CNS Stimulants

CNS Stimulants

Robert L. Copeland, Ph.D.

August 12, 2008



 Central Nervous System Stimulation primary action of a diverse group of pharmacological agents -adverse effect associated with many drugs



 Behavioral Manifestations of CNS Stimulation  mild elevation in alertness, decrease in drowsiness and lessening of fatigue (Analeptic Effect)  increased nervousness and anxiety convulsions.



Molecular Basis of CNS Stimulation

Imbalance between inhibitory and excitatory processes as in the brain. This hyper-excitability of neurons results from:  potentiation or enhancement of excitatory neurotransmission(e.g. amphetamine)  depression or antagonism of inhibitory transmission (e.g. Strychnine)  presynaptic control of neurotransmitter release (e.g. picrotoxin)



Classification of CNS Stimulants

 Analeptic Stimulants

 Respiratory Stimulants  Convulsants



 Psychomotor Stimulant

 Sympathomimetics or Adrenergic CNS Stimulants



 Methylxanthines



Analeptic Stimulants

 diverse chemical class of agents  majority can be absorbed orally  have a short duration of action - primary expression of pharmacological effect is convulsions (tonic-clonic) uncoordinated  pharmacological effect is terminated through hepatic metabolism  Possible Common Mechanism of Action -ability to alter movement of chloride ions across neuronal membranes  Therapeutic Uses Group as a whole has limited therapeutic use.



 Doxapram and Nikithamide - used to counteract postanesthetic respiratory depression and for acute hypercapnia in chronic pulmonary disease.  Pentylenetetrazole - used clinically as a tool for screening latent epileptics and experimentally to screen compounds for anti-epileptic activity.  Picrotoxin - used to study CNS mechanisms; it interferes with pathways that are strychnine resistant.



 Strychnine is a source of accidental poisoning. Also used to study CNS mechanism because of its relatively specific action as a glycine antagonist.  Adverse Reactions: Convulsion is characterized by opisthotonos, i.e., tonic extension of body and all limbs. Back is arched and only the back of the head and the heels are touching the touching the surface. All sensory stimuli produce exaggerated response and slight sensory stimulation may trigger convulsion.



Treatment of Strychnine Poisoning

(1) Remove/reduce external sensory stimuli (2) Diazepam or Clonazepam I.V. or nitrous oxide by inhalation to depress CNS and stop convulsions which can be fatal



PSYCHOMOTOR STIMULANTS

 Drugs of Primary Importance Amphetamine - prototype Methamphetamine Methylphenidate



CHARACTERISTICS

 all compounds are absorbed well orally  large portion of untransformed amphetamine is excreted unchanged  in the urine. Consequently, acidifying the urine with ammonium chloride hastens its clearance, and thus reduces its reabsorption in the renal tubules.  Overdose: hyperreflexia, tremors and convulsions  Fatalities: hyperthermia rather than cardiovascular effects



Pharmacological Actions

 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. Amphetamines also diminish the awareness of fatigue; person may push exertion to the point of severe damage or even death.



 Stimulate the respiratory center, especially when respiration is depressed by centrally acting drugs, (barbiturates and alcohol).  Amphetamine can reverse the marked sedation and behavioral retardation resulting from reserpine-like drug.  Depresses appetite by their action on the lateral hypothalamus rather than an effect on metabolic rate.



Mechanisms of Action

 Releases monoamines at synapses in the brain and spinal cord.  Inhibits neuronal uptake of monoamine  Direct agonist of DA and 5-HT receptors  Antagonist at certain adrenreceptors  May inhibit monoamine oxidase.



Therapeutic Uses

 Hyperkinesias - Methylphenidate  Narcolepsy - Amphetamine or methylphenidate  Obesity - Fenfluramine



Adverse Effects

 CNS: Euphoria, dizziness, tremor, irritability, insomnia, Convulsion (at higher doses), hyperthermia and coma  C.V. Cardiac stimulation leads to headache, palpitations, cardiac arrhythmias, anginal pain  Other: Weight loss, Psychotic Reaction which are often misdiagnosed as schizophrenia.  Addiction - including psychic dependence, tolerance and physical dependence.



