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

Classification

1. Convulsants

Strychnine, Picrotoxin, Bicuculline, Pentylenetetrazol (PTZ).

2. Analeptics

Doxapram

3. Psychostimulants

Amphetamines, Methylphenidate, Modafinil, Pemoline, Cocaine, Caffeine.

Many other drugs are capable of causing

CNS stimulation as side effect or at high doses.

CONVULSANTS

Strychnine

It is an alkaloid form the seeds of Strychnos nuxvomica, and a potent convulsant. The convulsions are reflex, tonicclonic 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 postsynaptic 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 (see Ch. No. 30).

Picrotoxin

Obtained from ‘fish berries’ of East Indies Anamirta 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 (see p. 395). Diazepam, which facilitates GABAergic transmission, is the drug of choice for picrotoxin poisoning. Picrotoxin has no therapeutic indication now.

Bicuculline

This synthetic convulsant has picrotoxinlike actions. It is a competitive GABA_A receptor (intrinsic Cl¯ channel receptor) antagonist, while GABA_B receptor (Gprotein 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 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. It is the most commonly used convulsant for testing anticonvulsant drugs in laboratory animals (see Ch. No. 30), 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 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:

ü As an expedient measure in hypnotic drug poisoning untill mechanical ventilation is instituted.

ü Suffocation on drowning, acute respiratory insufficiency.

ü Apnoea in premature infant.

ü 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 neurones. 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 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 in Ch. No. 9.

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 hyperkinetic children (attention deficit hyperkinetic disorder) 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.

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 compromized by fatigue and sleepiness. The approved indications are daytime sleepiness due to narcolepsy, sleep-apnoea syndrome and shiftwork 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 daytime sleepiness due to narcolepsy or sleep-apnoea syndrome; or 200 mg 1 hour before starting nightshift 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 daytime 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.

Cocaine (see Ch. No. 26)

Caffeine 

Out of the three naturally occurring methylxanthines, only caffeine is used as a CNS stimulant. Its pharmacological actions are described in Ch. No. 16 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

ü In analgesic mixture: caffeine benefits headache probably by allaying fatigue and boredom. It has no analgesic action of its own.

ü 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.

ü Apnoea in premature infants: as alternative to theophylline (see Ch. No. 16).

Caffeine is available only in combined formulations with ergotamine or analgesics in tablets.

CAFERGOT: Caffeine 100 mg + ergotamine 1 mg tab.

MICROPYRIN: Caffeine 20 mg + aspirin 350 mg tab.

Tonics containing caffeine are banned in India.