Analeptic

ANALEPTICS

Analeptics are CNS Stimulant. They are used to treat CNS depression, Attention deficit hyperactivity disorder.(ADHD) and respiratory depression.  They were used to counter CNS depressant intoxication. They have very low therapeutic index thus they are not preferred by physicians. They have little clinical use but they are important as drug of abuse. They can be divided into two groups

1.       Psychomotor Stimulants

a.       Methylxanthiene (Caffeine, Theobromine and Theophyline),

b.      Amphetamine,

c.        Cocaine,

d.      Methylphenidate,

e.       Nicotine,

2.       Psychotomimetic drug(Hallucinogens or psychedelic agents)

a.       Lysergic Acid diethylamide (LSD),

b.      Phencyclidine (PCP),

c.        Tetra hydro cannabonol (THC)

Psychomotor Stimulant: They elevate mood, sense of physical and metal well being, self esteem, euphoria and alertness, decrease appetite and need for sleep, dull pain sensation. Over dose produces anxiety and dysphoria. Their acute administration induces mydriasis, diaphoresis, hypertension, tachycardia, anorexia. Their high dose causes mental confusion and cardiac arrhythmias. Chronic use causes reversible psychosis. Paranoid behaviour hallucination, delusion, aggressiveness, hyperactivity, anxiety and irrational bizarre behaviour are some symptoms of chronic use of psychomotor stimulants. They also unmask symptoms of latent schizophrenia.

Adverse effect:  They have low therapeutic index. They induce serious adverse effects like cardiac arrhythmias, myocardial infractions, myocarditis, cerebrovascular spasm, hypertension, intracerebral hemerhage, respiratory depression convulsion and hyperpyrexia. Long term use may cause hepatic and renal failure.

Pharmacodynamics: They act as noradrenergic and dopaminergic agonist.

METHYL XANTHINES: They are natural analeptic agents. Ex. Caffeine (Present in Coffee seeds and tea leaves), Theobromine (Present in Cocoa and coffee seeds) and Theophylline (Present in tea leaves.)  Caffeine is most widely used CNS stimulant.  Coffee has highest concentration of caffeine. It is also found in tea, chocolate candy, cold drinks, cocoa, and energy drinks etc.

Mechanism of Action: Methyl xantheines act at cellular level to stimulate CNS.

1.        They inhibit enzyme Phosphodiestearase and

2.       Block adenosine receptors

to increase concentration of c AMP  (Cyclo Adenosine monophosphate) and c GMP (cyclo guanosine monophosphate).  Cyclo Adenosine monophosphate and cyclo guanosine monophosphate act as chemical messanger for intracellular signal transduction (transmission) in CNS. This helps to increase mental alertness.

3.       They increase intracellular calcium ion in skeletal muscles and cardiac muscles to induce to decrease fatigue.

Pharmacological Actions

1.       Central nervous System: Among all three caffeine is most active and theobromine is least active CNS stimulant. Small dose decreases fatigue and improve physical performance. High dose improves mental alertness, sense of well being, thought process and sleep disturbance. Slightly high dose produces anxiety, excitement, nervousness, tremor and confusion.

One to two cups of coffee contain 100 to 200 mg caffeine. This dose produces relief from skeletal muscle fatigue, increases mental alertness by stimulating brain cortex and other parts. 10 to 15 cups of coffee contain about 1.5 gm caffeine It produces anxiety and tremor. Very high dose 2 to 5 gm caffeine stimulate spinal cord

2.       Cardiovascular system: Caffeine induces inotropic and chronotropic effect on heart in high dose. This inotropic and chronotropic effect is harmful for patient suffering from angina pectoris and other heart diseases.

3.       Kidney:   Among all three theophulline is more potent than caffeine as diuretic. These drugs are mild diuretic. They increase excretion of sodium, potassium and chloride by increasing their glomerular filtration and inhibiting their renal reabsorption.

4.       Smooth Muscles: Among all three theophylline is more effective smooth muscle relaxant.  They have muscle relaxant effect on smooth muscles especially on bronchial muscles. This effect produces bronchodilation. It is used in treatment of asthma

5.       Skeletal muscle: Among all three caffeine is more effective to increase tonicity of skeletal muscles. They increase contractile power of skeletal muscles. This property is used to treat skeletal muscle fatigue.

6.       GIT: They stimulate secretion of hydrochloric acid and pepsin into stomach. Due to this consumption of tea, coffee, caffeine containing beverages etc in empty stomach promote peptic ulcer. Among all three theophylline is more dangerous to produce peptic ulcer.

