Cognition Enhancers

• These are a heterogenous group of drugs developed for use in

dementia and other cerebral disorders.
• Indications/Uses
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. Head injury, ECT, brain surgery.
 Cognition Enhancers

• The mechanism by which they are believed to act are:

1. Increasing global/regional cerebral blood flow (CBF)
2. Direct support of neuronal metabolism.
3. Enhancement of neurotransmission.
4. Improvement of descrete cerebral functions,
• e.g. memory.
 Alzheimer’s Disease
https://www.youtube.com/watch?v=euzRPrvrwj0
 Introduction
• AD is a progressive neurologic disorder associated with aging that
develops over a period of years.
• Initially, people experience memory loss and confusion, which may be
mistaken for the kinds of memory changes that are sometimes associated
with normal aging.
• It is the most common cause of dementia among people age 65 and older.
 Pathophysiology

• AD is caused by reduced synthesis of the neurotransmitter

acetylcholine.
• There are three major hallmarks in the brain that are associated with
the disease processes of AD.
– Amyloid plaques
– Neuro- fibrillary tangles (NFTs)
– Loss of connections between neurons responsible for memory and learning.
• The disease affects neurons in the basal forebrain, amygdala, hippocampus, and
cerebral cortex.
• The brains of people with AD have an abundance of two abnormal structures:
– Beta-amyloid plaques are dense deposits of protein and cellular material that accumulate
outside and around nerve cells.
– Neurofibrillary tangles, which are twisted fibers that build up inside the nerve cell.
 Causes

• Deposition of Amyloid: Amyloid is derived from breakdown of APP. The

breakdown products are β amyloid. Deposition of β amyloid and another less
soluble form of amyloid called as Aβ particles aggregate to form amyloid
fibrils. In familial AD, mutations cause over production of APP, or alter
metabolism of APP such that more Aβ particles are deposited.
• Hyperphosphorylation of protein Tau: Tau is an intracellular protein that is
involved in assembly of intra axonal microtubules. Many structural
abnormalities are associated with accumulation of hyperphosphorylated
forms of tau.
• Expression of specific alleles of apoprotein E: The ε4 allele of apoE is
expressed with increased frequency of APP molecules. Studies have indicated
that apoE may contribute to AD but alone it is neither sufficient nor essential
for AD
• Genetic: Mutations in at least 4 genetic loci have been linked to familial AD.
Alteration in chromosome 21 that encodes for a protein ‘Amyloid Precursor
Protein’ (APP), presenilin I, and presenilin II located on chromosomes 14 and
1 respectively appear to account for AD.
 Classification of drugs for Alzheimers/Cognition
enhancers
The cerebroactive drugs may be grouped into:
a. Cholinergic activators:
• Tacrine, Rivastigmine, Donepezil, Galantamine
b. Glutamate (NMDA- N-methyl-D-aspartate) antagonist:
• Memantine
c. Miscellaneous cerebroactive drugs:
• Piracetam, Pyritinol (Pyrithioxine), dihydroergotoxine,
(Codergocrine), Citicoline, Piribedil, Ginkgo biloba.
 Cholinergic activators

• Rivastigmine
– This carbamate derivative of physostigmine inhibits both
AChE and BuChE, but is more selective for the isoform of
AChE that predominates in certain areas of the brain.
– Rivastigmine is highly lipid-soluble—enters brain easily.
– mild peripheral effect
– Inhibition of cerebral AChE for upto 10 hours despite the 2
hr plasma t½ of the drug.
– Disease progression is briefly slowed or is not affected.
– Rivastigmine is indicated in mild to- moderate cases of AD,
but not in advanced disease.
 Cholinergic activators

• Donepezil
– Cerebroselective and reversible anti-AChE
– improvement in several cognitive as well as non-cognitive (activities of
daily living) scores in AD- for few years.
– 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.
– Can be used even in relatively severe case of AD.
 Cholinergic activators

• 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.
 Glutamate (NMDA) antagonist
Memantine
• Glu is recognized to be the main excitatory neurotransmitter in the CNS,
estimated to be released at up to half of the synapses in the brain.
• In addition, Glu is also an excitotoxin that can destroy CNS neurons by
excessive activation of excitatory receptors on dendritic and somal surfaces.
• Glu exerts excitotoxic activity through three receptor subtypes, which
belong to the ionotropic family. Of these three, the NMDA receptor has
been the most extensively studied and the most frequently implicated in
CNS diseases.
• NMDA receptor hypofunction within the brain is associated with memory
and learning impairments, with psychosis, and ultimately with excitotoxic
brain injury.
• As the brain ages, the NMDA receptor system becomes progressively
hypofunctional, contributing to decreases in memory and learning
performance.
 Glutamate (NMDA) antagonist

