In this essay we will discuss about the drugs used for treating the diseases of sympathetic and parasympathetic nervous system.
Essay # 1. Drugs Used for Treating the Diseases of Sympathetic Nervous System:
1. Sympathomometic Drugs:
Sympathomimetic drugs have effects similar to those produced by activity of sympathetic nervous system. However, drugs differ quantitatively in responses on the two adrenergic receptors.
For practical purposes, the sympathomimetic drugs can be grouped on the basis of their predominant effects and therapeutic uses into:
i. Adrenaline (Epinephrine):
Adrenaline, the circulating hormone of adrenal medulla, acts on both α and β receptors.
Adrenaline is not available for oral administration as it is rapidly conjugated and oxidized. It is given by parenteral routes. The liver is the main organ for its degradation. COMT and MAO metabolize the majority of the dose and the metabolites are excreted in the urine.
Adrenaline, in large doses causes vasoconstriction in the subcutaneous, mucosal, splanchnic, and renal vascular beds by α receptor mediated mechanism. The venous tone (α2-mediated response) is increased, resulting in increased venous return to the heart. Vasoconstriction in coronary and cerebral circulation is minimal.
At low concentrations, it may cause vasodilatation, because β receptors are more sensitive to adrenaline than α receptors. Adrenaline acts on β1 receptors in the heart and causes an increase in heart rate, enhancement of cardiac contractility, and increase in conduction velocity. The cardiac output is increased by enhancing the venous return due to increased venous tone (α2 effect) and more effective ventricular contractions. Cardiac stimulation increases myocardial oxygen consumption.
The systolic blood pressure rises due to increased cardiac output. The diastolic pressure shows little change as adrenaline produces vasoconstriction only in the skin and the splanchnic area (α1 effect) and vasodilation in the arteries in muscle (β2 effect).
Adrenaline relaxes the urinary bladder and intestinal muscles, while the corresponding sphincters are stimulated. Uterine contractions may be inhibited (β receptor) or stimulated (a receptor), depending on menstrual phase or stage of gestation. Adrenaline induces bronchodilator by a β2 receptor mechanism.
Adrenaline increases metabolic rate. In a variety of tissues, adrenaline stimulates the breakdown of stored fuel with the production of substrate for local consumption, glycogenolysis in the heart. It also accelerates fuel metabolism in liver, adipose tissue, and skeletal muscle, liberating substances (glucose, free fatty acids, and lactate) into the circulation for use throughout the body.
Adipose tissue lipolysis and skeletal muscle glycogenolysis a β receptor mediated and hepatic glycogenolysis and gluconeogenesis is both α and β receptor mediated effects of adrenaline. Adrenaline inhibits the secretion of insulin (α receptor mediated response).
Adrenaline is the lifesaving drug and is used for cardiopulmonary resuscitation. In acute anaphylactic reactions, it relieves edema and swelling by causing vasoconstriction (0.5 ml of a 1:1000 solution intramuscularly). Adrenaline is given as an intravenous bolus in a dose of 1 mg (10 ml of 1:1000 solution) to restore cardiac activity in cardiac arrest.
Other uses of adrenaline include, along with local anesthetics (with the exception of cocaine) to prolong the duration of infiltration anesthesia and topically in the eye to facilitate aqueous drainage in chronic open angle glaucoma (α effect).
Adrenaline can cause anxiety, tremor, headache, and in overdoses arrhythmias, cerebral hemorrhage and pulmonary edema.
ii. Noradrenaline (Norepinephrine):
Noradrenaline is the neurotransmitter of the postganglionic sympathetic neurons. Its most important action is to produce widespread vasoconstriction leading to a rise in both systolic and diastolic blood pressure. Noradrenaline is rarely used for the treatment of hypotension during anesthesia, because of its potent vasoconstrictor action which reduces the blood flow in essential organs, particularly in the kidney; need of regular monitoring of blood pressure and rapid inactivation by the body (given only as intravenous infusion). Its use is contraindicated in absence of facilities for monitoring blood pressure and in pregnancy.
