CNS Stimulants and Cognition Enhancers

Chapter 35

CNS Stimulants and Cognition Enhancers

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. Given below is a working classification based primarily on the clinical use, because clearcut differences do not exist.

CLASSIFICATION

1. Convulsant Strychnine, Picrotoxin, Bicuculline, Pentylenetetrazol (PTZ).
2. Analeptics Doxapram
3. Psychostimulants Amphetamines, Methylphenidate, Modafinil, Pemoline, Cocaine, Caffeine.

CONVULSANTS

 Strychnine 

• It is an alkaloid form the seeds of Strychnos nux-vomica, and a potent convulsant. The convulsions are reflex, tonic-clonic and symmetrical. It has been labelled as a spinal convulsant because the dose producing convulsions is the same in spinal and intact animals; actually, it stimulates the whole cerebrospinal axis.

• 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. Due to loss of synaptic inhibition, any nerve impulse becomes generalized, resulting in apparent excitation and convulsions.

• There are no valid uses of strychnine now. Tonics containing strychnine are banned in India. It is only of toxicological importance. Accidental poisonings, especially in children, do occur. Treatment of poisoning is similar to that of status epilepticus 

Picrotoxin 

• Obtained from ‘fish berries’ of East Indies Anamitra cocculus. It is a potent convulsant— convulsions are clonic, spontaneous and asymmetrical. The convulsions are accompanied by vomiting, respiratory and vasomotor stimulation. Though regarded as a medullary stimulant, it has little selectivity in site of action.
• 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. Diazepam, which facilitates GABAergic transmission, is the drug of choice for picrotoxin poisoning. Picrotoxin has no therapeutic indication now.

Bicuculline 

• This synthetic convulsant has picrotoxin-like actions. It is a competitive GABAA receptor (intrinsic Cl¯ channel receptor) antagonist, while GABAB receptor (G-protein coupled receptor) is insensitive to it. It is used only as a research tool.

Pentylenetetrazol (PTZ, Metrazol, Leptazol)

• It is a powerful CNS stimulant, believed to be acting by directdepolarization of central neurons. 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. It is the most commonly used convulsant for testing anticonvulsant drugs in laboratory animals, but there is no clinical use.

ANALEPTICS (Respiratory stimulants)

• These are drugs which stimulate respiration and can have resuscitative value in coma or fainting. They do stimulate respiration in subconvulsive 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 safer.

• The role of analeptics in therapeutics is very limited. Situations in which they may be employed are:

• As an expedient measure in hypnotic drug poisoning until mechanical ventilation is instituted

• Suffocation on drowning, acute respiratory insufficiency. 

• Apnoea in premature infant. 

• Failure to ventilate spontaneously after general anesthesia.

• The overall utility of analeptics is dubious; given in coma they are not active except in near convulsive doses.

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.e., infusion of doxapram has been found to abolish episodes of apnoea in the premature infant not responding to theophylline. Other uses: see above.

• Dose: 40–80 mg i.m. or i.v.; 0.5–2 mg/kg/hr i.v. infusion. CAROPRAM 20 mg/ml in 5 ml amp.

• Reflex stimulation Smelling ammonia or a drop of alcohol in the nose may be enough for hysterical fainting; analeptics should not be used.

PSYCHOSTIMULANTS

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

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. Their pharmacology and uses are described.

Methylphenidate 

• It is chemically and pharmacologically similar to amphetamine. Both acts 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 hyperkinetic children (attention deficit hyperkinetic disorder) because it causes lesser tachycardia and growth retardation. Behaviors 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.

• Methylphenidate is well absorbed orally, metabolized and excreted in urine, plasma t½ is 4–6 hours, but central effect lasts much longer. Twice daily dosing (morning and afternoon) is enough.

• Side effects are anorexia, insomnia, abdominal discomfort and bowel upset.

• Dose: Adults 5–10 mg BD; children 0.25 mg/kg/day initially, increased up to 1 mg/kg/day if needed. RETALIN 5, 10 mg tab.

Modafinil 

• It is a recently introduced psychostimulant that is getting popular with nightshift (call centre) workers and other professionals who want to improve alertness and keep awake. It is claimed to increase attention span and improve accuracy compromised by fatigue and sleepiness. The approved indications are day-time sleepiness due to narcolepsy, sleepapnoea syndrome and shift-work sleep disorder. It has also been found to reduce euphoria produced by cocaine and to suppress cocaine withdrawal symptoms; is being evaluated as a drug to reduce 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.

• Dose: 100–200 mg morning and afternoon for day-time sleepiness due to narcolepsy or sleep-apnoea syndrome; or 200 mg 1 hour before starting night-shift work. MODALERT 100, 200 mg tabs.

Pemoline 

• Though chemically unrelated, pemoline has CNS stimulant actions similar to those of methylphenidate. Sympathomimetic and CVS actions are insignificant. It probably activates dopaminergic mechanisms in the brain. Pemoline has been used in attention deficithyperkinetic disorder, narcolepsy and excessive day-time sleepiness, with benefits and side effects similar to methylphenidate. However, therapeutic effect develops gradually over 3–4 weeks and a single morning dose is enough because of its longer t½ (8–12 hrs.'). Reports of hepatotoxicity have limited its use.

Caffeine 

• Out of the three naturally occurring methylxanthines, only caffeine is used as a CNS stimulant. Its pharmacological actions are described in along with those of theophylline.

• Pharmacokinetics 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; volume of distribution is 0.5 L/kg. It is nearly completely metabolized in liver by demethylation and oxidation and 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 are produced at toxic doses—nervousness, insomnia, agitation, muscular twitching, rigidity, rise in body temperature, delirium and convulsions.

• Tachycardia, occasionally extrasystoles. Caffeine is to be avoided in peptic ulcer patients. It is not contraindicated in gout because it is not converted in the body to uric acid. Moderate coffee drinking does not contribute to development of hypertension.

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 an attack. It appears to benefit by augmenting constriction of cranial vessels by its direct action and by enhancing absorption of ergotamine form the g.i.t. 
3. Apnoea in premature infants: as alternative to theophylline

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 vegetative state. Atrophy of cortical and subcortical areas is associated with deposition of β amyloid 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:

1. Senile dementia of Alzheimer type (DAT) and multi-infarct dementia (MID). 
2. ‘Common symptoms’ of the elderly; dizziness and memory disturbances.
3.  Mental retardation in children, learning defects, attention deficit disord
4. Transient ischemic attacks (TIAs), cerebrovascular accidents—stroke.
5. 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-ischemic areas to the detriment of ischemic area. Cerebral blood flow is reduced in AD, but this is probably a consequence of loss of neurons and not its cause.

The cerebroactive drugs may be grouped into:

Cholinergic activators: 

Tacrine, Rivastigmine, Donepezil, Galantamine

Glutamate (NMDA) antagonist: 

Memantine

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 (antiChEs) like physostigmine produce symptom improvement, but at the cost of marked peripheral side effects. Over the past decade 4 cerebroselective antiChEs 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 lipid-soluble—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.

• 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 at least upto 2 years. The benefit is ascribed to elevation of ACh level in the cortex, especially in the surviving neurons 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 bedtime; 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).

• 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).

• 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 antiAchEs 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.

• Facilitation of synaptic transmission and interhemisphere information transfer.

• 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 ischemic brain areas. It has been promoted for:

1. Sequelae of cerebrovascular accidents, head injury, prolonged anaesthesia.  
2. Infants and children with developmental disorders of CNS, delayed milestones. 
3. 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.

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

Ginkgo biloba 

• The dried extract of this Chinese plant contains a mixture of ginkgoflavon 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.