CNS StimulantsCNS Stimulants

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

Behavioral Manifestations of CNS Behavioral Manifestations of CNS Stimulation Stimulation

mild elevation in alertness, decrease in mild elevation in alertness, decrease in drowsiness and lessening of fatigue drowsiness and lessening of fatigue (Analeptic Effect) (Analeptic Effect)

increased nervousness and anxiety -increased nervousness and anxiety -convulsions. convulsions.

Molecular Basis of CNS Molecular Basis of CNS StimulationStimulation

Imbalance between inhibitory and excitatoryImbalance between inhibitory and excitatory

processes as in the brain. This hyper-excitabilityprocesses as in the brain. This hyper-excitability

of neurons results from: of neurons results from: potentiation or enhancement of excitatory potentiation or enhancement of excitatory

neurotransmission(e.g. amphetamine) neurotransmission(e.g. amphetamine) depression or antagonism of inhibitory depression or antagonism of inhibitory

transmission (e.g. Strychnine) transmission (e.g. Strychnine) presynaptic control of neurotransmitter release presynaptic control of neurotransmitter release

(e.g. picrotoxin) (e.g. picrotoxin)

Classification of CNS Classification of CNS StimulantsStimulants

Analeptic StimulantsAnaleptic Stimulants Respiratory Stimulants Respiratory Stimulants ConvulsantsConvulsants

Psychomotor StimulantPsychomotor Stimulant Sympathomimetics or Adrenergic CNS Sympathomimetics or Adrenergic CNS

StimulantsStimulants

MethylxanthinesMethylxanthines

Analeptic StimulantsAnaleptic Stimulants diverse chemical class of agents diverse chemical class of agents majority can be absorbed orally majority can be absorbed orally have a short duration of action - primary have a short duration of action - primary

expression of pharmacological effect is expression of pharmacological effect is convulsions (tonic-clonic) uncoordinated convulsions (tonic-clonic) uncoordinated

pharmacological effect is terminated through pharmacological effect is terminated through hepatic metabolism hepatic metabolism

Possible Common Mechanism of Action -ability to Possible Common Mechanism of Action -ability to alter movement of chloride ions across neuronal alter movement of chloride ions across neuronal membranes membranes

Therapeutic Uses Group as a whole has limited Therapeutic Uses Group as a whole has limited therapeutic use. therapeutic use.

Doxapram and NikithamideDoxapram and Nikithamide - used to - used to counteract postanesthetic respiratory depression counteract postanesthetic respiratory depression and for acute hypercapnia in chronic pulmonary and for acute hypercapnia in chronic pulmonary disease. disease.

PentylenetetrazolePentylenetetrazole - used clinically as a tool for - used clinically as a tool for screening latent epileptics and experimentally to screening latent epileptics and experimentally to screen compounds for anti-epileptic activity.screen compounds for anti-epileptic activity.

PicrotoxinPicrotoxin - used to study CNS mechanisms; it - used to study CNS mechanisms; it interferes with pathways that are strychnine interferes with pathways that are strychnine resistant.resistant.

StrychnineStrychnine is a source of accidental poisoning. is a source of accidental poisoning. Also used to study CNS mechanism because of Also used to study CNS mechanism because of its relatively specific action as a glycine its relatively specific action as a glycine antagonist. antagonist.

Adverse Reactions:Adverse Reactions:Convulsion is characterized by Convulsion is characterized by opisthotonosopisthotonos, i.e., , i.e., tonic extension of body and all limbs. Back is tonic extension of body and all limbs. Back is arched and only the back of the head and the arched and only the back of the head and the heels are touching the touching the surface. heels are touching the touching the surface. AllAll sensory stimuli produce exaggerated response sensory stimuli produce exaggerated response and slight sensory stimulation may trigger and slight sensory stimulation may trigger convulsion.convulsion.

Treatment of Strychnine Treatment of Strychnine PoisoningPoisoning

(1) Remove/reduce external sensory stimuli (1) Remove/reduce external sensory stimuli

(2) Diazepam or Clonazepam I.V. or nitrous (2) Diazepam or Clonazepam I.V. or nitrous oxide by inhalation to depress CNS and oxide by inhalation to depress CNS and stop convulsions which can be fatal stop convulsions which can be fatal

PSYCHOMOTOR STIMULANTSPSYCHOMOTOR STIMULANTS

Drugs of Primary ImportanceDrugs of Primary Importance

Amphetamine - prototype Amphetamine - prototype MethamphetamineMethamphetamine

MethylphenidateMethylphenidate

CHARACTERISTICSCHARACTERISTICS

all compounds are absorbed well orallyall compounds are absorbed well orally large portion of untransformed amphetamine is large portion of untransformed amphetamine is

excreted unchanged excreted unchanged in the urine. Consequently, acidifying the urine in the urine. Consequently, acidifying the urine

with ammonium chloride hastens its clearance, with ammonium chloride hastens its clearance, and thus reduces its reabsorption in the renal and thus reduces its reabsorption in the renal tubules.tubules.

