Cns stimulants

MEDICINAL CHEMISTRY NOTES

1. CNS Stimulants By: Mrs. Dhanashri R Mali Assistant Professor, GES’s Sir Dr. M. S. Gosavi College of Pharmaceutical Education and Research, Nashik

2. Learning outcome Student should able to : Define of CNS stimulants Classify CNS stimulants Explain different types of drugs used as CNS stimulants, and their MOA.

3. DEFINATION Central nervous system (CNS) stimulants are drugs that stimulate the CNS. Compounds that increase an initial low level of physiological activity are generally classified as CNS stimulant. Their effects vary from the increase in the alertness and wakefulness (as with caffeine) to the production of convulsion (as with strychnine) and sometimes lead to death in over dose.

4. General signs and symptoms of CNS stimulation: ↑ Heart rate. ↑ Respiratory rate. Instability & restlessness. Muscle twitching (tremors). Convulsion but at high dose may lead to death.

5. Three broad categories: Convulsants and respiratory stimulants. Psychomotor stimulants. Psychomimetic drugs or hallucinogenic drugs. Convulsants or respiratory stimulants (analeptics): Little effect on the mental function Appear to act mainly on the brain stem and spinal cord Producing reflex excitability, as increase in the activity of the respiratory and vasomotor centre and with higher doses it produce convulsions.

6. Psychomotor stimulants: A marked effect on mental function and behaviour Producing excitement, cessation of fatigue, and increase in motor activity. Examples: (amphetamine, caffeine, and cocaine) Psychomimetic drugs: Affect through pattern, perception, and mood producing effects superficially resemble the changes seen in schizophrenia.

7. Analeptics: Greek word –restorative meaning ‘picking up’ those who have been cast down. Also called respiratory stimulants are general CNS stimulants. A group of potent and relatively nonselective CNS stimulants When administered stimulate all the parts of CNS, especially the brain medulla.

8. Counteracting the depressant activity due to the administration of excess CNS depressants. The convulsive dose lies near their analeptic dose. Stimulate the CNS system and in large doses, they cause generalized convulsions. Newer agents are more selective Use: as respiratory Stimulants In narcolepsy (chronic sleep disorder characterized by overwhelming daytime drowsiness and sudden attacks of sleep)

9. Classification According to the mode of action, analeptics may be divided into four groups. They are as follows: A. Respiratory stimulants B. Psychomotor stimulants C. Convulsant stimulants D. Psychomimetic drugs (hallucinogenic drugs)

10. A. Respiratory stimulants

11. B. Psychomotor stimulants or central stimulants ( sympathomimetics ) I. β– Phenylethylamine derivatives

12. II. Oxazolidinone derivatives III. Methylxanthines

13. C. Convulsants and stimulants

14. D. Psychomimetic drugs (hallucinogenic drugs) a. (+) Lysergic acid diethylamide b. Indole derivative Psilocyn C. Cannabis D. Dissociate Agents Phencyclidine HCl

15. A. Respiratory stimulants Doxapram Hydrochloride 1-ethyl-4-(2-morpholinoethyl)-3,3- diphenyl -2- pyrrolidinone hydrochloride hydrate MOA: Stimulates respiration by action on peripheral carotid chemoreceptors . Use: As a respiratory stimulant postanesthetically , after CNS depressant drug overdose, in chronic obstructive pulmonary diseases, and in the apneas. Administered exclusively by IV injection. Must never be given to neonates (Because of the benzyl alcohol content)

16. b. Nikethamide N,N- diethylnicotinamide weak analeptic employed as respiratory stimulant. Produces respiratory stimulation at doses that have only little CNS excitation. Its duration of action is very transient.

17. c. Bemigride 4-Ethyl-4-methyl piperidine-2,6-dione This agent is used in the treatment of barbiturate intoxication. It causes a rapid stimulation of the CNS

18. B. Psychomotor Stimulants A marked effect on mental function and behaviour Producing excitement, cessation of fatigue, and increase in motor activity. I. β– Phenylethylamine derivatives II. Oxazolidinone derivatives III. Methylxanthines

19. I. β– Phenylethylamine derivatives Central sympathomimetic agents: . A few simple structural changes produce compounds that are more resistant to metabolism, more nonpolar , and better able to cross the blood-brain barrier. These effects increase the ratio of central to peripheral activity and act centrally as sympathomometic agents.

20. They produce CNS-stimulating effects, manifested as excitation , increased wakefulness, and exert an anorexiant effect. Along with sympathomimetic , have other central effects, notably dopaminergic and serotoninergic effects. The ratio of excitation and increased wakefulness to anorexiant effects is decreased, and the agents are markete as anorexiants . Anorexiants are: phendimetrazine and sibutramine The alerting agents: methylphenidate and pemoline , useful in attention- deficient disorders.

