Lecture 2 CNS Stimulants (University of Al-Ameed, Pharmacology II, 2024/2025)

Lecture 2 CNS stimulants ‫جامعة العميد – كلية الصيدلة‬ Fourth stage – First semester Pharmacology-II 2024/9/28 1 Dr. Ghufran Lutfi Ismaeel  CNS stimulants Psychomotor stimulants and hallucinogens are two groups of drugs that act...

Lecture 2 CNS stimulants ‫جامعة العميد – كلية الصيدلة‬ Fourth stage – First semester Pharmacology-II 2024/9/28 1 Dr. Ghufran Lutfi Ismaeel  CNS stimulants Psychomotor stimulants and hallucinogens are two groups of drugs that act primarily to stimulate the central nervous system (CNS). The psychomotor stimulants cause excitement and euphoria, decrease feelings of fatigue, and increase motor activity. The hallucinogens produce profound changes in thought patterns and mood, with little effect on the brainstem and spinal cord. 2 3  A. Methylxanthines 1. Theophylline (found in tea): long-acting, prescribed for night-time asthma 2. Theobromine: found in cocoa. 3. Caffeine: (short-acting) the most widely consumed  found in coffee (200 mg/cup),  carbonated soft drinks (60 mg/can),  cocoa and chocolate 4 Mechanism of action of methylxanthine several mechanism have been proposed Mechanism of action of methylxanthine 1-It inhibits phosphodiesterase enz. → ↑ cAMP → ↓ ↓calcium in Smooth muscles ↑ calcium in CNS & heart 2- Adenosine (A1, A2 and A3) receptors antagonist almost equally, which explains many of its cardiac effects A2 receptors antagonist responsible for CNS stimulation & smooth muscles relaxation 5 Mechanism of actions of methylxanthines, including : A. translocation of extracellular calcium, B. increase in cyclic adenosine monophosphate and cyclic guanosine monophosphate caused by inhibition of phosphodiesterase, and C. blockade of adenosine receptors 6 Mechanism of actions of methylxanthines, including : A. translocation of extracellular calcium, B. increase in cyclic adenosine monophosphate and cyclic guanosine monophosphate caused by inhibition of phosphodiesterase, and C. blockade of adenosine receptors a. CNS:  decrease in fatigue, increased alertness: 100-200 mg caffeine in 1 or Actions: 2 cups of coffees  Anxiety & tremors- 1.5 g of caffeine: 12-15 cups of coffee  Spinal cord stimulation: 2-5 g (very high dose) Tolerance can rapidly develop Withdrawal symptoms: feeling of fatigue & sedation. 7  b. CVS: at high dose of caffeine +ve inotropic and Actions: chronotropic effects on the heart, ↑COP c. Diuretic action: mild ↑ urinary output of Na+, Cl- and K+ d. Gastric mucosa: all methylxanthines stimulate secretion of HCl (peptic ulcers should avoid ) e. Respiratory smooth muscle: bronchodilator, Rx asthma replaced by β-agonists, corticosteroids. Moderate doses: insomnia, anxiety, agitation High doses: emesis, convulsion Adverse effects: Lethal dose (10 gm of caffeine): cardiac arrhythmia Suddenly stop: lethargy, irritability, headache 8 Terms:  +ve Inotropic: Increases Contractile Strength  -ve Inotropic: Decreases Contractile Strength  +ve Chronotropic: Increase in heart rate  -ve Chronotropic: Decrease in heart rate  + ve Dromotropic: Increased Conduction Velocity  -ve Dromotropic: Decrease Conduction Velocity 9 Therapeutic uses: Caffeine and its derivatives:  relax the smooth muscles of the bronchioles.  Previously the mainstay of asthma therapy, theophylline has been largely replaced by other agents, such as β2 agonists and corticosteroids  Caffeine is also used in combination with the analgesics acetaminophen and aspirin for the management of headaches in both prescription and over-the-counter products 10 B. Nicotine: Nicotine is the active ingredient in tobacco. this drug is not currently used therapeutically Used in smoking cessation therapy, Nicotine remains important, because:  it is 2nd only to caffeine as the most widely used CNS stimulant  and 2nd only to alcohol as the most abused drug. Actions of Nicotine: Low dose: ganglionic stimulation by depolarization. High dose: ganglionic blockade 11 B. Nicotine: Actions I. CNS: 1. Low dose: euphoria, arousal, relaxation, improves attention, learning, problem solving and reaction time. 2. High dose :central respiratory paralysis and severe hypotension (medullary paralysis( 3. Nicotine is an appetite suppressant II. Peripheral effects: Stimulation of sympathetic ganglia and adrenal medulla→↑ BP and HR (harmful in HTN patients) Stimulation of parasympathetic ganglia→↑ motor activity of the bowel At higher doses, BP falls & activating ceases in both GIT and bladder 12  B. Nicotine: Pharmacokinetics: highly lipid soluble absorbed everywhere (oral mucosa, lung, GIT, skin). Crosses the placental membrane, secreted with milk. Most cigarettes contain 6-8 mg of nicotine, by inhaling tobacco smoke, the average smoker takes in 1 to 2 mg of nicotine per cigarette. the acute lethal dose is 60 mg, 90% of nicotine inhaled in smoke is absorbed. Tolerance to toxic effects of nicotine develops rapidly. 