Abuse of Amphetamine and Khat (Psychostimulants) PDF

Abuse of amphetamine and Khat (psychostimulants) 1  By the end of this lecture, students should be able to: Discuss their Pharmacokinetics and pharmacodynamics of Khat, Amphetamine and related drugs Review the adverse drug reactions of the abuse of...

Abuse of amphetamine and Khat (psychostimulants) 1  By the end of this lecture, students should be able to: Discuss their Pharmacokinetics and pharmacodynamics of Khat, Amphetamine and related drugs Review the adverse drug reactions of the abuse of Khat, Amphetamine and related drugs Identify signs and symptoms of abuse, toxicity and withdrawal symptoms of Khat, Amphetamine and related drugs Develop a therapeutic management plan for treatment of abuse, acute toxicity and withdrawal symptoms of Khat, Amphetamine and related drugs. 2  Types of amphetamines 1. Amphetamine, Methamphetamine 2. Methylphenidate, pemoline. 3. Ephedrine, pseudoephedrine, 4. Fenfluramine, phentermine 5. Naphazoline, oxymetazoline, xylometazoline Cathinone is the active ingredient in freshly gathered leaves of the Khat). 3  Pharmacokinetics The most used amphetamine is: 1. Amphetamine sulphate (oral or injectable) 2. Free-base amphetamine can be smoked,. Onset of action is most rapid with inhalation, followed by IV and most delayed with oral administration Amphetamine’s biological half-life is about 8 hours, and methamphetamine’s is about 12 hours; powerful psychic effects can therefore last several hours (compared with 30 to 90 minutes for cocaine) With repeated use, drug accumulation occurs. 4  Mechanism of action A central stimulant and a peripheral sympathomimetic. Enhance the synaptic activity of biogenic amines: “norepinephrine, dopamine, and serotonin” 1. All amphetamines: stimulates the release of dopamine and norepinephrine 2. Methylphenidate, pemoline: additionally, Inhibits the reuptake of the catecholamines. 3. Ephedrine, pseudoephedrine: additionally, Directly activate catecholamine receptors. 5  Therapeutic uses of amphetamines Treatment of: 1. Narcolepsy 2. Attention deficit hyperactivity disorder (ADHD) in children. 6  Acute effects 1- Oral dextroamphetamine produces alertness, euphoria, increased motor activity, improved coordination, and greater physical activity. The feeling of well-being can lead to overconfidence and impaired judgment. Some subjects are initially drowsy, becoming hyperalert only after 1 or 2 hours Some experience agitation, dysphoria, confusion, headache, palpitations, and fatigue. 7 Systolic blood pressure is raised, often with reflex bradycardia, and there is mild pupillary dilatation. Sleep is reduced. 8 2- Intravenous amphetamine Produces a brief “flash” or “rush,” a sharp awakening that may be compared to an electric shock. The rush is even more rapid and powerful following inhalation of crystal methamphetamine “ice”. 9  Acute overdose Lead to excitement, confusion, headache, chest pain, hypertension, tachycardia, flushing, profuse sweating, and mydriasis. Progressing to delirium, hallucinations, hyperpnea, cardiac arrhythmia, hyperpyrexia (sometimes over [42.7°C]), seizures, shock, coma, and death. Seizures are less frequent among amphetamine users than cocaine users. 10  Treatment of overdose 1- reducing excitement and protecting against injury. The combination of hyperthermia and agitation can be rapidly fatal. The sedative of choice, is an intravenous benzodiazepine, rapidly titrated until the patient is calm. Very large doses may be necessary, for example more than 100 mg of diazepam 11 2- Cardiorespiratory support is provided as needed. 3- Seizures are treated with a benzodiazepine and phenytoin. 4-For severe hypertension, Preferable are: a. Direct vasodilators Nitrates (e.g., Nitroprusside). b. or alpha-blockers (e.g., phenoxybenzamine or phentolamine). Beta-blockers alone carry the risk of unopposed alpha-adrenergic activity and aggravation of blood pressure. The combined alpha- and beta-blocking drug labatalol has greater beta- than alpha-blocking properties. 12 5- Forced diuresis and acidification of urine enhance drug excretion. but acidification is given only in the absence of metabolic acidosis and myoglobinuria. 