CNS STIMULANTS CNS Stimulants are a family of

CNS STIMULANTS

CNS Stimulants are a family of compounds chemically and pharmacologically dissimilar; when ingested in sufficient dosage they cause a wide variety of effects related to central stimulation ……. enhance the intensity of our reactions to external stimuli…… “Heightened awareness, quick thinking, elevated mood”

CNS Stimulants Specific stimulant concerned are: § Amphetamine-like drugs § Cocaine § Methylxanthines

Amphetamine-like drugs Ø Numerous derivatives have been used over the years to modify a variety of medical conditions Narcolepsy, Hyperkinesis (Attention Deficit Hyperactivity Disorder (ADHD) ), Short-term treatment of obesity In many states are nowadays banned, so their clinical usage has declined significantly Ø However, in many countries, despite the tight control, amphetamine abuse, is still ranked overall as a very significant medical problem Ø

Amphetamines • Amphetamine • Methamphetamine – (“speed”, “crack”, smoked form “ice”) • Methylene-dioxy-amphetamine, – (MDA) • Methylene-dioxy-met-amphetamine, – (MDMA, ecstasy, XTC)

Amphetamines • Methylphenidate – used to treat attention deficit disorder and hyperactivity disorders in children • Atomoxetine ADHD • Phenmetrazine – (no more used to treat obesity)

Amphetamines-like Modafinil is a non-amphetamine stimulant used in the treatment of narcolepsy Cathinone (found in the shrub Catha edulis, or khat), methcathinone, and mephedrone (4 methylmethcathinone) are chemically related drugs with amphetamine-like effects…. . Sold on internet as ‘bath salts”

Mechanism of Toxicity Ø 1. 2. 3. 4. Amphetamine and related drugs activate the sympathetic nervous system Induce peripheral release of catecholamines Inhibition of neuronal catecholamines, and reuptake of Inhibition of monoamine oxidase Some also cause serotonin release and block neuronal serotonin uptake.

Toxicokinetics All these drugs are well absorbed orally Have large volumes of distribution (Vd = 3– 33 L/kg) They are generally extensively metabolized by the liver Excretion of most amphetamines is highly dependent on urine p. H……. eliminated more rapidly in an acidic urine

TOXIC DOSES Ø Ø Low therapeutic index, with toxicity at levels only slightly above usual doses…BUT high degree of tolerance Acute ingestion of more than 1 mg/kg of dextroamphetamine is considered potentially lifethreatening

Characteristics of amphetamine toxicity grouped by severity S&S Euphoria, restlessness, irritability, insomnia, tremor, hyperreflexia, sweating, mydriasis Severity +1 Hyperactivity, confusion, tachypnea, tachycardia, hypertension, mild fever +2 Delirium, mania, arrhythmias, hyperpyrexia +3 All above+ convulsion, coma, circulatory collapse, death +4

CLINICAL PRESENTATION ü ü ü Death may be caused by ventricular arrhythmia, status epilepticus, intracranial hemorrhage or hyperthermia Hyperthermia results from seizures and muscular hyperactivity (cause rhabdomyolysis) and druginduced vasoconstriction (especially in athletes abusers prior to race) The toxic lethal dose varies but has been reported as 20 -25 mg/kg

CHRONIC EFFECTS AMPETAMINE ABUSE INCLUDES: Weight loss, Cardiomyopathy, Pulmonary hypertension, Dental changes, Stereotypic behavior (eg, picking at the skin), Paranoid psychosis After cessation of habitual use, patients may experience fatigue, hypersomnia, hyperphagia, and depression lasting several days.

Treatment v v ABC Treat agitation, seizures, coma, and hyperthermia if they occur Continuously monitor the temperature, other vital signs, and the ECG for a minimum of 6 hours Agitation: benzodiazepines usually satisfactory. Antipsychotics (haloperidol, olanzapine) may be needed Hypertension best treated with sedation. If not effective, a parenteral vasodilator (phentolamine or nitroprusside)

Treatment Treat tachyarrhythmias with propranolol or esmolol!! Decontamination. Administer activated charcoal orally if conditions are appropriate. Gastric lavage is not necessary after small to moderate ingestions Dialysis and hemoperfusion are not effective Renal elimination may be enhanced by urine acidification……BUT not recommended. . may aggravate nephrotoxicity of myoglobinuria

Cocaine Cocaine is one of the most popular drugs of abuse May be sniffed (snorted), smoked, or injected IV Occasionally injected combined with heroin ("speedball“) Purchased on the street may contain adulterants (lidocaine, benzocaine, caffeine, methamphetamine, ephedrine, and phencyclidine) Most contains levamisole, an antiparasitic drug that can cause agranulocytosis

Mechanism of toxicity The primary actions are local anesthetic effects, CNS stimulation, and Inhibition of neuronal uptake of catecholamines Results in a state of generalized sympathetic stimulation very similar to that of amphetamine intoxication Has also some affinity to the DAT and SERT

