Cognition Enhancers

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Chapter: Essential pharmacology : CNS Stimulants and Cognition Enhancers

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 and therapeutic benefits are uncertain.


COGNITION ENHANCERS

(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 and therapeutic benefits are uncertain.

 

Dementia Refers to acquired global impairment of intellect, memory and personality (cognitive functions) in the absence of gross clouding of consciousness or motor involvement. 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 βamyloid protein in the form of senile plaques, and formation of neurofibrillary tangles. There is marked cholinergic deficiency in the brain, though other neurotransmitter systems are also affected.

 

The indications of cognition enhancers include:

 

·      Senile dementia of Alzheimer type (DAT) and multi infarct dementia (MID).

·      ‘Common symptoms’ of the elderly; dizziness and memory disturbances.

·      Mental retardation in children, learning defects, attention deficit disorder.

·      Transient ischaemic attacks (TIAs), cerebrovascular accidents—stroke.

·      Organic psychosyndromes and sequelae of head injury, ECT, brain surgery.

 

The above therapeutic field is barren and commercially highly profitable. A variety of drugs have been briskly promoted by manufacturers and wishfully prescribed by physicians. 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 descrete cerebral functions, e.g. memory.

 

All cerebroactive drugs are tested for their vasodilator activity. The basic assumption has been that improvement in cerebral circulation is possible, real and therapeutically useful. However, precise measurements have shown that in many cases such claims are merely expectations. In stroke a global vasodilator effect may even be harmful—may worsen cerebral edema; and induce ‘steal’ phenomenon, i.e. diversion of blood flow to non-ischaemic areas to the detriment of ischaemic area. Cerebral blood flow is reduced in AD, but this is probably a consequence of loss of neurones and not its cause.

 

The cerebroactive drugs may be grouped into:

 

1. Cholinergic activators:

 

Tacrine, Rivastigmine, Donepezil, Galantamine

 

2. Glutamate (NMDA) antagonist:

 

Memantine

 

3. Miscellaneous cerebroactive drugs:

 

Piracetam, Pyritinol (Pyrithioxine), Dihydroergotoxine (Codergocrine), Piribedil, Ginkgo biloba

 

 

Cholinergic Activators

 

Since brain ACh 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. Over the past decade 4 cerebro-selective anti-ChEs have been introduced for use in AD.

 

Tacrine

 

It is the first centrally acting anti-ChE to be introduced for AD. In clinical trials tacrine produced significant improvement in memory, attention, praxis, reason and language. However, it does not alter course of the underlying disease process. Frequent side effects and hepatotoxicity have restricted its use.

 

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 lipidsoluble—enters brain easily. Greater augmentation of cholinergic transmission in brain is obtained with mild peripheral effect. The carbamyl residue introduced by rivastigmine into AChE dissociates slowly resulting in inhibition of cerebral AChE for upto 10 hours despite the 2 hr plasma t½ of the drug.

 

In clinical trials an average of 3.8 point improvement in Alzheimer’s Disease Assessment Scale (ADAS-cog) has been obtained compared to placebo. Other symptoms like apathy, delusions, hallucinations and agitation also improve, though disease progression is not affected. Peripheral cholinergic side effects are mild. It has not produced liver damage.

 

Dose: Initially 1.5 mg BD, increase every 2 weeks by 1.5 mg/day upto 6 mg/BD.

 

EXELON, RIVAMER 1.5, 3, 4.5, 6.0 mg caps.

 

Donepezil

 

This cerebro-selective and reversible anti-AChE produces measurable improvement in several cognitive as well as noncognitive (activities of daily living) scores in AD, which is maintained at least 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. It is generally well tolerated and is not hepatotoxic.

 

Dose:  5 mg OD HS (max 10 mg OD);

 

DONECEPT,  DOPEZIL  5,  10  mg  tabs.

 

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.

Dose:  4 mg BD (max 12 mg BD)

 

GALAMER 4, 8, 12 mg tabs.