6- For severe refractory cases, peritoneal dialysis or hemodialysis can be instituted 13 Chronic effects of amphetamines 14  Tolerance Tolerance develops rapidly to the anorectic (anorexia), cardiovascular, and hyperthermic effects. 100 mg amphetamine can be fatal to a novice, addicts have taken 1000 of milligrams daily. 15  Withdrawal Depression, fatigue, and increased appetite and sleep. Not life-threatening, Depression, sometimes suicidal, can last for weeks, requiring hospitalization and treatment with tricyclic antidepressants. 16  Dependence Following a “rush,” the subject, stops taking the drug and falls asleep for usually 12 to 18 hours (“crashing”). Longer “rush” are followed by more prolonged sleep (“crashing”), sometimes lasting several days. When wakes up, there is hunger , lethargy, and depression. Injections are then resumed, and a new “rush” begins. 17  Other Chronic Effects of amphetamine abuse Sleeping problems, anxiety, suppression of appetite, and high blood pressure. Neurotoxicity: Hallucination and brain damage. Decrease in dopamine D2 receptor availability in the caudate and putamen, may cause motor and cognitive impairment. Psychosis that is very similar to schizophrenia. 18 Hepatocellular toxicity. Myocardial infarction (less often than with cocaine). Cardiomyopathy. Increases the risk of coronary artery atherosclerosis. Stroke. 19  Parenteral amphetamine 1. High risk of Infections 2. often involve unusual organisms and affect the nervous system. 3. a risk for human immunodeficiency virus (HIV) infection. Inhaled amphetamine May cause pneumomediastinum. 20  Treatment of amphetamine abuse No treatment has been demonstrated to be effective for the treatment of amphetamine dependence and abuse. BUT: 1. Fluoxetine may decrease craving. 2. Imipramine may increase duration of adherence to treatment. 21  METHAMPHETAMINE ANALOGUES (MDMA; ecstasy) Usually taken by mouth (tablet, capsule, or powder), It can also be smoked, snorted, or injected. Effects 1. Euphoria. 2. CNS stimulant. 3. Mild hallucinogenic effect. 4. It increases HR, BP. 5. It destroys serotonin producing neurons. 22 Khat 23  Khat  Contains two amphetamine-like substance, cathinone and cathine.  Common in Somalia, Yemen and Ethiopia  The leaves are chewed or brewed as a beverage.  Some khat users also smoke the drug, make it into tea or sprinkle it on food.  Heavy use can result in dependence and physical and mental problems. 24  Pharmacokinetics The euphoric effect appears shortly after the chewing begins, suggesting absorption from the oral mucosa. Metabolism of cathinone is rapid, occurring mainly in the liver. Only a small fraction (about 2%) appears unchanged in the urine. Most cathinone is metabolized to NOREPHEDRINE and is excreted in this form. When taking khat and large amounts of non- alcoholic drinks are consumed. There is pharmacological synergism with drinks containing methylxanthines (e.g. tea and cola), which therefore enhances the effects of khat. 25  Mechanism of action  Like amphetamine 1. It releases catecholamines from presynaptic storage sites, 2. Inhibiting their reuptake 3. Increase dopamine or serotonin release Effects on CNS The acute effects of the khat include: 1. Increased levels of alertness. 2. Enhanced ability to concentrate. 3. Flow of ideas. 26  Long-term khat abuse leads to: A. CNS complications: 1. Insomnia, Violence, impairment of mental health (learning and memory). 2. khat-induced psychosis: Depression,, Manic and delusional behavior, hallucinations, paranoia. 27  B. Effects on GIT 1. Anorexia, weight loss 2. Dental problems, Stomatitis, gastritis 3. Constipation, hemorrhoids 4. liver damage 5. Increase incidence of oral malignancies. C. Effects on CVS increasing risk of hypertension, acute heart attack, Ischemic heart diseases, stroke and death. 28  Essential reading: Katzung, Bertram, and Anthony Trevor. Basic and Clinical Pharmacology. 13th ed. New York: Lange Publishers. (563-564) Ruiz P, Strain E. Substance Abuse: A Comprehensive Textbook. 2011. Lippincott Williams & Wikins. (238-254) 29 30