Toxicokinetics Well absorbed from all routes, local anesthetic toxicity after mucosal application Smoking and IV injection produce maximum effects within 1– 2 minutes, Oral or mucosal absorption may take up to 20– 30 minutes Elimination by metabolism and hydrolysis, T 1/2 ~60 minutes With ethanol, it is transesterified to cocaethylene…. . similar pharmacologic effects but longer T 1/2

Cocaine Toxicity ü ü Variety of S & S…. Euphoria followed by anxiety, agitation, delirium, psychosis, muscle rigidity or hyperactivity, and seizures Hyperthermia, intracranial hemorrhage, HTN and coma, hypovolemia CV toxicity: tachycardia, hypertension with hemorrhagic stroke, fibrillation Most common cause of drug-induced stroke

Cocaine Toxicity ü ü ü Death due to arrhythmia, status epilepticus, intracranial hemorrhage, or hyperthermia Hyperthermia is usually caused by seizures, muscular hyperactivity, or rigidity…. . ……. may cause rhabdomyolysis, myoglobinuric renal failure Following an initial period of HTN…. blood pressure falls and cardiac depression ensues Respiratory system: initial stimulation resulting in tachypnea followed by respiratory arrest…. . cause of death!

Management ü ü ü ABC Treat coma, agitation, seizures, hyperthermia, arrhythmias, Tachycardia, and Ventricular dysrhythmias, and hypotension if they occur Benzodiazepines are a good choice for initial management of hypertension and tachycardia associated with agitation Hyperthermia must be controlled Cocaine-induced psychosis: neuroleptic agents or lithium

Management ü ü ü Decontamination v Activated charcoal…. if necessary gastric lavage v Most cocaine use occurs by intravenous or by nasal routes…… Dialysis is not effective Acidification of the urine not effective and may aggravate myoglobinuric renal failure

Methylxanthines Three alkaloids present naturally Caffeine Theophylline Theobromine

Caffeine § Most widely used psychoactive substance! § Present in coffee, tea, colas, chocolate, and § Many OTC / prescription oral medications (injectable caffeine sodium benzoate occasionally used for neonatal apnea)

Caffeine § § Occasionally combined with other stimulants (MDMA) Has a wide therapeutic index, BUT there are cases of accidental, suicidal, and iatrogenic intoxication, some resulting in death

Physiologic effects Caffeine Stimulate CNS (sleep suppressant) Stimulate cardiac function Anorectant Promote gastric acid secretion Induce diuresis Caffeine used as co-analgesic

Mechanism of toxicity 1. 2. 3. nonselective inhibition of adenosine receptors…. variety of response…… Bronchial smooth muscle relaxation, peripheral vasoconstriction, and increase cardiac pacemaker discharge Promote release of endogenous catecholamines…. positive inotropic and chronotropic cardiac activity Directly stimulate the respiratory and vasomotor center of the brain to increase rate and depth of breathing

Pharmacokinetics Caffeine is rapidly and completely absorbed orally (Vd 0. 7– 0. 8 L/kg) Metabolized in the liver by cytochrome P-450 (CYP), Metabolism is inhibited by oral contraceptives, cimetidine, norfloxacin, and alcohol Tobacco (and marijuana) smoking accelerates caffeine metabolism Elimination half-life 4– 6 hours (range from 3 hours in healthy smokers to 10 hours in nonsmokers)

Toxic dose The reported lethal oral dose of caffeine is 10 g In children, ingestion of 35 mg/kg…. . moderate toxicity Coffee contains 50– 200 mg (tea, 40– 100 mg) of caffeine/cup No-Doz and other sleep suppressants contain about 200 mg per tablet "Thermogenic" energy beverages (eg, Red Bull), bars, capsules, tablets, or liquid drops, contain 40– 200 mg of caffeine per serving

Clinical Manifestations The earliest symptoms of ACUTE caffeine poisoning are usually anorexia, tremor, and restlessness, followed by nausea, vomiting, tachycardia, and agitation With serious intoxication: delirium, seizures, supraventricular and ventricular tachyarrhythmias,

Clinical Manifestations q q Metabolic derangements due to catecholamines stimulation, renal wasting, and vomiting: hypokalemia and hyperglycemia Ingestion of caffeine-containing diet is associated with sudden death in people with bulimia or laxative abuse…. most likely due to aggravation of hypokalemia

Clinical Manifestations v v Hypotension is caused by excessive beta 2 -mediated vasodilation…. characterized by a low diastolic pressure and a wide pulse pressure Chronic high-dose caffeine intake “caffeinism” causes nervousness, irritability, anxiety, tremulousness, muscle twitching, insomnia, palpitations, and hyperreflexia

Management Maintain an open airway and assist ventilation if necessary Treat seizures with diazepam, lorazepam Treat hypotension and tachyarrhythmias with propranolol, or esmolol If vasopressors are required, vasopressin or phenylephrine

Management Hypokalemia usually resolves without Tx. but in severe poisonings may need treatment Monitor ECG and vital signs for at least 6 hours after ingestion

