CNS Stimulants

1. CNS Stimulants

2. CNS Stimulants • 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”

3. CNS Stimulants • Specific stimulant concerned are: • Amphetamine-like drugs • Cocaine • Methylxanthines

4. Amphetamine-like drugs • 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 manystates are nowadays banned, so their clinical usage has declined significantly • However, in many countries, despite the tight control, amphetamine abuse, is still ranked overall as a very significant medical problem

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

6. Amphetamines • Methylphenidate • used to treat attention deficit disorder and hyperactivity disorders in children • AtomoxetineADHD • Phenmetrazine • (no more used to treat obesity)

7. 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”

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

10. 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 pH…….eliminated more rapidly in an acidic urine

11. TOXIC DOSES • 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 life-threatening

12. Characteristics of amphetamine toxicity grouped by severity

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

14. 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.

15. Treatment • 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)

16. 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

17. 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

18. 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

20. 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, T1/2 ~60 minutes • With ethanol, it is transesterified to cocaethylene….. similar pharmacologic effects but longer T1/2

21. Cocaine Toxicity • 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

22. Cocaine Toxicity • 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!

23. Management • 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

24. Management • Decontamination • Activated charcoal….if necessary gastric lavage • 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

25. Methylxanthines • Three alkaloids present naturally • Caffeine • Theophylline • Theobromine

26. 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)

27. 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

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

29. Mechanism of toxicity • 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

30. 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)

31. 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

32. 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,

33. Clinical Manifestations • 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 laxativeabuse….most likely due to aggravation of hypokalemia

34. Clinical Manifestations • Hypotension is caused by excessive beta2-mediated vasodilation….characterized by a low diastolic pressure and a wide pulse pressure • Chronichigh-dose caffeine intake “caffeinism” causes nervousness, irritability, anxiety, tremulousness, muscle twitching, insomnia, palpitations, and hyperreflexia

35. Management • Maintain an openairway 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

36. 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

37. 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

38. Theophylline • Methylxanthine used for the treatment of asthma • Mechanism of toxicity: • Exact mechanism not known….BUT: • Antagonist of adenosinereceptors, and • Inhibits phosphodiesterase at high levels, increasing intracellular cAMP • Also known to release endogenous catecholaminesat therapeutic concentrations

39. 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

40. 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

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

42. Clinical Presentation • Chronic intoxication: If doses administered over time or intercurrentillness or interactingdrug 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)

43. 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

44. 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

45. Dextromethorphan(dxm)

46. 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

47. 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

48. 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

49. 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

50. 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