• This new 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.
• 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.
• Memantine can be used for other types of dementia as well.
CNS Stimulants
 CNS Stimulants

• These are drugs whose primary action is to stimulate the CNS

globally or to improve specific brain functions.
• The CNS stimulants mostly produce a generalized action
which may, at high doses, result in convulsions.
 CNS Stimulants

Strychnine
• It is an alkaloid from the seeds of Strychnos nux-vomica, and a potent
convulsant.
• Strychnine acts by blocking post-synaptic inhibition produced by the
inhibitory transmitter glycine.
• There are no valid uses of strychnine now. Accidental poisonings,
especially in children, do occur.
• Picrotoxin
• It is a potent convulsant— convulsions are clonic, spontaneous and
asymmetrical.
• 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 a distinct site and prevents Cl¯ channel opening
 CNS Stimulants

• Pentylenetetrazol (PTZ, Metrazol, Leptazol)

• 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.
 Analeptics
• These are drugs which stimulate respiration and can have resuscitative
value in coma or fainting.
• They do stimulate respiration in sub convulsive doses, but margin of
safety is narrow; the patient may get convulsions while still in coma.
• Mechanical support to respiration and other measures to improve
circulation are more effective and safe.
• The role of analeptics in therapeutics is very limited.
• Situations in which they may be employed are:
(a) As an expedient measure in hypnotic drug poisoning until
mechanical ventilation is instituted.
(b) Suffocation on drowning, acute respiratory insufficiency.
(c) Apnoea in premature infant.
(d) Failure to ventilate spontaneously after general anaesthesia.
 Analeptics
Doxapram
• It acts by promoting excitation of central neurons. At low
doses it is more selective for the respiratory centre than other
analeptics.
• Respiration is stimulated through carotid and aortic body
chemoreceptors as well. Falling BP rises.
• Continuous i.v. infusion of doxapram may abolish episodes of
apnoea in premature infant not responding to theophylline.
 Psychostimulants

• Amphetamines
• These are central sympathomimetics.
• Compared to amphetamine, higher central: peripheral activity
ratio is exhibited by dextroamphetamine and
methamphetamine. They stimulate mental rather than motor
activity; convulsive doses are much higher.
 Psychostimulants
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.
• high doses can produce convulsions.
• Methylphenidate is considered superior to amphetamine for
attention deficit hyperkinetic disorder (ADHD) because it causes
lesser tachycardia and growth retardation.
• Behaviour and learning ability are improved in 3 out of 4 treated
children. It 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.
Caffeine (refer chapter Drugs for cough and
asthma)
• Caffeine and theophylline are CNS stimulants belonging to
class Methylxanthines, primarily affect the higher centers.
• Caffeine 150–250 mg produces a sense of wellbeing,
alertness, beats boredom, allays fatigue, thinking becomes
clearer even when dullness has tended to prevail after a
sustained intellectual effort. It tends to improve performance
and increase motor activity.
• Higher doses cause nervousness, restlessness, panic, insomnia
and excitement. Still higher doses produce tremors, delirium
and convulsions
 Caffeine
• Mechanism of action Three distinct cellular actions of
caffiene have been defined—
• (a) Release of Ca2+ from sarcoplasmic reticulum, especially in
skeletal and cardiac muscle.
• (b) Inhibition of phosphodiesterase (PDE) which degrades
cyclic nucleotides intracellularly.
• (c) Blockade of adenosine receptors: adenosine acts as a local
mediator in CNS, CVS and other organs
 Caffeine
• Caffeine has poor water solubility; is rapidly but irregularly 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
 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/regionalCBF, but may
reduce blood viscosity. In India and some othercountries it has been
promoted for cognitive impairment and dementia in the elderly as well as
for mental retardation in children for over 30 years
• Studies have demonstrated a neuroprotective effect of piracetam during
coronary bypass surgery, and that it may benefit cognitive disorders of
cerebrovascular and traumatic origin.
• It is used for adjunctive treatment of cortical myoclonus, but is not
recommended for children.
• Side effects are minor: gastric discomfort, nervousness, excitement,
insomnia, dizziness and skin rash.
 Review
Fill in the blanks Options Answer
(option
a/b/c)
1. Loss of _____________neurons is a major a. Dopaminergic,
hall mark of Alzheimer’s disease. b. Serotonin,
c. Cholinergic
2. _____________is seen in brains of patients a. Increase in brain gyri
suffering from AD b. Amyloid plaques
c. Neuropathy
3.Agents that may ___________ be used to a. Increase anti cholinergic
treat AD activity
b. Increase cholinergic activity
c. Increase adrenergic activity
4. Atropine can be sued to treat AD. a. True
b. False
5. Memantine acts by inhibiting____receptors a. muscarinic
b. NMDA
c. beta 2