Overdose: hyperreflexia, tremors and Overdose: hyperreflexia, tremors and convulsionsconvulsions

Fatalities: hyperthermia rather than Fatalities: hyperthermia rather than cardiovascular effects cardiovascular effects

Pharmacological ActionsPharmacological Actions

The primary effects of an oral dose are The primary effects of an oral dose are wakefulness, alertness, decrease fatigue; wakefulness, alertness, decrease fatigue; mood elevation, increased ability to mood elevation, increased ability to concentrate; an increase in motor and concentrate; an increase in motor and speech activity. Amphetamines also speech activity. Amphetamines also diminish the awareness of fatigue; diminish the awareness of fatigue; person may push exertion to the point of person may push exertion to the point of severe damage or even death. severe damage or even death.

Stimulate the respiratory center, especially when Stimulate the respiratory center, especially when respiration is depressed by centrally acting drugs, respiration is depressed by centrally acting drugs, (barbiturates and alcohol).(barbiturates and alcohol).

Amphetamine can reverse the marked sedation Amphetamine can reverse the marked sedation and behavioral retardation resulting from and behavioral retardation resulting from reserpine-like drug.reserpine-like drug.

Depresses appetite by their action on the lateral Depresses appetite by their action on the lateral hypothalamus rather than an effect on metabolic hypothalamus rather than an effect on metabolic rate. rate.

Mechanisms of ActionMechanisms of Action

Releases monoamines at synapses in Releases monoamines at synapses in the brain and spinal cord.the brain and spinal cord.

Inhibits neuronal uptake of monoamineInhibits neuronal uptake of monoamine Direct agonist of DA and 5-HT receptorsDirect agonist of DA and 5-HT receptors Antagonist at certain adrenreceptorsAntagonist at certain adrenreceptors May inhibit monoamine oxidase. May inhibit monoamine oxidase.

Therapeutic UsesTherapeutic Uses

Hyperkinesias - MethylphenidateHyperkinesias - Methylphenidate Narcolepsy - Amphetamine or Narcolepsy - Amphetamine or

methylphenidatemethylphenidate Obesity - Fenfluramine Obesity - Fenfluramine

Adverse EffectsAdverse Effects

CNSCNS: Euphoria, dizziness, tremor, irritability, : Euphoria, dizziness, tremor, irritability, insomnia, Convulsion (at higher doses), insomnia, Convulsion (at higher doses), hyperthermia and comahyperthermia and coma

C.VC.V. Cardiac stimulation leads to headache, . Cardiac stimulation leads to headache, palpitations, cardiac arrhythmias, anginal pain palpitations, cardiac arrhythmias, anginal pain

OtherOther: Weight loss, Psychotic Reaction which : Weight loss, Psychotic Reaction which are often misdiagnosed as schizophrenia.are often misdiagnosed as schizophrenia.

AddictionAddiction - including psychic dependence, - including psychic dependence, tolerance and physical dependence. tolerance and physical dependence.

Drug Interactions:Drug Interactions: Tricyclic antidepressantTricyclic antidepressant Antihypertensive AgentsAntihypertensive Agents Foods high in tyramine content Foods high in tyramine content

METHYLXANTINESMETHYLXANTINES

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

Theophylline: Tea and cocoaTheophylline: Tea and cocoa Theobromine: CocoaTheobromine: Cocoa

Mechanisms of ActionMechanisms of Action

Increase cyclic nucleotide concentration Increase cyclic nucleotide concentration

Blocks adenosine receptorsBlocks adenosine receptors Alters intracellular calcium distributionAlters intracellular calcium distribution

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

Caffeine is a physically addictive Caffeine is a physically addictive drugdrug

Pharmacological Activity/Pharmacological Activity/Adverse EffectsAdverse Effects

Low DosesLow Doses: 50-250mg/Caffeine (Oral Doses) : 50-250mg/Caffeine (Oral Doses) Increase mental alertness, decrease Increase mental alertness, decrease drowsiness Lessen fatigue drowsiness Lessen fatigue

Larger DosesLarger Doses: 250-600mg/Caffeine Irritability, : 250-600mg/Caffeine Irritability, restlessness, tremor, insomnia, headache, restlessness, tremor, insomnia, headache, palpitations and hyperesthesia GIT upsetpalpitations and hyperesthesia GIT upset