13  B. Nicotine: CNS; irritability and tremors Adverse effects: Intestinal cramps, diarrhea ↑ heart rate and blood pressured nicotine is addictive substance Withdrawal physical dependence on nicotine develops rapidly syndrome: and can be severe. bupropion an antidepressant : can reduce the craving for cigarettes transdermal patch and chewing gum containing nicotine to reduce nicotine withdrawal symptom 14  C. Varenicline Partial agonist at Nicotinic receptor in CNS. It produces less euphoric effects than those produced by nicotine itself (nicotine is full agonist at these receptors.) Thus, it is useful as an adjunct in the management of smoking cessation in patients with nicotine withdrawal symptom. SE: Nausea, change in taste, vomiting, abdominal pain, flatulence, and constipation. Serious side-effects, including suicidal behavior and depression 15  D. Cocaine (highly addictive drug) Mechanism of action: blockade of reuptake of the monoamines (NE, serotonin and dopamine). Thus, potentiates and prolongs the CNS and peripheral actions of these monoamines. Only clinical use as local anesthetics. 16  D. Cocaine Action: Initially produces the intense euphoria by prolongation of dopaminergic effects in the brain’s pleasure system (limbic system) producing the “Rush”. This follows by dysphoria in few minutes as it is degraded by plasma estrases Chronic intake of cocaine depletes dopamine. This depletion triggers the vicious cycle of craving for cocaine. 17 D. Cocaine Pharmacological effects: a. CNS-behavioral effects result from powerful stimulation of cortex and brain stem. Cocaine acutely increases mental awareness and produces a feeling of wellbeing and euphoria similar to that produced by amphetamine. Like amphetamine, cocaine can produce hallucinations and delusions of paranoia or grandiosity. Cocaine increases motor activity, and at high doses, it causes tremors and convulsions, followed by respiratory and vasomotor depression. 18  D. Cocaine Pharmacological effects: b. Sympathetic NS: peripherally potentiate the action of NE→ fight or flight c. Hyperthermia: impair sweating & cutaneous vasodilation ↓Perception of thermal discomfort d. local anesthetic action: blockade of voltage- activated Na+ channel. Cocaine is the only LA that causes vasoconstriction, chronic inhalation of cocaine powder → necrosis and perforation of the nasal septum Cocaine is often self-administered by chewing, intranasal snorting, smoking, or intravenous (IV) injection. 16  D. Cocaine Adverse effects: Anxiety reaction that includes: Because of the irritability, many users take cocaine with alcohol. A product of is cocaethylene, which is also psychoactive and cause cardiotoxicity. Depression: Like all stimulant drugs, cocaine stimulation of the CNS is followed by a period of mental depression. Addicts withdrawing from cocaine exhibit physical and emotional depression as well as agitation. The latter symptom can be treated with Toxic effects: Seizures treated by I.V diazepam Fatal cardiac arrhythmias treated by propranolol 17  E. Amphetamine Is a non catecholamine, (shows neurologic and clinical effects quite similar to those of cocaine). dextroamphetamine is the major member of this class compounds. methamphetamine (speed) is a derivative of amphetamine that can be smoked and it is preferred by many abusers. Methylenedioxymethamphetamine (also known as MDMA, or Ecstasy) is a synthetic derivative of methamphetamine with both stimulant and hallucinogenic properties. 21  E. Amphetamine Mechanism of action: Amphetamine, act by  releasing intracellular stores of catecholamines.  also inhibits MAO and is a weak reuptake transport inhibitor, high level catecholamines are readily released into synaptic spaces. 