Management Activated charcoal: extremely effective in limiting gut absorption Seriously intoxicated patients: …. with multiple seizures, tachyarrhythmias, or intractable hypotension may require hemodialysis or charcoal hemoperfusion

Theophylline § Methylxanthine used for the treatment of asthma § Mechanism of toxicity: § Exact mechanism not known…. BUT: i. Antagonist of adenosine receptors, and ii. Inhibits phosphodiesterase at high levels, increasing intracellular c. AMP iii. Also known to release endogenous catecholamines at therapeutic concentrations

Pharmacokinetics Absorption may be delayed with sustained-release preparations The normal elimination half-life is 4– 6 hours May be doubled by illnesses (eg, liver disease, congestive heart failure, influenza) OR Interacting with drugs (eg, erythromycin, cimetidine) that slow hepatic metabolism

Toxic Levels Serum levels are essential for diagnosis and determination of emergency treatment After acute oral overdose, obtain repeated levels every 2– 4 hours Levels <80– 100 mg/L after acute overdose usually are not associated with severe symptoms (mild) With chronic intoxication, severe toxicity may occur with levels of 40– 60 mg/L

Clinical Presentation Acute single overdose: due to suicidal attempt, or accidental childhood ingestion but also accidental or iatrogenic misuse : Ø Ø Ø Vomiting (sometimes hematemesis), tremor, anxiety, and tachycardia Metabolic effects include pronounced hypokalemia, hypophosphatemia, hyperglycemia, and metabolic acidosis Severe intoxication (levels > 90– 100 mg/L): hypotension, ventricular arrhythmias, and seizures

Clinical Presentation Chronic intoxication: If doses administered over time or intercurrent illness or interacting drug interferes with the hepatic metabolism Vomiting may occur but not as common as in acute overdose Tachycardia is common, but hypotension is rare No hypokalemia, no hyperglycemia Seizures may occur with lower serum levels (eg, 40– 60 mg/L)

Treatment Maintain an open airway and assist ventilation if necessary Treat seizures, arrhythmias, and hypotension if they occur Tachyarrhythmias and hypotension are best treated with propranolol or esmolol Hypokalemia due to intracellular movement of potassium (does not reflect total body deficit)…. usually resolves spontaneously Monitor vital signs, ECG, and serial theophylline levels for at least 16– 18 hours after a significant oral overdose

Treatment Decontamination. Administer activated charcoal orally if conditions are appropriate Consider repeated doses of activated charcoal and WBI after a large ingestion of a sustained-released formulation Enhanced elimination. Hemodialysis, or charcoal hemoperfusion are effective (small Vd 0. 5 L/kg), It is protein-bound at therapeutic concentrations, BUT the free fraction dominates at higher levels

DEXTROMETHORPHAN (DXM)

Dextromethorphan Common antitussive agent found in many OTC cough and cold preparations Found in combination products containing antihistamines, decongestants, ethanol, or acetaminophen Structurally related to opioids (codeine), but no activity at mu or kappa receptors and not typical opioid syndrome in overdose

Mechanism of toxicity Metabolized in the liver by the cyt. P-450 to dextrorphan Antagonize N-methyl-d-aspartate (NMDA) glutamate receptors (dextrorphan is more potent and responsible for the psychoactive effects) Extensive metabolizers are more likely to experience the “desirable” psychoactive effects with recreational use…. hallucination and dissociation from reality

Mechanism of toxicity Dextromethorphan and dextrorphan inhibit reuptake of serotonin and may lead to seratonin syndrome …. . especially with SSRI or MAOI Inhibits adrenergic neurotransmitter reuptake in the peripheral and central nervous system Serotoninergic effects, as well as NMDA glutamate receptor inhibition, may explain the acute and chronic abuse potential of dextromethorphan

Clinical presentation Mild to moderate intoxication. N, V, nystagmus, mydriasis or miosis, tachycardia, HTN, dizziness, lethargy, agitation, ataxia, euphoria, dysphoria, and auditory and visual hallucinations Severe poisoning. Disorientation, stupor, psychosis, dissociative hallucinations, seizures, coma, hyperthermia, respiratory depression, pulmonary and cerebral edema, and death can occur

Clinical presentation Serotonin syndrome. Severe hyperthermia, muscle rigidity, altered mental status, and hypertension Withdrawal syndrome. Abdominal pain, vomiting, diarrhea, tachycardia, hypertension, depression, dysphoria, insomnia, tremor, myalgias, restlessness, and drug craving have been reported

Treatment Most patients with mild symptoms (ie, restlessness, ataxia, or mild drowsiness) can be observed for 4– 6 hours Maintain an open airway and assist ventilation if needed Treat seizures and coma if they occur Rarely, DXM poisoning is associated with profound coma and, respiratory depression may respond to naloxone Decontamination. Administer activated charcoal orally if conditions are appropriate Enhanced elimination. The Vd is very large, and there is no role for enhanced removal procedures