 Drug Interactions:

 Tricyclic antidepressant  Antihypertensive Agents  Foods high in tyramine content



METHYLXANTINES

 Caffeine:

 Coffee (100-150 mg/cup)  Tea (30-40 mg/cups)  Cocoa (15-18mg/cup)



 Theophylline: Tea and cocoa  Theobromine: Cocoa



Mechanisms of Action

 Increase cyclic nucleotide concentration  Blocks adenosine receptors  Alters intracellular calcium distribution



 Caffeine, the most widely used drug in the world, is a stimulant. Commonly found in coffee, tea, soft drinks, chocolate and a wide variety of over-thecounter medications, it is legal to buy and easily accessible.  Caffeine is a physically addictive drug



Pharmacological Activity/ Adverse Effects

 Low Doses: 50-250mg/Caffeine (Oral Doses) Increase mental alertness, decrease drowsiness Lessen fatigue  Larger Doses: 250-600mg/Caffeine Irritability, restlessness, tremor, insomnia, headache, palpitations and hyperesthesia GIT upset  Large Doses: > 1000 mg Overt excitement, delirium and clonic seizures



 Cardiovascular System: Increase rate and force of the heart by directly stimulating myocardium (low doses) Tachycardia and arrhythmias at higher doses. Peripheral vasodilation decease in blood pressure (acute administration) Hypotension and cardiac arrest (rapid i.v. theophyline)



 Smooth Muscles: Relaxes vascular smooth muscle (Theophylline »Caffeine)  Kidney: All xanthines are capable of producing some degree of diuresis in humans (Theophylline > Caffeine)  Miscellaneous: Xanthines shorten clotting time by increasing tissue prothrombin and factor V.



Adverse effects

 Stimulate gastric secretions in patients with ulcer  Dehydration in children due to vomiting and transient diuretic action (theophyline)  Allergic reaction (aminophylline)  Psychic Dependence (Caffeine)



Therapeutic Uses

 Caffeine + plus ergot alkaloid (Ergotamine): used to treat migraine headaches  OTC preparations: Theophylline: Prophylaxis for chronic asthma Respiratory Stimulant Bronchodilator for relief of asthmatic symptoms



NICOTINE

 CNS Effects:

 Powerful CNS stimulant at lower doses; Large doses produce clonic convulsion, then depress CNS, compounding postictal depression  Stimulates respiration  Produces emesis  Tolerance to central actions with chronic use



 Cardiovascular Effects

    Tachycardia Increased blood pressure Pupillary constriction Cardiovascular collapse - due to CNS depression  Ganglionic blockade and arrhythmias Fatalities: Due to respiratory failure



COCAINE

 Psychomotor stimulant  local anesthetic  Chemistry- alkaloid from coca plant alkaloid is highly lipid-soluble hydrochloride salt is water soluble



Routes of Administration

 Chewing: with an-alkaloid material (South America)  Sniffing: hydrochloride salt -absorption: nasal mucous membranes -local vasoconstriction slows absorption and prolongs effect  Oral: large doses are needed for effect rapid onset  Smoking: cocaine is converted to alkaloid (freebase or "crack") which is readily volatilized undegraded at lower temperature. I.V. and smoking: reaches CNS in seconds in high concentration produces more immediate and intense effects



Pharmacokinetics

 large vol. of distribution  quickly metabolized: half-life 30-90 minutes  principal metabolites: a) Ecogonine methylester - inactive b) Benzoylecogonine inactive c) norcocaine - active  half lives of metabolites: 4 to 6 hrs. metabolites: Excreted in urine  Drug Testing: BE - detectable for 1-3 days Cocaine - detectable for a few hours