THERAPEUTIC USES:

1.       Bronchodilator: Theophylline is widely used as bronchodilator to treat bronchial asthma. All methyl xanthines have bronchodilator effect.  But β agonists and corticosteroids have largely replaced methylxanthines in management of asthma.

2.       CNS Stimulant: Caffeine is usually mixed with analgesics to produce relief from body pain and headache due to fatigue.

3.       Migraine: Caffeine with ergotamine is used to treat migraine.

                                                           Alok

          

PHARMACOKINETICS: Methyl xanthenes are well absorbed from GIT, well distributed throughout body, cross blood brain barrier and placental barrier. They are metabolised in liver by demethylation and oxidation. Active drug and their metabolites are excreted through urine and breast milk.

Adverse effects: Moderate dose causes insomnia. Slightly high dose causes anxiety, excitement, nervousness, tremor and confusion. They have very high therapeutic index even very high dose does not cause death. High dose shows vomiting and convulsion. About 10 gm caffeine induces cardiac arrhythmias. Theophylline is more toxic than caffeine.

NICOTINE

Caffeine is most widely used CNS stimulant. Nicotine is second most widely used CNS stimulant. Similarly alcohol is most abused drug. Nicotine is second most abused drug. Nicotine is active constituent of tobacco. It is not therapeutically used.

Pharmacodynamics:  Nicotine acts as ganglionic stimulant at low dose and ganglionic blockade at high dose. Nicotinic receptor exists in CNS. Initially nicotine stimulates nicotinic receptor then block it.

Pharmacological Actions:

1.       Central Nervous System: Nicotine is highly lipid soluble. It crosses BBB rapidly. In low dose it stimulates CNS and produces euphoria, improve attention, learning, problem solving, reaction time along with relaxation. In high dose it depresses CNS, causes hypotension and respiratory paralysis.

2.       Cardiovascular System: Nicotine stimulates autonomic ganglia, adrenal medulla to produce vasoconstriction, increase blood pressure, tachycardia and cardiac arrhythmias. It stimulates release of antidiuretic hormone. This also causes constriction of peripheral and coronary blood vessel. Thus use of tobacco by hypertensive and heart patient is very harmful.

3.       Gastrointestinal Tract effect: It stimulates salivary and bronchial secretion. It stimulates chemoreceptor zone to produce nausea and vomiting, It stimulates gastric acid secretion that delays peptic ulcer healing. It increases motor activity in bowel.

4.       Enzyme effect: It stimulates enzymes activity in intestine, liver that alters metabolism of other drugs.

Pharmacokinetics: Nicotine is highly soluble in lipid. It is absorbed from intact skin, oral mucosa, GIT mucosa and lungs. It can cross blood brain barrier, placental barrier and secreted through breast milk. It is metabolised in liver and excreted through urine and breast milk both in free and metabolite form.

Tolerance:  Nicotine has several toxic effects. Tolerance to toxic effect of nicotine develops very quickly. Ex. Nausea, vomiting, sweating, fall in blood pressure occurs in first time smokers. Tolerance to these effects develops very rapidly. Tolerance to bowel activity and tachycardia does not develop.

Withdrawal Symptoms: Nicotine is addictive drug. Dependence to nicotine develops very quickly. Withdrawal symptoms are headache, irritability, restlessness, anxiety, concentration difficulty and insomnia. Withdrawal symptoms in smokers can be controlled by using nicotine transdermal patch or nicotine chewing gum. Nicotine transdermal patch or nicotine chewing gum produces concentration of nicotine in blood very less than cigarettes.

COCAINE

It is self administered by chewing, intranasal snoring, smoking and intravenous injection. Cocaine is highly addictive drug. It increases dopaminergic and noradrenergic activity. It blocks serotonin, dopamine and nor-epinephrine reuptake blockade at pre-synaptic terminals. This blockade enhances and extends duration of action of these neurotransmitters.  This affects limbic system and produces euphoria. Chronic use of cocaine depletes dopamine. This increases craving for cocaine and produces addiction.   

Pharmacological Actions:

A.      Behavioural effects: It acts as psychostimulant. It elevates mood, self esteem, physical and mental well being, Physical and mental alertness, euphoria, decreases appetite (anorexia) and need of sleep. Acute use produces mydriasis, diaphoresis, hypertension and tachycardia.  High dose may cause mental confusion and arrhythmias.

B.      Sympathetic nervous system: It stimulates sympathetic nervous system and increases activity of norepinephrine to produce “fight and flight” characteristics.