21. SAR Contain a β- phenethylamine moiety, Give some selectivity for presynaptic or postsynaptic NA systems. β - Phenethylamine , given peripherally, lacks central activity. Facile metabolic inactivation by monoamine oxidases (MAOs) is held responsible. Branching with lower alkyl groups on the carbon atom adjacent (α) to the amino nitrogen increases CNS rather than peripheral activity (e.g., amphetamine, presumably by retarding metabolism). The α- branching generates a chiral center. The dextro ( S ) - isomer = 10 times as potent as the levo ( R ) - isomer for alerting activity The dextro ( S ) - isomer = twice as active as a psychotomimetic agent.

22. Hydroxylation of the ring or hydroxylation on the β -carbon (to the nitrogen) decreases activity, largely by decreasing the ability to cross the BBB. For example, phenylpropanolamine , with a Has about 1/100th the ability to cross the BBB of its deoxy congener, amphetamine. (used as a decongestant and appetite suppressant) Halogenation (F, Cl , Br) of the aromatic ring decreases sympathomimetic activity but other activities may increase. p- Chloroamphetamine has strong central serotoninergic activity (and is a neurotoxin) Methoxyl or methylenedioxy substitution on the ring tends to produce psychotomimetic agents,(D2 receptors). N- methylation increases activity (e.g., methamphetamine ). Di- N- methylation decreases activity. Mono-N substituents larger than methyl decrease excitatory properties, but many compounds retain anorexiant properties. with less abuse potential than amphetamine.

23. Side effects: The abuse potential of the more euphoriant and stimulatory of the amphetamines and amphetamine-like drugs is well documented. They produce an exceedingly destructive addiction. Apparently, both a euphoric “high” (possibly related to D2 receptors) and a posteuphoric depression (especially among amine-depleting drugs) contribute to compulsive use of these agents.

24. Uses: medical indications for β– Phenylethylamine (amphetamine type of drug) include Narcolepsy (an extreme tendency to fall asleep, sleep disorder) Parkinson disease, Attention-deficient disorders, and, although not the preferred agents for obesity, appetite suppression.

25. A. Amphetamine/ Dextroamphetamine (+)-( S)- methylphenethylamine The dextrorotatory isomer has the ( S) configuration and fewer cardiovascular effects than the levorotatory ( R)-isomer. The dextro ( S ) - isomer = 10 times as potent as the levo ( R ) - isomer for alerting activity ( S ) - isomer = twice (R) as active as a psychotomimetic agent Has a better ratio of alerting to psychotomimetic effects

26. Mode of action: Major Mechanism: Increases synaptic dopamine and NA primarily by stimulating presynaptic release. Other mechanisms, such as inhibition of uptake, may make a small contribution to the overall effects. The alerting actions relate: Increased NE interact with postsynaptic receptors ( α 1). Anorexiant effect.: Central β -receptor activation Psychotomimetic effects: Release of DA and activation of postsynaptic receptors ( D2 and mesolimbic D3 receptors) Some behavioral effects: Effects on 5-HT systems ( 5-HT1A receptors and 5-HT7).

27. Pharmacokinetics: A strongly basic amine, ( pka from 9.77 to 9.94 ) Absorption from the gastrointestinal tract occurs as the lipid-soluble amine. Not extensively protein bound. Varying amounts are excreted intact under ordinary conditions. The amount is insignificant under conditions of alkaline urine. 60% to 70% excreted unchanged under systemic acidosis. This fact can be used to advantage in treating drug overdose.

28. Metabolism by MAO( α -methyl group slow down). Metabolized by N- dealkylation to phenylacetone and ammonia. Phenylacetone is degraded further to benzoic acid. Uses: It is an anorectic(reduces appetite) and has been used in the weight control of obese individuals. It has potential for abuse and cardiovascular effects.

29. B. Methamphetamine (+)-1-phenyl-2-methyl aminopropane hydrochloride The N-methyl analog of dextroamphetamine . Has more marked central and less peripheral action than dextroamphetamine . A very high abuse potential by the IV route, its salts are known as “speed.” Medicinally acceptable uses of methamphetamine are analogous to those of dextroamphetamine .

30. C. Phentermine α , α - dimethylphenethylamine , 1-phenyl-2- methyl aminopropane . A quaternary carbon atom with one methyl oriented like the methyl of ( S)-amphetamine and one methyl oriented like the methyl of ( R)-amphetamine Has pharmacological properties of both the ( R)- and ( S)-isomers of amphetamine. Used as an appetite suppressant and is a Schedule IV agent, indicating less abuse potential than dextroamphetamine .

