This document discusses central nervous system (CNS) stimulants. It defines CNS stimulants as drugs that stimulate the CNS and increase physiological activity. CNS stimulants are classified into three categories: convulsants and respiratory stimulants, psychomotor stimulants, and psychomimetic or hallucinogenic drugs. The document focuses on different types of CNS stimulant drugs, including β-Phenylethylamine derivatives like amphetamine and methamphetamine, oxazolidinone derivatives like pemoline, and methylxanthines like caffeine. It describes the mechanism of action, effects, metabolism, and uses of these important classes of CNS stimulant drugs.

2. 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. ↑ Heart rate.
 ↑ Respiratory rate.
 Instability & restlessness.
 Muscle twitching (tremors).
 Convulsion but at high dose may lead
to death.

5. Three broad categories:
I. Convulsants and respiratory stimulants.
II. Psychomotor stimulants.
III. 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.  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. 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. 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.

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

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 (α1).
 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 (2S,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 α1, β1, and
5-HT2C.
 These mechanisms fit its structure.
 Use: an antidepressant and an anorexiant

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(5H)-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.

39.  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]).

40. 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.

41.  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.

42. 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.

43. 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

44. 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.

45. a.Pentylenetetrazole
 6,7,8,9-tetrahydro-5H-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.

46. 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

47. 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

48.  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.

49.  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.

50. 1β-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.
1β-Arylamino
Hallucinogens
Indolethylamine
structural resemblance
to the 5-HT
Phenylethylamine
structural resemblance
to NE and DA
Both

51. 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.

52. 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.

53. 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.

54. 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.

55. 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