Central Nervous System Stimulants Tracy A. Womble, Ph.D. Florida A&M University College of Pharmacy and Pharmaceutical Sciences

Central Nervous System Stimulants Central nervous system (CNS) stimulants are medicines that speed up physical and mental processes. Used to treat attention-deficit hyperactivity disorder (ADHD), narcolepsy, and other disorders of the central nervous system. Drugs used to treat migraine headache

What are CNS Stimulants Prescription meds and illicit substances of recreational use mild elevation in alertness, decrease in drowsiness and lessening of fatigue (Analeptic Effect) increased nervousness, anxiety and convulsions.

What are CNS Stimulants (Cont) Occasionally referred to as “uppers” Enhanced alertness, awareness, wakefulness, endurance, productivity and motivation increased arousal, locomotion, heart rate and blood pressure perception of a diminished requirement for food and sleep

Biogenic Amines There are five established biogenic amine neurotransmitters. (3) catecholamines dopamine norepinephrin (noradrenaline) epinephrine (adrenaline) histamine serotonin (5-HT)

Catacholamines dopamine is a precursor to norepinephrine (noradrenaline) and then epinephrine (adrenaline) in the biosynthetic pathways. packaged into vesicles, which are released into the synapse in response to a presynaptic action potential. Activated by reuptake via the dopamine transport, then enzymatic breakdown by catechol-O-methyl-transferase (COMT) and monoamine oxidase (MAO), or repackaged into vesicles for reuse

CNS Stimulants Psychomotor Psychotomimetic Excitement, euphoria, decrease feelings of fatigue, increased motor activity Methylxanthines Caffeine Theobromine Theophylline Amphetamine Cocaine Methylphenidate Nicotine Hallucinogens, produce changes in thought patterns and mood, little effect on brain stem and spinal cord Lysergic acid diethylamide Phencyclidine Tetrahydrocannabinol

Methylxanthines Theophylline found in tea Theobromine found in cocoa Caffeine (most widely used stimulant in world) found in coffee, cola drinks, cocoa and chocolate. Mechanism of Action translocation of extracellular Ca+ adenosine antagonism (modulates AC activity – cause contraction of airway smooth muscle) [bronchodilator] inhibition of PDI resulting in increased cAMP and cGMP.

Methylxanthines (cont’) Actions CNS – caffeine (100-200 mg) dec. in fatigue, inc. mental alertness by cortex stimulation. (1.5 g) produces anxiety and tremors. Spinal cord is stimulated by high doses (2-5 g). Cardiovascular – high doses of caffeine has positive inotropic (harmful to pt. w/ angina pectoris) and chronotropic (PVC’s) effects on heart. Diuretic action – caffeine has mild diuretic effect, increased excretion of Na, K and Cl. GI – methylxanthines stimulate secretion of HCl from gastric mucosa, pt. w/ peptic ulcers should avoid.

Methylxanthines (cont’) Therapeutic use - Caffeine + plus ergot alkaloid (Ergotamine): used to treat migraine headaches Pharmacokinetics – well absorbed orally, cross placenta to fetus and secreted into the milk. Metab in liver and metabolites excreted in the urine. Adverse effects (600 mg/day and stop) – lethargy, irritability and h/a moderate dose - insomnia, anxiety and agitation. high dose – emesis, convulsions lethal dose – (10 g) induce cardiac arrhythmias (unlikely)

Nicotine Active ingredient in tobacco Not used therapeutically (except smoking cessation) Mechanism of action – ganglionic stimulation High doses causes ganglionic blockade CNS – lipid sol., cross BBB, small degree of euphoria and relaxation, improves attention, reaction time. High dose – central respiratory paralysis, severe hypotension Pharmocokinetics – lipid sol., absorbed in oral mucosa, lungs GI mucosa and skin, plancental membrane, secreted in milk of lactating women, cigarettes contain 6-8 mg, acute lethal dose is 60 mg. 90% inhaled is absorbed. Adverse effects – irratability, tremors, intestinal cramps, diarrhea, inc. heart rate / bp

Amphetamines The misuse and abuse of amphetamines is a significant problem which may include the house wife taking diet pills, athletes desiring an improved performance, the truck driver driving non-stop coast to-coast, or the pharmacy student cramming all night for Wednesday’s exam.

Therapeutic use of Amphetamines The primary effects of an oral dose are wakefulness, alertness, decrease fatigue; mood elevation, increased ability to concentrate; an increase in motor and speech activity. (narcolepsy) Methylphenidate is used to alleviate behavioral and attention deficits allowing children to focus and be involved in activities. (ADHD) Depresses appetite by their action on the lateral hypothalamus rather than an effect on metabolic rate. (obesity, appetite control)

Amphetamines Synthesized in late 1920’s, introduced into medical practice in 1936. Dextroamphetamine is major member methamphetamine (methedrine) “speed”, methlyphenidate (Ritalin) Amphetamine analogs with psychoactive effects 2,5-dimethoxy-4-methyllamphetamine (DOM, STP) Methylenedioxyamphetamine (MDA) Methylenedioxymethamphetamine (MDMA) “ectasy”

Action of Amphetamines 1) bind to the pre-synaptic membrane of dopaminergic neurons and induce the release of dopamine from the nerve terminal 2) interact with dopamine containing synaptic vesicles, releasing free dopamine into the nerve terminal 3) bind to monoamine oxidase in dopaminergic neurones and prevent the degradation of dopamine, leaving free dopamine in the nerve terminal 4) bind to the dopamine re-uptake transporter, causing it to act in reverse and transport free dopamine out of the nerve terminal.

