List of CNS Stimulants | Pharmacology

Here is a list of twenty-four CNS stimulants.

i. Analeptics:

Analeptics are drugs which stimulate the C.N.S., particularly the respiratory and other vital centres in the medulla and are used to stimulate and revive the patients with depressed respiratory and cardiovascular centres due to overdose of CNS depressants and produce increased respiratory exchange.

These are useful in barbiturates poisoning, drowning, neonatal asphyxia, chronic hypoventilation with CO₂ retension, post-anaesthetic respiratory depression, heat and electric shock. In addition to restoration of respiratory function these also restore depressed vasomotor and cerebral functions including consciousness.

ii. Doxapram Hydrochloride:

At low doses it is more selective for the respiratory centre than other analeptics. It directly stimulates the chemoreceptors of the carotid and aortic bodies and there is slight stimulation of the medullary respiratory centre. It also raises the falling BP. The convulsant dose of doxapram is 70-75 times more than the analeptic dose.

The respiratory volume is increased 200% within 1 minute of doxapram administration in dogs. It is considered a powerful respiratory stimulant and is superior to all other analeptics, however, duration of action is shorter than that of picrotoxin. Sheep and rabbits are far less sensitive than other species of animals to the analeptic effect of doxapram.

Clinical Use:

Used for the reversal of central respiratory depression due to barbiturates and inhalant anaesthetics. To neonatal puppies and kittens, it can be administered either by SC route or sublingually and through umbilical vein at the time of birth. In adults, it is administered by IV route.

Dose:

Dog and Cat: 5.5-11 mg/kg for barbiturate depression;

1.1 mg/kg for inhalant anaesthetic-induced depression.

Horse: 0.44-0.55 mg/kg for depression of inhalant anesthetics, chloralhydrate and pentobarbital anaesthesia.

Cattle: 0.45-0.60 mg/kg for xylazine-induced depression.

iii. Nikethamide (Coramine):

It is similar to doxapram as stimulates the chemoreceptors in the aortic and carotid bodies which reflexly stimulate the respiratory centres and result in an increased rate and depth of respiration.

Compared to doxapram, it is less selective as high doses of nikethamide stimulate the spinal cord and cerebral cortex and thus resulting in convulsions. It also causes a rise in BP via central action. It is a weak analeptic with a very brief duration of action.

Clinical Uses:

It is primarily used as an effective measure in cases of respiratory and circulatory failure. However, less efficacious than other analeptics.

Dose:

Dog: 22-44 mg/kg, oral, IV, IM or SC

iv. Picrotoxin:

It is obtained from the seeds of the shrub (Anamirta cocculus; fish berries). It stimulates the whole CNS and is a powerful stimulant of the medullary centres, the cortex and with large doses, the spinal cord. The respiratory rate and depth are increased. The convulsions are accompanied by vomiting, respiratory and vasomotor stimulation,

It acts by blocking the presynaptic inhibition mediated through GABA. It is contraindicated in morphine poisoning since both morphine and picrotoxin are spinal stimulants. Diazepam is the drug of choice for picrotoxin poisoning. It is no more used for analeptic purpose because of its slow action and as other better and more safe analeptics are available. Used only in life threatening cases in dogs by IV route @ 1.5-6 mg.

v. Pentylene tetrazol (PTZ, Metrazol, Leptazol):

It rapidly acts on the medulla and mid brain. It is believed to act via direct depolarization of central neurons. Recently, it has been shown to interfere with GABA- ergic inhibition similar to that of picrotoxin. The margin of safety is narrow. It is no more being used as analeptic. Rather, only used to induce experimental chemo shock seizures in mice.

vi. Bemegride:

It is also known by the name of megemide. It has got structural similarity with that of barbiturates and was initially used as specific barbiturate antagonist. It is recognised as general purpose analeptic and at higher doses acts as convulsant. The dose for all species is 30 mg/kg and by IV route.

vii. Carbon Dioxide:

Both physiologically and pharmacologically, it is one of the most potent stimulants of respiration. It acts on the carotid and aortic bodies and reflexly stimulates the respiratory centre. It directly also stimulates the respiratory centre. However, in higher concentrations it acts as anaesthetic and also used for euthanasia.

viii. Methyl Xanthine Derivatives:

Also known as xanthine or purine derivatives and are the weakest psychoanaleptics. Caffeine, theophylline and theobromine are the major naturally occurring alkaloids in coffee and tea. Coffee, obtained from the seeds to Coffee cirabica, mostly contains caffeine (1%) while tea leaves (Thea sinensis) contain around 3% theophylline and caffeine and cocoa seeds (Theobroma cocoa) contain caffeine and theobromine.

Caffeine has the most potent effect on all parts of the brain and is preferred for its powerful central stimulant action whereas the other alkaloids have more powerful peripheral actions. On the circulatory system, theophylline is most powerful and caffeine is least.

These dilate the coronary blood vessels and promote diuresis. Thus, caffeine is preferred as CNS stimulant while theophylline is used as diuretic and for relaxation of bronchial smooth muscles and thus for the treatment of asthama.

Mechanism of Action:

All xanthine alkaloids inhibit the phosphodiesterase enzyme which is responsible for the catabolism of intracellular cyclic neucleotides (cAMP), thus, there is an increase in the cyclic AMP levels which causes various pharmacological actions like increase in force of contraction of heart, relaxation of vascular and nonvascular smooth muscles.

In addition, these release Ca²⁺ from the sarcoplasmic reticulum, especially in the skeletal and cardiac muscles and also block the adenosine receptors. Adenosine is believed to be a neuromodulator in the brain, cardiovascular and other organs and contracts smooth muscles, specially bronchial, dilates cerebral blood vessels, depresses cardiac pacemaker and inhibits the gastric secretion.

