CHAPTER 7: PSYCHOMOTOR STIMULANTS Brought to you by: Stephanie Andrus, Kimberly Bernosky and Steve Marshall

General Effects of Psychomotor Stimulants: Increase in behavioral and motor activity Increase in alertness and disruption of sleep Pupil dilation, shift in blood flow from skin and organs to muscle, increased body temp. Increase in blood pressure and heart rate Increased O 2 and glucose levels in the blood Side effects of anxiety, insomnia and irritability Effects synaptic action of dopamine, serotonin & norepinephrine

Cocaine: Forms of Cocaine Coca leaves contain 0.5-1% active ingredient of cocaine (benzomethylecognone) Coca paste contains 60-80% cocaine, then is treated with HCl to produce H 2 O soluble salt. One line of cocaine = 25 mg This salt is injectable, but decomposes with heat Freebase (crack cocaine) is not H 2 O soluble, but it is soluble in alcohol, acetone & ether. Freebase is relatively heat tolerant, so it can be smoked. One dose of crack = 250–1000 mg

Cocaine Pharmacokinetics of Cocaine: Absorption Absorption through mucous membranes (snorting): Cocaine’s vasoconstrictive property limits its own absorption (20-30% absorbed). Peak reached in minutes Inhalation of freebase smoke: Onset of effect in 8-10 seconds. 6-32% reaching plasma. Peak plasma levels reached at 5 minutes, persisting for 30 minutes. Intravenous Administration: Onset of effect in sec

Cocaine Pharmacokinetics of Cocaine: Distribution & Metabolism Penetrates BBB rapidly, initial brain concentration far exceeds plasma concentration Removed slowly from brain Half-life in plasma = minutes Rapid enzymatic breakdown Detectable for 12+ hrs after use (metabolites detectable up to 2 weeks after use) Freely crosses placental barrier

Cocaine: Neurotransmitter Actions of Cocaine Potentiates synaptic action due to actively blocking the reuptake of DA, NE & serotonin Exerts inhibitory effect on postsynaptic dopamine receptors Blocks the presynaptic transporter protein for DA Increases levels of DA at the synaptic cleft, creating a euphoric sensation Serotonin binding provides additional reinforcement

Cocaine: Physiological Effects of Short-term Low- Dose Cocaine Use Low dose is hard to maintain due to increasing tolerance (progressively higher doses needed) Appetite repression See Slide 2: General effects of psychomotor stimulants (increased BP, HR, body temp etc.)

Cocaine: Psychological Effects of Short-term Low-dose Cocaine Use Euphoria, giddiness, boastfulness, self- consciousness (lasting 30 minutes) then mild euphoria, anxiousness (lasting minutes) Then cocaine craving & rebound depression Eventually, loss of coordination, tremors & seizures Increased interest in sex & increased sexual dysfunction

Cocaine: Effects of Long-term High Dose Cocaine Use Toxic Paranoid Psychosis – anxiety, sleep deprivation, hypervigilance, paranoia, suspiciousness Hyperreactivity, impulsiveness, aggression, homicidal tendencies Withdrawal can result in hallucinations

Cocaine: Treatment of Cocaine Addiction Obstacles – rewarding nature of cocaine, tendency towards relapse, presence of other disorders/addictions Areas of Need – antiwithdrawal agents, anticraving agents (blocking dopamine receptors), treatment of comorbid disorders New types of treatment – ritalin & tricyclic antidepressants

Amphetamines: Mechanism of Action CNS effects are caused by release of NE and DA from presynaptic storage sites in the nerve terminals, increasing the amounts available at the postsynaptic receptor (see attached Figure 7.2, page 186 in the text)

Amphetamines: Pharmacological Effects Response intensity and duration varies w/type of drug, dose & route of administration Low dose: typical psychomotor stimulation Moderate dose: tremors, insomnia, agitation, increased respiration Continuous high doses: repetitive activity, aggression, delusions, anorexia Detectable in urine for 48 hours

Amphetamines: ICE Analogous to crack cocaine Highly abused illicit substance Easily synthesized from obtainable chemical Methamphetamine HCl is used orally, IV & by snorting, but breaks down at the temperatures needed for smoking ICE does not break down at these temperatures, so it is smoked. Absorption through lungs & mucous membranes can be faster than IV administration of Meth. HCl

Amphetamines ICE: Pharmacokinetics Near immediate absorption into plasma with additional absorption over the next four hours Half-life ≈ 12 hours (intense, persistent drug action) 60% slowly metabolized in the liver Metabolized & unmetabolized ICE excreted through kidneys

Amphetamines ICE: Effects & Toxicity Effects are nearly indistinguishable from those of cocaine Repeated high doses result in long-lasting, irreversible decreases in DA and serotonin in the brain Change in sleep patterns, depression, movement disorders, sexual dysfunction & schizophrenic psychoses can result from these chemical changes Fatalities occur in cases of high cardiac toxicity, resulting in pulmonary edema or heart failure

Non-Amphetamine Behavioral Stimulants Differ from amphetamines in that they lack the basic amphetamine nucleus Have similar effects to amphetamines Include ephedrine (ma-huang) which is used among athletes as a stimulant and is found in some OTC weight loss treatments

Non-Amphetamine Behavioral Stimulants: Used in Weight Loss Sibutramine (Meridia) Serotonin and norepinephrine reuptake inhibitor Does not appear to have properties lending it to compulsive misuse Causes significant increases in heart rate and blood pressure, limiting its use Orlistal (Xenical) can be used as an alternative

Treatment of ADHD: Non-Amphetamine Behavioral Stimulants Methylphenidate (Ritalin) Used in treatment of ADHD to calm hyperactivity and improve attention (prescribed in 90% of cases) Half-life ≈ 2-4 hours Variable absorption rates, but generally a rapid onset with short duration (multiple administrations needed over the course of a day)

Treatment of ADHD: Non-Amphetamine Behavioral Stimulants Methylphenidate (continued) No currently available susatained-release preparation Low-abuse potential Increases syn. conc. of DA by blocking the presyn. DA transporter (like cocaine) and increases the release of DA (like amphetamine)

Treatment of ADHD: Non-Amphetamine Behavioral Stimulants Pemoline (Cylert) Structurally dissimilar to amphetamine & methylphenidate Decreases ADHD symptoms by potentiating dopaminergic transmission May cause hepatitis-like liver damage Modafinil Potentiates glutamate neurotransmission, and inhibits activity of GABA neurons in the nucleus accumbens and cerebral cortex Used in treatment of ADHD, narcolepsy and causes cognitive improvement in Alzheimer’s patients

Treatment of ADHD: Amphetamines Dextroamphetamine (Dexedrine) and an amphetamine mixture (Adderall) A one-time dose of Adderall is similar in effect to the typical two daily doses of methylphenidate

Treatment of ADHD Stimulants improve behavior and learning in % of correctly diagnosed children 10-30% of ADHD individuals are treatment resistant (little to no response to treatment) Alternatives: antidepressants like fluoxetine (Prozac), buproprion (Welbutrin) and buspirone (Buspar) With antidepressants, rare cases of high cardiac toxicity have been found