CNS Stimulants and Nootropics

CNS STIMULANTS
These are drugs whose primary action is to stimulate the whole CNS or to improve specific
brain functions.

Convulsants
1. Strychnine It is an alkaloid from the seeds of Strychnos nux-vomica, that is a potent
convulsant. The convulsions are reflex, tonic-clonic and symmetrical. Strychnine acts by
blocking post-synaptic inhibition produced by the inhibitory transmitter glycine. One of the
sites that has been clearly demonstrated is the Renshaw cell-motoneurone junction in the
spinal cord through which inhibition of antagonistic muscles is achieved.
Accidental strychnine poisoning may occur, especially in children. Treatment of poisoning
is similar to that of status epilepticus.
2. Picrotoxin It is obtained from ‘fish berries’ of East Indies Anamirta cocculus. Picrotoxin is
a potent convulsant— convulsions are clonic, spontaneous and asymmetrical. The
convulsions are accompanied by vomiting, respiratory and vasomotor stimulation.
Picrotoxin acts by blocking presynaptic inhibition mediated through GABA. However, it is
not a competitive antagonist; does not act on GABA receptor itself, but on an allosteric site
and prevents Cl¯ channel opening. Diazepam, which facilitates GABAergic transmission, is
the drug of choice to treat picrotoxin poisoning.
3. Bicuculline This synthetic convulsant has picrotoxin like actions. It is a competitive GABA
A receptor (intrinsic Cl¯channel receptor) antagonist. It is only a research tool.
4. Pentylenetetrazol (PTZ) It is a powerful CNS stimulant, believed to be acting by direct
depolarization of central neurones. However, it has also been shown to interfere with
GABAergic inhibition—may be acting in a manner analogous to picrotoxin.
Low doses cause excitation, larger doses produce convulsions which are similar in pattern
to those caused by picrotoxin. Antagonism of PTZ induced convulsions is an established
method of testing anticonvulsant drugs in laboratory animals.

Analeptics (Respiratory stimulants)

These are drugs which stimulate respiration and were believed to have resuscitative value in
coma or fainting. They do stimulate respiration in subconvulsive doses, but margin of safety
is narrow.
Doxapram and some other analeptics injected i.v. were used in the past as an expedient
measure in fainting, barbiturate poisoning, suffocation, drowning, ventilatory failure in
COPD, but are outmoded now.

Psychostimulants
These drugs have predominant cortical action; their psychic effects are more prominent than
those on medullary vital centres.