Large DosesLarge Doses: > 1000 mg Overt excitement, : > 1000 mg Overt excitement, delirium and clonic seizures delirium and clonic seizures

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

Smooth Muscles:Smooth Muscles: Relaxes vascular Relaxes vascular smooth muscle (Theophylline »Caffeine) smooth muscle (Theophylline »Caffeine)

KidneyKidney: All xanthines are capable of : All xanthines are capable of producing some degree of diuresis in producing some degree of diuresis in humans (Theophylline > Caffeine) humans (Theophylline > Caffeine)

MiscellaneousMiscellaneous: Xanthines shorten : Xanthines shorten clotting time by increasing tissue clotting time by increasing tissue prothrombin and factor V. prothrombin and factor V.

Adverse effectsAdverse effects

Stimulate gastric secretions in patients Stimulate gastric secretions in patients with ulcer with ulcer

Dehydration in children due to vomiting Dehydration in children due to vomiting and transient diuretic action (theophyline) and transient diuretic action (theophyline)

Allergic reaction (aminophylline)Allergic reaction (aminophylline) Psychic Dependence (Caffeine)Psychic Dependence (Caffeine)

Therapeutic UsesTherapeutic Uses

Caffeine + plus ergot alkaloid Caffeine + plus ergot alkaloid (Ergotamine): used to treat migraine (Ergotamine): used to treat migraine headachesheadaches

OTC preparations: Theophylline: OTC preparations: Theophylline: Prophylaxis for chronic asthma Prophylaxis for chronic asthma Respiratory Stimulant Bronchodilator for Respiratory Stimulant Bronchodilator for relief of asthmatic symptomsrelief of asthmatic symptoms

NICOTINENICOTINE

CNS EffectsCNS Effects: : Powerful CNS stimulant at lower doses; Powerful CNS stimulant at lower doses;

Large doses produce clonic convulsion, then Large doses produce clonic convulsion, then depress CNS, compounding postictal depress CNS, compounding postictal depressiondepression

Stimulates respirationStimulates respiration Produces emesis Produces emesis Tolerance to central actions with chronic useTolerance to central actions with chronic use

Cardiovascular EffectsCardiovascular Effects TachycardiaTachycardia Increased blood pressureIncreased blood pressure Pupillary constrictionPupillary constriction Cardiovascular collapse - due to CNS Cardiovascular collapse - due to CNS

depressiondepression Ganglionic blockade and arrhythmias Ganglionic blockade and arrhythmias

Fatalities: Due to respiratory failureFatalities: Due to respiratory failure

COCAINECOCAINE

Psychomotor stimulant Psychomotor stimulant local anesthetic local anesthetic

Chemistry- alkaloid from coca plant Chemistry- alkaloid from coca plant alkaloid is highly lipid-soluble alkaloid is highly lipid-soluble hydrochloride salt is water solublehydrochloride salt is water soluble

Routes of AdministrationRoutes of Administration

Chewing: with an-alkaloid material (South Chewing: with an-alkaloid material (South America)America)

Sniffing: hydrochloride salt -absorption: nasal Sniffing: hydrochloride salt -absorption: nasal mucous membranes -local vasoconstriction slows mucous membranes -local vasoconstriction slows absorption and prolongs effectabsorption and prolongs effect

Oral: large doses are needed for effect rapid onsetOral: large doses are needed for effect rapid onset Smoking: cocaine is converted to alkaloid Smoking: cocaine is converted to alkaloid

(freebase or "crack") which is readily volatilized (freebase or "crack") which is readily volatilized undegraded at lower temperature. I.V. and undegraded at lower temperature. I.V. and smoking: reaches CNS in seconds in high smoking: reaches CNS in seconds in high concentration produces more immediate and concentration produces more immediate and intense effects intense effects

PharmacokineticsPharmacokinetics

large vol. of distributionlarge vol. of distribution quickly metabolized: half-life 30-90 minutesquickly metabolized: half-life 30-90 minutes principal metabolites: a) Ecogonine principal metabolites: a) Ecogonine

methylester - inactive b) Benzoylecogonine - methylester - inactive b) Benzoylecogonine - inactive c) norcocaine - activeinactive c) norcocaine - active

half lives of metabolites: 4 to 6 hrs. - half lives of metabolites: 4 to 6 hrs. - metabolites: Excreted in urinemetabolites: Excreted in urine

Drug Testing: BE - detectable for 1-3 days Drug Testing: BE - detectable for 1-3 days Cocaine - detectable for a few hours Cocaine - detectable for a few hours