine

Behavioral StimulantsAmphetamines

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 StimulantsAmphetamines

Pharmacological effects Moderate dose

Stimulates respiration Tremors Restlessness Greater increase in motor activity Agitation Prevent fatigue Sleep deprivation

Behavioral StimulantsAmphetamines

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 StimulantsAmphetamines

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 StimulantsAmphetamines

ICE Free base methamphetamine - smokable

Behavioral StimulantsAmphetamines

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

Behavioral StimulantsEffects and Toxicity

Very similar to cocainePsychomotor stimulantPositive reinforcerSelf administration difficult to controlViolent/aggressive behaviorHigh 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 StimulantsOther drugs

Ritalin – amphetamine relativePemoline – non-amphetamine, lower abuse

potentialSibutramine – 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 StimulantsTreatment of ADHD

Ritalin – 90% of prescribed casesAmphetamines – similar responsePemolineBuspironeBupropionAntidepressants – nortriptyline, fluoxetine, etcLong-term efficacy of drug treatment of ADHD

unknown

CaffeineMost commonly used psychoactive drug

Coffee – caffeine - 50-150 mgTea –theophylline- 25–90 mgCola – caffeine - 25-75 mgChocolate - theobromine – 25mg/ozCocoa

CaffeineEnhanced mental alertnessIncreased energySense of well-beingDopaminergic?Reinforcing?

CaffeinePharmacokinetics

Absorption – 90 minDistribution – throughout total body waterCrosses blood-brain and maternal-placental

barriers, present at high conc in breast milkMetabolized in livert1/2 of 3.5-5 hr (extended in infants and

pregnant women)SSRIs may cause blockage of caffeine

metabolism and toxicity

CaffeinePharmacological effects

PsychostimulantRewarding effect: alertnessReduced fatigueSustained intellectual effortFine muscle control, timing, arithmetic skills

may be adversely affected’

CaffeinePharmacological effects

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

CaffeinePharmacological effects

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

CaffeineMechanism of action

Adenosine (depressant neurotransmitter – facilitates GABA binding) antagonist

Stimulates dopaminergic activity, due to above, in cerebral cortex rather than limbic system

CaffeineReproductive effects

UnknownHigh dose may cause spontaneous abortionFDA suggests pregnant women limit caffeine

CaffeineTolerance and Dependence

HabituationToleranceWithdrawal syndrome – headache, drowsiness,

fatigue, impaired intellect, motor skills, craving

NicotinePrimary active ingredient in tobacco

4000 compounds in tobacco smokeNicotine causes pharmacologic effects, but

other compound cause most of the long-term deleterious health effects – emphysema, cancer, etc.

NicotinePharmacokinetics

Absorbed from all sites in or on bodyPeak levels reached in minutesDistribution – brain firstt1/2 about 24-120 min.Major metabolite cotinineSimilar to caffeine – some SSRIs can inhibit

metabolism leading to toxicity

NicotinePharmacological effects

BrainSpinal cordPNSHeartNausea, vomitingStimulates hypothalamus to release ADH – fluid

retentionReduces muscle toneReduces appetiteADHDPotent behavior reinforcer

NicotinePharmacological effects

Increased Psychomotor activity Cognition Sensorimotor performance Attention Memory Anxiolytic Antidepressant

Higher doses Nervousness Tremors Seizures Panic attacks

NicotineMechanism of action

Activates acetylcholine receptorsIncreased bp, pulseReleases epinephrine from adrenalsIncreases GI activityStimulates presynatptic release of dopamine,

acetylcholine, glutamateIncreases dopamine in limbic systemIncreased acetylcholine, glutamate responsible

for improved mental functions

NicotineTolerance and dependence

Does not induce biological tolerancePhysiological and psychological dependence in

most smokersNicotine is highly addictiveWithdrawal – abstinence syndrome – craving.

Irritability, increased appetite, weight gain, insomnia – can last many months

More difficult to quit smoking than stop taking many other drugs

NicotineToxicity

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

NicotinePregnancy

Spontaneous abortionFetal demisePremature delivery, early postpartum deathGrowth retardation, Low birth weightFetal hypoxia – leads to a number of

brain/behavior problemsPredisposition to addiction?

NicotineTherapy for dependence

Replacement – gum, patch, sprays, etc.All equally efficaciousAntidepressantsAbout 10-30% of those who try to quit can

make it a year.