Therapeutic Uses: Cocaine is used as local anesthetic during nose, ear, eye and throat surgery. It blocks activated sodium channel and interact with potassium channel to produce anesthetic effect. It also acts as vasoconstrictor.

Adverse effects: It has very rapid onset of action and short lived effect. Thus there is great chance of over dose and drug dependence. It produces following adverse effects:

1.       Anxiety:  Hypertension, tachycardia, sweating and paranoia (psychosis), Hyperpyrexia, Convulsion.

2.       Depression: CNS stimulation followed by mental depression. Respiratory depression,

3.       Cardiac Disease: Myocardial infarction, Myocarditis, fatal cardiac arrhythmias

4.       Rhabdomyolysis: It is rapid break down of damaged skeletal muscles. Symptoms are muscle pain, weakness, vomiting and confusion. It may be associated with kidney and liver failure.

AMPHETAMINE: Amphetamine is adrenergic CNS stimulant. It produces action by increasing release of intracellular catecholamines (Norepinephrine, Serotonin and dopamine) and inhibiting Monoamine Oxidase (MAO).

Pharmacokinetics: It is completely absorbed from GIT, metabolised in liver and excreted through kidney.

Pharmacological Actions:

1.       Central Nervous System:  It stimulates CNS. It is potent drug. It produces euphoria i.e. 4 to 6 times longer than effect euphoric effect of cocaine. It shows addiction, dependence, tolerance and drug seeking behaviour.

CNS stimulant effect depends upon dose of amphetamine.

a.       In low dose:10 to 30 mg dose, It produces

                                                              i.        increases alertness, mental concentration, wakefulness and physical performance

                                                            ii.      reduces fatigue, apetite

                                                          iii.      Insomnia

b.      In high dose more than 30 mg it produces

                                                              i.      Respiratory stimulation

                                                            ii.      Convulsion and coma.

2.       Sympathetic nervous system: It stimulates adrenergic system.

Therapeutic Uses: Several safe and more selectively acting drugs has reduced its use. However it has following therapeutic uses:

1.       Hyperkinetic syndrome: It is hyper activity and attention deficit syndrome (lack of ability to concentrate on one activity for more than few minutes). Usually it occurs in children. Amphetamine reduces hyper kinesis and prolongs attention.

2.       Narcolepsy: It is uncontrollable desire for sleep or sudden desire of sleep in appropriatesituation. It can be treated by Amphetamine or its derivative methylphenidate.

3.       Anorexiant: To treat obesity.

Adverse effect:

1.       Central nervous System: Insomnia, irritability, weakness, dizziness, tremor, hyperactive reflex. Confusion, delirium, panic state, suicidal tendency. Chronic use causes amphetamine psychosis. Overdose of amphetamine can be treated by chlorpromazine.

2.       Cardivascular effects:  Palpitation, cardiac arrhythmias, hypertension angina pain, circulatory collapse. Cardiovascular effect also produces headache, chills and sweatinh

3.       Gastrointestinal effects: Anorexia, Nausea, Vomiting, diarrhoea and abdominal cramp

PSYCHOTOMIMETIC DRUG (HALLUCINOGENS OR PSYCHEDELIC AGENTS):  

Hallucinogens cause profound destortion in peroson’s perception of reality. It is accompanied by bright, colourful changes in perception along with constantly change in colour and shapes. It interferes in normal thought process and person will not be able to take rational decision. It elevates mood, behaviour and perception. Thus it is called psychomimetic drug,

1.       Lycergic acid diethylamide (LSD):  It is very potent drug. It produces action in very low dose. It is rapidly absorbed from GIT and effects last for 2-4 hours that disappear in 6 hours. Extent of effect varies from person to person and time to time. Tolerance develops to dose but it does not produce addiction or dependence.

It acts as serotonin (5 HT) agonist. It activates sympathetic nervous system to produce papillary dilation, increase in blood pressure and temperature, flushing. Tachycardia, lacrrmation, hyperreflexia

In low dose, 25 to 50 µg, it produces hallucination, perceptual changes and mood change, Mood change may be euphoric (ecstasy) fear or depression. Occasionally feeling of panic, severe anxiety, intense depression, suicidal thoughts and visual disturbance may appear. These symptoms are termed as bad trip. It can be treated by diazepam.

2.       Phencyclidine (PCP):  PCP acts as dissociative anesthesia (insensitive to pain, remain consciousness, flat face, rigid muscle, slurred speech, staggered gait, numbness in extremities and staring gaze) and analgesic. In very low dose, it induces  emotional withdrawal, strange response,
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