22  E. Amphetamine Actions: a. CNS: the major behavioral effects of amphetamine result from a combination of its dopamine and NE release enhancing properties. Amphetamine stimulates the entire cerebrospinal axis, brainstem, and medulla. This leads to increase alertness, decrease fatigue, depressed appetite, and insomnia. b. Sympathetic Nervous System: indirectly stimulating the receptors through NE release. 23  E. Amphetamine Adverse effects: The amphetamines may cause a. CNS: insomnia, irritability, weakness, dizziness, tremor, hyperactive reflex, confusion, delirium, panic states, and suicidal tendencies, especially in mentally ill patients. -Chronic amphetamine use produces a state of “amphetamine psychosis” that resembles the psychotic episodes associated with schizophrenia. -Whereas long-term amphetamine is associated with psychic and physical dependence, tolerance to its effects may occur within few weeks. 24 E. Amphetamine Adverse effects: The anorectic effect of amphetamine is due to its action in the lateral hypothalamic feeding center. b. CVS: palpitations, cardiac arrhythmia, HTN, anginal pain, and circulatory collapse. Headache, chills, and excess sweating may also occur. c. GIT: anorexia, nausea, vomiting, abdominal cramps, and diarrhea. Overdoses are treated with chlorpromazine or haloperidol, with urine acidification to enhance excretion. Contraindications: HTN, CV diseases, glaucoma, hyperthyroidism, patients with a history of drug abuse 25 E. Amphetamine Therapeutic uses: Factors that limit the therapeutic usefulness of amphetamine include psychological and physiologic dependence similar to those with cocaine and, with chronic use, the development of tolerance to the euphoric and anorectic effects. a. Attention deficit hyperactivity disorder (ADHD): Some young children are hyperkinetic and lack the ability to be involved in any one activity for longer than a few minutes. Dextroamphetamine, methamphetamine, and methylphenidate can help improve attention span and alleviate many of the behavioral problems associated with this syndrome, in addition to reducing hyperkinesia. Atomoxetine It is a NE reuptake inhibitor (should not be taken by individual on MAO inhibitors and narrow angle glaucoma). Approved for ADHD (significant problems of attention, hyperactivity, or acting impulsively) in children and adults. SE: Nausea, Xerostomia (dry mouth), appetite loss, Insomnia, Irritability, hypertension and Hostility. 26  b. Narcolepsy: (day time sleepiness) Amphetamine, methylphenidate. Recently, a new drug modafinil (wakefulness- promoting agent) and its R- enantiomer derivative, armodafinil ,considered first-line agents for the treatment of narcolepsy. Modafinil produces fewer psychoactive and euphoric effects as well as, alterations in mood, perception, thinking, and feelings typical of other CNS stimulants. c. Appetite suppression: are sympathomimetic amines that are related structurally to amphetamine. These agents are used for their appetite-suppressant effects in the management of obesity 27  F. Methylphenidate It has CNS stimulant properties similar to those of amphetamine and may also lead to abuse. Methylphenidate is a more potent dopamine transport inhibitor than cocaine, thus making more dopamine available. Methylphenidate is a dopamine and norepinephrine transport inhibitor and may act by increasing both dopamine and norepinephrine in the synaptic space It has less potential for abuse than cocaine, because it enters the brain much more slowly than cocaine and, does not increase dopamine levels as rapidly. 28  Therapeutic uses: Methylphenidate and its active isomer, (Dexmethylphenidate), have been used for several decades in the treatment of ADHD in children aged 6 to 16. Unlike methylphenidate, dexmethylphenidate is not indicated in the treatment of narcolepsy 29  Adverse effects: GIT effects are the most common; abdominal pain and nausea. Other reactions include anorexia, insomnia, nervousness, and fever. In seizure patients, methylphenidate seems to increase the seizure frequency, especially if the patient is taking antidepressants. Methylphenidate is contraindicated in patients with glaucoma. Methylphenidate can inhibit the metabolism of warfarin, phenytoin, phenobarbital, primidone, and the tricyclic antidepressants 30