Stimulant DrugsPart 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

PhentermineFastin®

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

FenfluraminePondimin®

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

AtomoxetineStrattera®

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 1000-3000 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 atDA 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.

Cathine Cathinone Methcathinone

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