31. D. Fenfluramine ( ± ) N-ethyl α --methyl-m-( trifluoromethyl ) phenethylamine hydrochloride unique in this group of drugs, in that it tends to produce sedation rather than excitation. Effects are mediated principally by central serotoninergic , rather than central NA, mechanisms. It was withdrawn from human use after reports of heart valve damage and pulmonary hypertension. used as respiratory stimulant.

32. E. Phendimetrazine (2 S,3S)-3,4-dimethyl-2-phenyl morpholine -L-(+)- tartrate is considered an effective anorexiant less abuse than amphetamine F . Sibutramine an uptake inhibitor of NE and 5-HT. Receptors principally involved are α 1, β 1, and 5-HT 2 C. These mechanisms fit its structure. Use: an antidepressant and an anorexiant drug.

33. G. Methylphenidate has two asymmetric centers, there are four possible isomers. The threo racemate is the marketed compound and is about 400 times as potent as the erythro racemate . MOA: acts by its p- hydroxy metabolite, blocks NE reuptake, acts as a postsynaptic agonist, and has effects on dopaminergic systems.

34. It is an ester drug. The pKa values are 8.5 and 8.8. The protonated form in the stomach reportedly resists ester hydrolysis. Absorption of the intact drug is very good. After absorption however, 80% to 90% of the drug is hydrolyzed rapidly to inactive ritalinic acid. The extent of hydrolysis : five times that for (+) versus (-). Another 2% to 5% : oxidized by liver microsomes to the inactive cyclic amide. About 4% of a dose of the racemate reportedly reaches the brain and there is p- hydroxylated to yield the active metabolite. Use: It is a potent CNS stimulant. Indications include narcolepsy and attention-deficit disorder

35. II. Oxazolidinone derivatives Pemoline 2-amino-5-phenyl-4(5 H)- oxazolone An overall effect on the CNS like that of methylphenidate. Requires 3 to 4 weeks of administration, however, to take effect. A partial explanation for the delayed effect may be to increase the rate of synthesis of DA. Use: in the treatment of narcolepsy fatigue, mental depression, chronic schizophrenia, and as a mild stimulant in geriatric patients.

36. III. Methylxanthines The naturally occurring xanthine derivatives are caffeine, theophylline , and theobromine . Generally cause mild CNS stimulation, and relax -smooth muscles, So used in the treatment of asthma. Produce diuresis by increasing glomerular filtration and blocking tubular reabsorption of sodium ions. It stimulates the medullary centre and overcomes fatigue.

37. Mode of action: These agents have mild stimulant action and increase the epinephrine secretion and enhance the neural activity in several areas of the brain. These agents act by producing antagonism of adenosine receptor (A1 and A2A receptors). Adenosine is a neuromodulator , which influences numerous functions in the CNS and the blocking is responsible for stimulation.

38. Caffeine and theophylline have pharmaceutically important chemical properties. Both are weak Brønsted -Lowry bases. The pKa values are 0.8 and 0.6 for caffeine and 0.7 for theophylline . These values represent the basicity of the imino nitrogen at position 9. As acids, caffeine has a pKa above 14, and theophylline , a pKa of 8.8. In theophylline , a proton can be donated from position 7 (i.e., as a Brønsted acid). Caffeine cannot donate a proton(Methyl group) from position 7 and does not act as a Brønsted acid at pH values less than 14. Caffeine does have electrophilic sites at positions 1, 3, and 7. In addition to its Brønsted acid site at 7, theophylline has electrophilic sites at 1 and 3. Both compounds are electron-pair donors, but only theophylline is a proton donor in most pharmaceutical systems. Although both compounds are quite soluble in hot water. Consequently, various mixtures or complexes designed to increase solubility are available (e.g., citrated caffeine, caffeine and sodium benzoate, theophylline– ethylenediamine compound [ aminophylline ]).

39. A. Caffeine Caffeine is often used as it occurs in brewed coffee, brewed tea, and cola beverages. 85 to 250 mg of caffeine acts as a cortical stimulant and facilitates clear thinking and wakefulness, promotes an ability to concentrate on the task at hand, and lessens fatigue. the dose is increased, side effects indicating excessive stimulation (e.g., restlessness, anxiety, nervousness, tremulousness) become more marked. With further increases in dosage, convulsions can occur.

40. Not highly protein bound; More lipophilic than theophylline Reputedly achieves higher brain concentrations. The half-life : is 5 to 8 hours. About 1% is excreted unchanged. Metabolized in the liver. The major metabolite is 1-methyluric Not metabolized to uric acid, and they are not contraindicated in gout.