Phosphodiesterase inhibition and release of calcium are probably exerted at concentrations much higher than the therapeutic plasma concentrations while the adenosine receptors blockade effects are exerted at concentrations in the therapeutic range, however, it is not fully accepted.

ix. Caffeine:

Now it is an obsolete analeptic agent as still other better drugs are available. Margin of safety is wide.

x. Aminophylline:

It is a more soluble salt form of theophylline. It is a short acting but potent diuretic, dilates coronary blood vessels, increases blood flow to heart and increases mechanical efficiency of heart. It also has lipolytic and hypocalcemic actions.

Clinical uses:

1. Broken wind in horses,

2. Congestive heart failure in dogs, administered along with the cardiac glycosides,

3. Bronchial spasm during anesthetic emergency,

4. Bronchial asthma.

Dose:

Cats: 50 mg orally every 6 hrs.

Horses: Loading dose-12 mg/kg orally

Maintenance dose-5 mg/kg 12 hrs

xi. Amphetamine and Methyl amphetamine:

Both are powerful central sympathomimetics and CNS stimulants and because of strong medullary stimulation, they are used as analeptics. The respiratory and vasomotor centres along with cerebral cortex are strongly stimulated.

Methyl amphetamine is more powerful than amphetamine. They are mainly used as analeptics especially in cases of shock with circulatory and respiratory collapse. But it is less commonly used and has certain side effects e.g. loss of appetite, sleep etc.

Spinal Stimulants:

xii. Strychnine:

It is an alkaloids obtained from the seeds of Strychnos nuxvomica. It was used and even used now as a bitter stomachic to increase the appetite. It is generally used as a nerve tonic causing improved reflexes and stimulates the cerebral cortex.

Most potent action of strychnine is to stimulate reflex action of spinal cord and thus also called as a spinal stimulant or convulsant. It is very toxic, thus its therapeutic use has declined and is only used as a poison for dogs etc.

Symptoms of strychnine poisoning are stiffness in the muscles of neck and face, twitching in the face and limbs, violent tonic convulsions of the entire body, continuous state of muscle contraction and poisoned animals are hyper-responsive to stimuli of all types. Death results from respiratory failure and asphyxia or exhaustion after tonic spasm and cerebral hypoxia.

Mechanism of Action:

Site of action is the Renshaw cells in the Moto neuron junction in the spinal cord. Renshaw cells exert an inhibitory influence on the flow of nerve impulses along motor neurons in the spinal cord. Glycine is the inhibitory neurotransmitter to Moto neurons and interneurons in the spinal cord.

Strychnine acts as selective competitive antagonist and blocks the inhibitory effects of glycine at all glycine neurons or by blocking the postsynaptic inhibition produced by inhibitory transmitted glycine. Therefore, due to loss of synaptic inhibition the generalized excitation and convulsions are produced.

xiii. Opiate Antagonists:

These are used for terminating the CNS depressant effects to opiate compounds, particularly for the treatment of accidental poisoning or overdosing with opiate compounds.

xiv. Nalorphine:

Chemically it is related to morphine and is used as antagonist of morphine and thiambutene, a synthetic opiate. Margin of safety is wide.

xv. Levallorphan:

Its opiate antagonist potency is 4 times to that of nalorphine.

xvi. Naloxone:

Antagonistic potency is 15 times to that of nalorphine.

xvii. Diprenorphine:

Antagonistic Potency is 30 times to that of nalorphine.

xviii. Psychomimetics:

These may be useful for the treatment of CNS depression as these alter the qualitative and quantitative aspects of sensory perception and thought. However, these effects have led to abuse of these drugs and thus are not used clinically; but these are only used to experimentally. Some of the important compounds of this category are : LSD (lysergic acid di-ethyl-almide), psilocybin, Mescaline and cannabis.

xix. Cerebro-Active Drugs (Cerebral Activators):

These are generally used for a variety of cerebral disorders particularly in human beings. The indications are dizziness and memory disturbances, common symptoms of mental retardation in children, learning defects, cerebrovascular accidents etc. These drugs are believed to act by increasing the regional cerebral blood flow, support neuronal metabolism and improve memory etc. Some of the important drugs are :

xx. Piracetam:

It is a cyclic GABA derivative but lacks GABA like activity. It increases the ATP/ADP ratio in the brain and stimulates synaptic transmission in the brain.

xxi. Dihydroergotoxine:

It is semisynthetic ergot alkaloid, selectively increases the cerebral blood flow and also protects altered brain metabolism.

xxii. Pyritinoal (Pyrithioxine):

It acts by improving the regional blood flow in ischaemic brain areas, increases glucose uptake in brain and activates cerebral metabolism by a selective change in membrane permeability thus increasing the transport of glucose and sodium.

Miscellaneous CNS Stimulants:

xxiii. 4 Amino pyridine:

It has potent CNS stimulant activity and at high does produces convulsions. It is used as antagonist to tubocurarine. It increases neuronal uptake of Ca² and increase Ach release. It also block the K⁺ channels in excitable membrane. It also reverses the neuroleptanalgesic action of droperidol-fentanyl and thiopental anaesthesia.

xxiv. Alpha₂ Adrenoceptor Antagonists:

e.g. Yohimbine and Tolazoline:

These antagonists the action of xylazine and clonidine. Also antagonize the effects of barbiturates, ketamine and benzodiazepines. But these drugs can only be used as stimulants under specific CNS depressant conditions. These can not be acclaimed to be directly acting CNS stimulants.