Stimulant Drugs Part 3 Kim Edward Light, Ph.D. Professor, College of Pharmacy University of Arkansas for Medical Sciences

Objectives part 3 Discuss prescription amphetamine products and uses. Discuss other prescription stimulant drugs and their uses and problems. Discuss use and abuse of cocaine. Identify the differences between cocaine abuse and methamphetamine abuse. Discuss other illicit stimulants such as khat and arecoline (betel).

Amphetamine Products Adderall ® Adderall-XR ® Benzedrine ® Biphetamine ® Dexedrine ® Dexedrine Spansule ®

Amphetamine - Uses Treatment  Attention Deficit Hyperactivity Disorder (ADHD)  Narcolepsy  Obesity Extended or sustained release to reduce dosing frequency.

Amphetamine - Side Effects Similar to methamphetamines but more cardiovascular Abuse often leads to abuse of methamphetamine Escalating use among college students as “study drug”

Other Stimulant Drugs Treatment of ADHD  Methylphenidate - Ritalin ®  Atomoxetine - Strattera ® Treatment of Obesity  Phenmetrazine – Preludin ®  Phentermine – Fastin ®  Fenfluramine - Pondimin ® Treatment of Narcolepsy  Modafinil - Provigil ®  Methylphenidate - Ritalin ®

Methylphenidate Ritalin ® Treatment of narcolepsy and ADHD Onset of action within one hour Duration of action is less than 4 hours.  Sustained or extended release preparations. Used as a “study drug” Side effects similar to methamphetamine and amphetamine May lead to abuse of methamphetamine

Phenmetrazine Preludin ® Anorexiant drug for treatment of obesity  Sustained release preparation once daily - AM. Tolerance development (within a few weeks). Actions, mechanisms, and adverse consequences are similar to those of amphetamines and methylphenidate. Less availability - less evident abuse Popular among medical professionals due to their increased access

Phentermine Fastin ® Anorexiant drug in treatment of obesity  Sustained release preparation once daily - AM. Actions and adverse consequences are similar Dosage escalation is a common feature Less availability - less evident abuse Also popular among medical professionals due to increased access

Fenfluramine Pondimin ® Anorexiant drug in treatment of obesity Generally administered three times daily before meals Duration generally 4-6 hours Mechanism of action includes CNS serotonin systems Combined with phentermine → Phen-fen. Cardiovascular problems - palpitations, hypertension and valvular heart disease led to discontinuation. Development of pulmonary hypertension Tolerance, dependence, and addiction

Atomoxetine Strattera ® Treatment of ADHD Administered once or twice daily Must take for several weeks before onset of acceptable effect Classified as non-stimulant in 2004 but must carry warning label for possible liver toxicity. Not stimulatory like amphetamines, although increases in  blood pressure  heart rate  weight loss

Modafinil Provigil ® Approved in 1999; Schedule IV drug, Once daily dosing Treatment of narcolepsy, obstructive sleep apnea and excessive daytime sleepiness. Adverse effects may include hypertension, headache, dizziness, agitation, and insomnia. Mechanism of action and effects are markedly different from amphetamines, may enhance glutamate neurotransmission.

Cocaine - History From the leaves of the plant Erytrhroxylon coca; grows in the Andes Mountains m above sea level Used by natives for suppression of appetite, thirst, and tiredness especially on long hunting trips Inca civilizations used coca in religious rituals

Cocaine - History Sigmund Freud and Carl Koller introduced cocaine into clinical practice  Koller (an ophthalmologist) was intrigued by its activity as a local anesthetic  Freud, working as a neurologist (~1884), was more interested in the stimulant effects

Cocaine - History Late 1800’s -- early 1900’s  ingredient in many products as an elixir, balm or other medicinal Early 1900’s, awareness of problems resulted in a decrease in its availability Passage of the Narcotics Tax Acts in 1914 further decreased its availability

Cocaine - Mechanism Blocks reuptake of neurotransmitters - dopamine, norepinephrine, epinephrine, and serotonin.