41. Uses: CNS stimulants. It stimulates the respiratory centre, increases rate and depth of respiration. The diuretic action of caffeine is weaker than theophylline . May be used in treating poisoning from CNS-depressant drugs, although it is not a preferred drug. Have valuable bronchodilating properties in asthma. Finally, because of central vasoconstrictive effects, has value in treating migraine and tension headaches and may have actual analgesic properties in the latter use. Used along with ergotamine in the treatment of migraine.

42. b. Theophylline Used as nonselective phosphodiesterase inhibitor ( xanthine ) and in the treatment of reversible airways obstruction. At high doses, the tendency to produce convulsions is greater for theophylline than for caffeine The important use: in bronchial asthma 50% bound to plasma protein; The half-life: about 3.5 hours. About 1% is excreted unchanged. The major metabolite of of theophylline , 1,3-dimethyluric acid

43. C. Theobromine Has very little CNS activity (probably because of poor physicochemical Properties for distribution to the CNS). It is a nonselective phosphodiesterase inhibitor ( xanthine ) Uses: In the treatment of reversible airways obstruction. as diuretic and in the treatment of angina pectoris and hypertension.

44. C. Convulsant stimulants a.Pentylenetetrazole 6,7,8,9-tetrahydro-5 H-tetrazolo [1,5-a] azepine , 1,5-pentamethylenetetrazole Mode of action: A powerful CNS stimulant, acting by direct depolarization of the central neurons . acts as a convulsant by interfering with chloride conductance inhibited action on GABA channel openings. binds to an allosteric site on the GABAA receptor and acts as a negative modulator. Low doses cause excitation, high doses cause convulsion.

45. Uses: It is used to induce convulsion in animals to locate epileptic foci in conjugation with the electro encephalograph. It is used as a laboratory tool in determining potencies of potential anticonvulsant drugs in experimental animals

46. b . Picrotoxin Picrotoxinin , the active ingredient of picrotoxin MOA: Acts by blocking presynaptic inhibition mediated by GABA. not a competitive antagonist, it acts on the distinct site of GABA receptors and prevents the chloride channel opening. Thus , produces depolarization of neurons and excite the central nervous system.

47. It is a potent convulsant , produces clonic spontaneous and asymmetrical convulsions. The convulsions are accompanied by vomiting, respiratory and vasomotor stimulation . useful in determining mechanisms of action of sedative–hypnotics and anticonvulsants.

48. D. Psychomimetic drugs (hallucinogenic drugs) These are characterized by the fact that they affect thought perception and mood, without causing marked psychomotor stimulation or depression . All of the drugs are drugs of abuse These drugs fall broadly into two groups. Those with a chemical resemblance to known neurotransmitter catecholamine: These include LSD and psilocybin, which are related to 5-HT and mescaline that is similar in structure to amphetamine . Drugs unrelated to monoamine neurotransmitter : Cannabis and phencyclidine.

49. 1 β -Arylamino Hallucinogens It alter the perception of stimuli. Reality is distorted, and the user may undergo depersonalization. The effects are those of a psychosis. Additionally , the drugs can produce anxiety , fear, panic, frank hallucinations, and additional symptoms that may be found in a psychosis. Accordingly, they are classed as hallucinogens and psychotomimetics .

50. INDOLETHYLAMINES Dimethyltryptamine It is a very weak hallucinogen , active only by inhalation or injection, with a short duration of action. It possesses pronounced sympathomimetic (NE) side effects .

51. Psilocybin and Psilocin Psilocybin is the phosphoric acid ester of psilocin It occurs in a mushroom, Psilocybe mexicana . Both drugs are active orally, with a short duration of action.

52. 2-PHENYLETHYLAMINES Mescaline 3,4,5-trimethoxyphenethylamine , hallucinogen with many complex effects on the CNS. . The oral dose required for its hallucinogenic effects is very high, as much as 500 mg of the sulfate salt. The low oral potency probably results from facile metabolism by MAO.

53. BOTH (+)-Lysergic Acid potent hallucinogen. The stereochemistry is exceedingly important for activity. Has marked effects on serotoninergic and dopaminergic neurons. its actions have been suggested as being more typical of schizophrenic psychotic reactions than the model based on amphetamine.

54. Dissociative Agents Phencyclidine was introduced as a dissociative anesthetic for animals. In humans, PCP produces a sense of intoxication, hallucinogenic experiences. The drug affects many systems, including those of NE, DA, and 5-HT. blocks glutaminergic N-methyl-D- aspartate receptors. This action is the basis for many of its CNS effects. The psychotic state produced by this drug is also cited as a better model than amphetamine psychosis for the psychotic state of schizophrenia.