Amphetamines (cont’) Amphetamines – Methamphetamine Desoxyn), Dextroamphetamine (Dexedrine) Mechanism of action – (action is indirect) releases intracellular stores of catecholamines, block MAO, high levels Therapeutic use – ADHD -Methylphenidate to alleviate behavioral and attention deficits allowing children to focus and be involved in activities. Narcolepsy , depression, hyperactivity in children, appetite control CNS – stimulates medullary respiratory center, psychosis depends on dose, wakefulness, alertness, decreased fatigue, elevation of mood, elation and euphoria. Mechanism of action – (action is indirect) releases intracellular stores of catecholamines, block MAO, high levels are released. behavioral effects similar to cocaine Increased alertness, delusions, paranoia, hallucinations, convulsions, decreased fatigue, depressed appetite and insomnia. Indirect stimulation of adrenergic system (norepi release.) Therapeutic use – ADHD -Methylphenidate to alleviate behavioral and attention deficits allowing children to focus and be involved in activities. Narcolepsy , depression, hyperactivity in children, appetite control Adverse effects – insomnia, irritability, weakness, dizziness, tremor, psychic and physical dependence Cardiovascular effect - palpitations, cardiac arrhythmias, hypertension, angina, h/a. Gl effect – anorexia, n/v, abdominal cramps and diarrhea. Pharmacokinetics – completely absorbed by GI, metab. by liver, excreted in urine.

Amphetamines (cont’) Cardiovascular effect - palpitations, cardiac arrhythmias, hypertension, angina, h/a. Gl effect – anorexia, n/v, abdominal cramps and diarrhea, xerostomia. Fatal poisoning terminate in convulsions, coma, and cerebral hemorrhaging. Pharmacokinetics – completely absorbed by GI, metab. by liver, excreted in urine. Toxicity and Adverse effects – insomnia, irritability, weakness, dizziness, tremor, psychic and physical dependence, talkativeness, insomnia, aggressiveness, anxiety, paranoid hallucinations, panic states, suicidal or homicidal tendencies. Mechanism of action – (action is indirect) releases intracellular stores of catecholamines, block MAO, high levels are released. behavioral effects similar to cocaine Increased alertness, delusions, paranoia, hallucinations, convulsions, decreased fatigue, depressed appetite and insomnia. Indirect stimulation of adrenergic system (norepi release.) Therapeutic use – ADHD -Methylphenidate to alleviate behavioral and attention deficits allowing children to focus and be involved in activities. Narcolepsy , depression, hyperactivity in children, appetite control Adverse effects – insomnia, irritability, weakness, dizziness, tremor, psychic and physical dependence Cardiovascular effect - palpitations, cardiac arrhythmias, hypertension, angina, h/a. Gl effect – anorexia, n/v, abdominal cramps and diarrhea. Pharmacokinetics – completely absorbed by GI, metab. by liver, excreted in urine. These medications have a paradoxically calming and “focusing” effect on individuals with ADHD. Researchers speculate that because methylphenidate amplifies the release of dopamine, it can improve attention and focus in individuals who have dopamine signals that are weak

Non-amphetamine CNS stimulants Methylphenidate (Ritalin), Dexmethylphenidate, (Focalin) Used for ADHD and narcolepsy Structurally related to amphetamine > effect on mental than physical, short DOA t½ 6 hrs. Contraindicated in pts. w/ glaucoma Pemoline (Cylert) Structurally dissimilar to methylphenidate Similar effects, less effective than Methylphenidate Minimal effects on cardiovascular system Used to tx ADHD, used qd x 1 Associated with severe hepatic failure These agents exhibit sympathomimetic activity and may induce transient mydriasis. glaucoma – mydriasis may increase intraocular pressure, sympathetic stimulation of alpha-1 adrenergic receptor

Non-amphetamine CNS stimulants Modafinil (Provigil)– different from amphetamine in structure, neurochemical profile and behavioral effects Inhibits NE and DA transport Increases levels of NE and DA, 5-HT and glutamate Decreases GABA levels Used for narcolepsy Increases BP and HR Ephedrine – α and β agonist, release of NE

Cocaine Therapeutic uses – local anesthetic action, applied topically during eye, ear, nose and throat surgery, causes vasoconstriction (responsible for necrosis of nasal septum associated with chronic inhalation of cocaine powder) Adverse effects – toxic response to acute cocaine ingestion results in anxiety, hypertension, tachycardia, sweating and paranoia. Depression – cocaine stimulation of CNS is followed by mental depresssion Heart disease – cocaine induces seizures and cardiac arrhythmias

Psychotomimetic (Lysergic acid Diethylamide) A class of drugs reliably inducing temporary states of altered perception, often with symptoms similar to those of psychosis. Individual incapable of normal decision making. LSD- 5-HT agonist activity at presynaptic receptors

Psychotomimetic (Tetrahydrocannabinol) THC – main alkaloid in marijuana is dronabinol, (THC) produces euphoria followed by drowsiness and relaxation. Impairs short term memory and mental activity. decreases muscle strength and impairs motor skills (driving). Increases appetite, causes xerostomia, visual hallucinations, delusions, enhances sensory activity. Tx of severe emesis caused by some cancer chemotherapeutic agents.

Psychotomimetic (Phencyclidine) PCP – (angel dust) inhibits re-uptake of dopamine, 5-HT, and NE, also has anticholinergic activity Causes dissociative anesthesis (insensitivity to pain without loss of consciousness) and analgesis. Produces numbness of extremities, staggered gait, slurred speech, muscle rigidity, hostile and bizarre behavior. Increased dosage, anesthesia, stupor or coma with eyes open. Increased sensitivity to external stimuli. Tolerance often develops with continued use.