 

There is now firm evidence that rivastigmine, donepezil and galantamine afford similar, but modest symptomatic benefit in AD. Cognitive decline is slowed, but not prevented. Their side effects are also comparable. However, role of these drugs in non-Alzheimer dementia is not clear.

 

Memantine

 

This new NMDA receptor antagonist, related to amantadine (also a NMDA antagonist), has been found to slow the functional decline in moderate-to-severe AD, but benefit in milder disease are unclear. 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 and drowsiness. It is indicated in moderate-to-severe AD.

 

Dose: Initially 5 mg OD, increase gradually upto 10 mg

 

BD; stop if no clinical benefit in 6 months.

 

ADMENTA 5, 10 mg tabs.

 

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 purportedly by:

 

a. Enhancement of learning and memory.

b. Facilitation of synaptic transmission and inter-hemisphere information transfer.

c. Increased tonic cortical control on subcortical areas.

 

Piracetam is not a vasodilator, does not affect total/ regional CBF, but may reduce blood viscosity. In India and some other countries it has been promoted for cognitive impairment and dementia in the elderly as well as for mental retardation in children for nearly 30 years. However, a recent (2004) Cochrane Database review has concluded that published data does not support such use. In the UK, it is approved for adjunctive treatment of cortical myoclonus, and is not recommended for children. It is not approved in the USA.

 

Side effects are minor: gastric discomfort, nervousness, excitement, insomnia, dizziness and skin rash. Dose: 0.8–1 g TDS oral; children 20 mg/kg BD–TDS; 1–3 g i.m. 6 hourly in stroke/head injury.

 

NORMABRAIN, NEUROCETAM, NOOTROPIL 400, 800 mg cap, 500 mg/5 ml syr., 300 mg/ml inj.

 

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.

 

ENCEPHABOL 100, 200 mg tab. 100 mg/5 ml suspension; 200 mg dry powder with 2 ml solvent for i.v. infusion.

 

Dose: 100–200 mg TDS, children 50–100 mg TDS orally; 200–400 mg every 4–6 hours (max. 1 g/day) has been given i.v. for recovery from cerebral hypoxia due to cardiac arrest, anaesthesia, brain operations and stroke.

 

Side effects: Only mild g.i. upset was reported initially. Later skin rashes, itching and taste disturbances (attributable to the disulfide moiety) have been reported. It has been withdrawn in some countries.

 

Dihydroergotoxine (Codergocrine):

 

It is a semisynthetic ergot alkaloid having adrenergic blocking property; claimed to increase cerebral blood flow selectively. It is believed to act by protecting altered brain metabolism. In a dose of 1.0–1.5 mg TDS oral/sublingual or 0.3 mg i.m. OD, it has been recommended for DAT, MID and in the elderly with mild to moderate dementic symptoms, but therapeutic valve is not established.

 

HYDERGINE 1 mg tab, 0.3 mg/ml inj. CERELOID 1 mg tab.

 

Side Effects: flushing, headache, nasal congestion, postural hypotension, g.i. disturbances and rashes.

 

Piribedil

 

It is a dopaminergic agonist claimed to improve memory, concentration, vigilance, giddiness and tinnitus in the elderly, but benefit is unsubstantiated. Mild efficacy in parkinsonism has also been reported. Side effects are mild g.i. complaints.

 

Dose:  50 mg OD, BD; TRIVASTAL LA 50 mg tab.

 

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 argued that G. biloba will prevent cerebral impairment in MID. It has been promoted for a variety of cognitive and behavioral disorders in the elderly, but a controlled trial has failed to detect improvement in agerelated memory impairment or dementia.

 

Side effects are mild upper g.i.t. symptoms, but i.v. infusion has caused fever, shock and arrhythmia. Dose: 40 mg TDS for a minimum period of 4 weeks; GINKOCER, BILOVAS, GINKOBA 40 mg tab.

 


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