1. Amphetamines Amphetamine (racemic), dexamphetamine (d-isomer) and

methamphetamine are synthetic sympathomimetic compounds with predominant central
actions. The latter two have higher central: peripheral activity ratio than amphetamine. All
three stimulate mental rather than motor activity; convulsive doses are much higher.
2. Methylphenidate It is chemically and pharmacologically similar to amphetamine. Both
act primarily by releasing NA and DA in the brain. Both produce increase in mental
activity at doses which have little action on other central and peripheral functions.
Methylphenidate is considered superior to amphetamine for attention deficit hyperkinetic
disorder (ADHD) in children, because it causes lesser tachycardia and growth retardation.
Behaviour and learning ability are improved in 3 out of 4 treated children.
Methylphenidate can also be used for concentration and attention defect in adults, and for
narcolepsy, but should not be employed to treat depression, dementia, obesity or to keep
awake.
Methylphenidate is well absorbed orally, metabolized and excreted in urine, plasma t½ is
4–6 hours, but central effects last much longer. Twice daily dosing (morning and afternoon)
 is enough. Side effects are anorexia, insomnia, growth retardation, abdominal discomfort
and bowel upset.
3. Atomoxetine This is a selective NA reuptake inhibitor, unrelated to amphetamine as well as
to imipramine, which does not enhance DA release in the brain, and is neither a CNS
stimulant nor an antidepressant. However, it has been found to improve attention span and
behaviour in ADHD. It is indicated in children >6 years and in adults with concentration
and attention problems.
Atomoxetine is absorbed orally, hydroxylated by CYP2D6 and excreted in urine, mainly as
glucuronide. While majority of individuals are extensive metabolizers (EM), few are poor
metabolizers (PM) due to polymorphism of CYP2D6. Inhibitors of CYP2D6 like fluoxetine,
paroxetine, quinidine increase concentration and toxicity of atomoxetine. It should not be
given with MAO inhibitors and is contraindicated in glaucoma.
Atomoxetine is relatively well tolerated. Common side effects are dyspepsia, anorexia and
other abdominal symptoms. Others are sleep disturbances, mood swings, emotional lability,
rarely suicidal thoughts and hepatotoxicity. Growth retardation is possible in children.
4. Modafinil This newer psychostimulant is popular with night-shift (call centre) workers and
other professionals who want to improve alertness and keep awake. It is claimed to increase
attention span and improve accuracy that has been compromized by fatigue and sleepiness.
Although, modafinil has been shown to inhibit NA and DA uptake as well as alter junctional
concentration of glutamate and GABA, its actual mechanism of action is not known. The
approved indications are day-time sleepiness due to narcolepsy, sleep-apnoea syndrome and
shift-work disorder (SWD). It has also been found to reduce euphoria produced by cocaine
and to suppress cocaine withdrawal symptoms. Modafinil is being evaluated as a drug to
prevent relapse of cocaine dependence.
The most common side effects are insomnia and headache. Others are nausea, dyspepsia,
dizziness, confusion, amnesia, personality disorders, tremors and hypertension. Dependence
is a possibility on long-term use.
Modafinil is absorbed within 2–4 hours of oral administration, and is eliminated with a t½
of 15 hours.
5. Caffeine Out of the three naturally occurring methylxanthines, only caffeine is used as a
CNS stimulant.
Pharmacokinetics Caffeine has poor water solubility; is rapidly but inconsistently absorbed
after oral administration. It is < 50% bound to plasma proteins, distributed all over the body,
and nearly completely metabolized in liver by demethylation and oxidation. Metabolites are
excreted in urine; plasma t½ is 3–6 hours in adults.
Adverse effects Toxic effects of caffeine are extensions of its pharmacological actions.
Caffeine poisoning is rare, and it is less toxic than theophylline.
Gastric irritation, nausea and vomiting may occur as side effects.
Excitatory and motor effects such as nervousness, insomnia, agitation, muscular twitching,
rigidity, rise in body temperature, delirium and convulsions are produced at toxic doses.
Tachycardia, occasionally extrasystoles occur at high doses.
Caffeine is to be avoided in peptic ulcer patients.
Uses
1. In analgesic mixture: caffeine benefits headache probably by allaying fatigue and
boredom. It has no analgesic action of its own.
2. Migraine: Caffeine is used in combination with ergotamine for treatment of migraine
attack. It appears to benefit by augmenting constriction of cranial vessels and by
enhancing absorption of ergotamine from the g.i.t.
3. Apnoea in premature infants: as alternative to theophylline.
Nootropics or Cognition Enhancers or Cerebroactive drugs
These are a heterogenous group of drugs developed for use in dementia and other cerebral
disorders. They do elicit pharmacological effects, but widely different mechanisms of action
are claimed. Therapeutic benefits are limited, and at the best, short-lasting.
Dementia Refers to acquired impairment of intellect, memory, ability to comprehend and
recognize people, loss of orientation and other cognitive functions, in the absence of gross
clouding of consciousness or motor dysfunction. Memory, capacity to solve problems of day
to day living, performance of learned motor skills, social skills and control of emotions are
primarily affected.
Alzheimer’s disease (AD) A progressive neurodegenerative disorder which affects older
individuals and is the most common cause of dementia. It may progress to a totally vegitative
state. Atrophy of cortical and subcortical areas is associated with deposition of β-amyloid
protein in the form of extracellular senile (amyloid) plaques and formation of intracellular
neurofibrillary tangles made up of ‘tau’ protein. These abnormal proteins accumulate mostly
due to reduced clearance, but in some cases, due to overproduction, and cause neuronal
damage followed by neuron loss. There is marked cholinergic deficiency in the brain, though
other neurotransmitter systems, especially glutamate and neuropeptide, are also affected.

The indications of cognition enhancers include:

1. Alzheimer’s disease (AD) and multi-infarct dementia (MID).
2. Mild cognitive impairment (MCI) or ‘common symptoms’ of the elderly; dizziness and
episodic memory lapses.
3. Mental retardation in children, learning defects, attention deficit disorder.
4. Transient ischaemic attacks (TIAs), cerebrovascular accidents, stroke.
5. Organic psychosyndromes and sequelae of head injury, ECT, brain surgery.

The mechanism by which they are believed to act are:

 Increasing global/regional cerebral blood flow (CBF)
 Direct support of neuronal metabolism.
 Enhancement of neurotransmission.
 Improvement of discrete cerebral functions, e.g. memory.
I. Cholinergic activators Since brain Ach and choline acetyl transferase levels are
markedly reduced and cholinergic neurotransmission is the major sufferer in AD, various
approaches to augment brain ACh have been tried. Precursor loading with choline or
lecithin have failed because there is no shortage of these substrates in the brain.
Cholinergic agonists (arecoline, bethanechol, oxotremorine) and conventional
anticholinesterases (anti-ChEs) like physostigmine produce symptom improvement, but
at the cost of marked peripheral side effects.
1. Rivastigmine This carbamate derivative of physostigmine inhibits both AChE and
BuChE, but is more selective for the G1 isoform of AChE that predominates in certain
areas of the brain. Rivastigmine is highly lipid-soluble—enters brain easily. Greater
augmentation of cholinergic transmission in the brain is obtained with mild peripheral
effect. The carbamyl residue introduced by rivastigmine into AChE molecule dissociates
slowly resulting in inhibition of cerebral AChE for upto 10 hours despite the 2 hr plasma
t½ of the drug.
2. Donepezil This cerebroselective and reversible anti-AChE produces measurable
improvement in several cognitive as well as non-cognitive (activities of daily living)
scores in AD, which is maintained upto 2 years. The benefit is ascribed to elevation of
ACh level in the cortex, especially in the surviving neurones that project from basal
forebrain to cerebral cortex and hippocampus. Therapeutic doses produce only weak
peripheral AChE inhibition: cholinergic side effects are mild. Because of long t½ (~70
hr), donepezil is administered once daily at bed time; a distinct advantage over
rivastigmine and galantamine which need twice daily dosing. Moreover, it can be used
even in relatively severe case of AD. Donepezil is generally well tolerated and is not
hepatotoxic.
3. Galantamine It is a natural alkaloid which selectively inhibits cerebral AChE and has
some direct agonistic action on nicotinic receptors as well. Galantamine has produced
 cognitive and behavioural benefits in AD which are comparable to rivastigmine and
donepezil. It is well tolerated, but needs twice daily dosing.

NMDA antagonist
Memantine This newer NMDA receptor antagonist, related to amantadine (that is also a
NMDA antagonist), has been found to slow the functional decline in moderate-to-severe AD,
but benefit in milder disease is unclear. Symptom relief is similar to or lesser than anti-
AChEs. It appears to block excitotoxicity of the transmitter glutamate in a noncompetitive
and use-dependent manner. Beneficial effects have also been noted in parkinsonism.
Memantine is better tolerated than anti-AChEs used in AD. Side effects are constipation,
tiredness, headache, dizziness, and drowsiness. It is indicated in moderate-to-severe AD,
either to replace anti-AChEs or to supplement them.

Miscellaneous
1. Piracetam This cyclic GABA derivative has no GABA like activity and has been called
‘nootropic’ meaning a drug that selectively improves efficiency of higher telencephalic
integrative activities.
Piracetam is not a vasodilator, does not affect total/ regional CBF, but may reduce blood
viscosity. In India and some other countries, it has long been promoted for cognitive
impairment and dementia in the elderly as well as for mental retardation in children.
Side effects are minor: gastric discomfort, nervousness, excitement, insomnia, dizziness
and skin rash.
2. Pyritinol (Pyrithioxine) Pyritinol consists of two pyridoxine molecules joined through a
disulfide bridge, but has no vit B6 activity. It is claimed to activate cerebral metabolism
by selectively increasing glucose transport across blood-brain barrier and improving
regional blood flow in ischaemic brain areas. It has been promoted for:
 Sequelae of cerebrovascular accidents, head injury, prolonged anaesthesia.
 Infants and children with developmental disorders of CNS, delayed milestones.
 Concentration and memory defects, senility, organic brain syndromes.
However, therapeutic benefit, if any, is uncertain. Pyritinol has been withdrawn in some
countries due to risk of reactions.
3. Dihydroergotoxine (Codergocrine): It is a semisynthetic ergot alkaloid having α
adrenergic blocking property; claimed to increase cerebral blood flow selectively. It is
believed to act by protecting altered brain metabolism.
Side effects: flushing, headache, nasal congestion, postural hypotension, g.i. disturbances
and rashes
4. Piribedil: It is a dopaminergic agonist claimed to improve memory, concentration,
vigilance and to suppress giddiness, tinnitus in the elderly caused by cerebral circulatory
insufficiency, but benefit is unsubstantiated. Minor symptomatic relief in parkinsonism
has also been reported. Side effects are mild g.i. complaints.
5. Citicoline It is a compound derived from choline and cytidine, that is involved in
biosynthesis of lecithin. Citicoline is believed to improve cerebral function by increasing
blood flow to the brain and enhancing cerebral metabolism. In the absence of effective
medicines and under promotional pressure, citicoline is being prescribed for impaired
brain function due to ischaemic stroke, parkinsonism, head injury, etc.
6. Ginkgo biloba The dried extract of this Chinese plant contains a mixture of ginkgo
flavon glycosides (e.g. ginkgolide B) which have PAF antagonistic action. Since PAF has
been
implicated in cerebral thrombosis and infarcts, it is professed that G. biloba will prevent
cerebral impairment in cerebrovascular insufficiency. Side effects are mild upper g.i.t.
symptoms, and increased risk of bleeding.