Cocaine - Pharmacokinetics Duration of action is minutes. Rapidly metabolized  esterase enzymes - in blood & tissues. Rapid metabolism results in  rapid decrease in euphoria  intense craving or drug “hunger” results

Cocaine - Routes of Administration

Cocaine Powder Crack or Freebase

Cocaine – Binding Sites VTA NcA Caudate

Cocaine - Adverse Effects Tolerance & Sensitization Restlessness, irritability, anxiety, aggressiveness, hypersexuality, and paranoia Acute toxicity and death  seizures or stroke in the brain  arrhythmias or infarctions in the heart Vasoconstriction may lead to necrosis and tissue death in the sinuses or injection sites.

Cocaine – Use Patterns Binge Combination  Marijuana  Benzodiazepines  Heroin (“Speedball”)  Alcohol Cocaine + Ethanol  Cocaethylene

Cocathethylene Equipotent with cocaine at  DA sites Less potent at serotonin sites. More euphorigenic and addictive. More toxic to the liver & heart.

Methamphetamine vs Cocaine Origins  Methamphetamine is man-made  Cocaine is plant-derived Common Methods of Use  Smoked, injected intravenously, or snorted.  Methamphetamine also is commonly ingested orally.

Methamphetamine vs Cocaine Euphoria  Intense pleasurable rush or high  Duration of the high is major difference Methamphetamine - 8 to 24 hours Cocaine - 20 to 30 minutes.

Methamphetamine vs Cocaine Chronic Use  Methamphetamine may result in more violent behavior  Methamphetamine withdrawal drug hunger anhedonia.

Methamphetamine vs Cocaine Methamphetamine  Damage to the neurons that produce dopamine and serotonin. Cocaine  No demonstrated damage to dopamine or serotonin neurons.

Transmission of HIV/AIDS Intravenous injection of both contributes to transmission of HIV/AIDS High-risk sexual behaviors and in exchange of drugs for sex

Other Stimulant Plants Khat derived from Catha Edulis, a small tree/shrub that grows in East Africa and Arabian Peninsula Arecoline derived from Betel nuts of the palm tree Areca catechu prevalent throughout southeast Asia

Khat - History Cultivated in East Africa since the early 1300s. Predates the use of coffee in the region 20th century - some countries in region officially banned its use - seldom enforced. Increased publicity a result of the U.S. efforts in Somalia during 1993.

Khat Contains cathinone and cathine, Methcathinone is semisynthetic from cathinone Cathine much less potent than cathinone or methcathinone. Cathine is a Schedule IV drug; cathinone and methcathinone are Schedule I drugs. CathineCathinoneMethcathinone

Khat - Use Leaves and shoots are chewed,  like tobacco, for the stimulation and appetite suppression effects. Cathinone only present in fresh leaves since it degrades within about 48 hours.  Often refrigerated immediately upon harvesting for transport.

Khat - Effects Similar to amphetamines.  mild euphoria and excitement  reduced appetite  increased HR & BP Withdrawal symptoms  lethargy  depression  nightmares and tremors.

Arecoline - History Widely used in India, Thailand, Indonesia and other Asian countries. Used by more people in the world than any other single plant.  Traditionally used for intestinal worms and as an antihelminthic in veterinary medicine. Crushed betel nuts wrapped in pieces or leaves from the Piper betel vine along with lime and sometimes other flavorings including tobacco.

Arecoline - Mechanisms Acts by stimulation of cholinergic neurotransmission in both CNS and ANS May also act on other neurotransmitter systems (i.e. GABA) Produces mild stimulation and euphoric not unlike tobacco Increased risk of throat & mouth cancers.

Summary (part 3) Amphetamine in therapeutics Methylphenidate, Phenmetrazine Phentermine, Fenfluramine Atomoxetine, Modafinil Cocaine Methamphetamine vs Cocaine Khat – cathine, cathinone  Methcathinone Arecoline – Betel nut