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Learning Objectives: Stimulant Drugs 1.

Describe the mechanisms of action, effects of, clinical use, toxicity and toxicity treatment for stimulant drugs.





Strychnine a. Competitive antagonist at glycine receptor, strong action in spinal cord b. General excitation of CNS (disinhibition) with hyperreflexia to sensory stimuli c. It’s a PESTICIDE with no clinical use; also it’s a RAT POISON so sometime infants EAT IT. d. Pathognomonic symptom is opisthotonus —contraction of all four limbs’ musculature, so extreme that body is convex outwards, head goes back to touch ground next to heels. Also hypoxia, postictal depression, death. e. Treat with diazepam for convulsions, support respiration, lavage with charcoal (used to use KMnO4, tea tannins too) Picrotoxin a. Blocks GABA Chloride channels in brain, causing general CNS excitation (disinhibition). b. Formerly used to treat CNS depressant overdose c. Symptoms are uncoordinated tonic/clonic convulsions, coma, death d. Treatment is same for strychnine poisoning. Pentylenetetrazole (Metrazole) a. Same as picrotoxin, blocks GABA Cl- channels in brain, exciting CNS by disinhibition b. Sometimes used to activate EEG during differential diagnosis of seizure disorders; used in animals for anticonvulsant drug screening (it creates convulsions) c. Same symptoms and treatment as picrotoxin Xanthines—Caffeine, Theophyline, Theobromine a. Non-specific blockade of adenosine A1 and A2 receptors in striatum, causing intracellular calcium elevation, phosphodiesterase blockade, camp elevation (high doses only) b. Potent CNS stimulants, esp. of medullary respiratory centers; increases alertness, reduces drowsiness/fatigue (85-250 mg caffeine). c. High doses cause nervousness, insomnia, tremors, hyperesthesia, convulsions (with theophylline), bronchial sm relaxation, gastric acid secretions increase, nausea/emesis, diuresis, heart rate/blood pressure increase d. Theophylline is a bronchodilator for asthma, good for apnea in premature infants; caffeine in headache/migraine drugs e. Toxicity shows excitement then delirium, emesis, convulsions, tachycardia, arrhythmia, premature ventricular contractions f. Treat toxic levels with Diazepam + barbiturates or anticonvulsants like phenytoin; lavage with charcoal. Amphetamines a. Stimulates release of DA and NE from nerve terminals, and blocks their

reuptake Sympathomimetic with mood elevation/euphoria/hyperactivity, insomnia, appetite reduction, increased BP, reflex bradycardia, medullary respiratory center stimulation, prevention of narcolepsy, occasional arrhythmias, psychosis with chronic use c. Used clinically to treat narcolepsy, ADHD, obesity d. Toxic effects are nervousness, hyperactivity, insomnia, tremor, sweating, anorexia, euphoria (convulsion/coma with higher dose). Fatigue, depression, rebound sleep after high ends. Can have anginal pain, HTN, arrhythmia, circulatory failure. e. Chronic effects are psychosis, motor stereotypy, necrotizing arteritis leading to brain hemorrhage or renal failure f. Treat with dopamine receptor antagonists for brain; alpha-adrenergic antagonists or sodium nitroprusside for periphery; acidify urine with ammonium chloride to enhance elimination.

Cocaine a. Blocks dopamine reuptake causing similar euphoria and stimulation as amphetamines. b. Medical use as a vasoconstrictor and local anesthetic for nasal surgery 7. Phenylephrine and Pseudoephedrine a. Vasoconstrictors for nasal decongestion 8. Nicotine a. Acts at alpha4—beta2 receptors and alpha 7 receptors for nicotine in CNS b. Releases dopamine in nucleus accumbens (euphoria) c. Releases NE and Epi causing stimulation d. Desensitizes nicotinic receptors; can produce depression or calming effect on behavior depending on inhalation kinetics e. Symptoms are alertness, euphoria, muscle relaxation, appetite reduction, respiration/heart rate/blood pressure elevation and then depression (biphasic response), higher GI motility, biphasic salivary response, birth defects. f. Clinical use in alzheimers, schizophrenia, parkinsonism (self medication for loss of cholinergic or dopaminergic neurons?) g. Overdose causes tremor and convulsions, CNS depression, respiratory failure, emesis with central paralysis and peripheral respiratory neuromuscular blockade h. Treatment is vomiting and charcoal, respiratory assistance. i. Withdrawal causes hostility, dysphoria, weight gain, anxiety; can be helped with clonidine, bupropion, varenicline, or nicotine patch. 9. Doxapram (Dopram) a. Respiratory stimulant used to correct respiratory insufficiency in COPD/ accelerate recovery from anesthesia/prevent or reverse narcotic or depressant induced respiratory depression b. Acts in carotid artery chemoreceptors, selectively blocking potassium channels, increasing dopamine release from carotid DA neurons c. Toxicity includes high BP, tachycardia, skeletal muscle hyperactivity—treat toxicity with a short-acting IV barbiturate d. This drug is most widely used and safest in its class. 2. Define adenosine receptor, phosphodiesterase, narcolepsy, amphetamine psychosis. 1. Adenosine Receptors promote sleepiness/cns depression (opposite of caffeine, which is an adenosine receptor antagonist) 2. Phosphodiesterase hydrolyzes cAMP and cGMP, leading to vasoconstriction, etc. 3. Narcolepsy is a condition where a person falls asleep and loses all muscle tone upon excitement, at many times in the day 4. Amphetamine psychosis is like schizophrenia induced by long term amphetamine use.

3. List the major nicotinic receptor types in the brain and their function. 1. Alpha-4, beta-2 receptors predominate in the brain, and cause pre and post synaptic excitation by increasing sodium and potassium permeability 2. Alpha-3 beta-4 also cause pre and post excitation in brain 3. Alpha-7 receptors in brain too, cause pre and post excitation by increasing calcium