It is an alkaloid obtained from Ephedra vulgaris. It is absorbed orally and is long acting since it is resistant to COMT and MAO. Ephedrine is a mixed acting sympathomimetic that is it has both direct and indirect action. It causes release of noradrenaline from storage in nerve terminals and also produces direct stimulation of α and β receptors. It crosses the blood brain barrier and causes CNS stimulation. Tachyphylaxis occurs with repeated administration.
Ephedrine is rarely used intravenously for hypotension due to spinal or epidural anesthesia. Topically, ephedrine is the safest sympathomimetic nasal decongestant. Ephedrine is less suitable and less safe for use as a bron-chodilator because it is likely to cause arrhythmia, insomnia, anxiety and restlessness.
It is a direct acting sympathomimetic and has an action like noradrenaline but is less potent. It increases systolic and diastolic blood pressure via vasoconstriction, and produces a marked reflex bradycardia. It has little stimulant action on the CNS. Its major use is in the emergency treatment of acute hypotension.
It is a direct acting stimulator of α receptors with pharmacological properties similar to metaraminol. It is more suitable for treatment of acute hypotension when associated with tachycardia.
vi. Isoproterenol (Isoprenaline):
It is related to adrenaline but stimulates only p receptors with little or no effect on a receptors. It is rarely used in heart block or severe bradycardia because over dosage can cause dangerous cardiac arrhythmias.
It is a naturally occurring catecholamine with an important role as neurotransmitter in the CNS. It is a direct agonist acting on β1 receptors and releases noradrenaline in the cardiac muscle, thus resulting in increased contractility with little effect on the rate.
In addition, dopamine stimulates receptors in the renal blood vessels, causing vasodilatation and increase renal perfusion. This action is useful in shock, where there is generally a decline in renal function. Given as intravenous infusion, dopamine is used in cardiogenic shock in myocardial infarction or cardiac surgery. Higher doses may cause intense vasoconstriction, which may result in gangrene of extremities.
Dobutamine is similar to dopamine, but has no effect on the kidneys. It has a greater effect on the contractility than rate of the heart. It is used to improve myocardial function in myocardial infarction because oxygen demands are less than other sympathomimetics due to its minimal action on the heart rate. It can be combined with dopamine for the treatment of cardiogenic shock, septic shock and cardiomyopathies.
Phenylephrine is a direct acting an agonist that raises blood pressure by increasing peripheral resistance and causes reflex bradycardia. It is used in the treatment of hypotension and paroxysmal supraventricular tachycardia and as a topical nasal decongestant. It can cause adverse effects like that of noradrenaline. Chronic use as a nasal decongestant may lead to rebound nasal congestion.
Selective β2agonists are the drugs of choice for the treatment of an acute attack of bronchial asthma, since they cause effective bronchodialation with minimal effects on the heart.
Salbutamol is the most widely used β2 agonist bronchodilator. It is only used to relieve the acute symptoms of asthma. It has no prophylactic value and prolonged use may lead to tachyphylaxis. Orally, it is extensively bio-graded as it passes through liver (first pass metabolism). Its action lasts for 3-4 hours.
Inhalation of 100-200 microgram (1-2 puffs) of salbutamol is the preferred route for an acute attack of bronchial asthma, because it provides immediate relief and causes fewer systemic side effects (such as tremors and nervous tension).
Orally, in doses of 2-4 mg three or four times daily, salbutamol is given in patients, who cannot manage the inhaled route. Oral preparations have a slower onset but a slightly more prolonged action than the aerosol inhalers.
Intravenous (3-20 microgram/ minute) and occasionally subcutaneous (500 microgram) injections are given for severe bronchospasm. Salbutamol is also used to inhibit premature labour.
Large doses of salbutamol may cause tremors, tachycardia, occasionally night cramps and hypokalemia. Hypersensitivity reactions have been reported. β2 agonists should be used cautiously in hyperthyroidism, myocardial insufficiency, arrhythmias, hypertension, pregnancy and breast-feeding. Plasma potassium levels require monitoring because of development of hypokalemia.
The other selective β2 agonists have similar actions as that of salbutamol and differ in their route of administration and duration of action (Table 2.1).
Sympathomimetic vasoconstrictors such as ephedrine and xylometazoline are used to relieve nasal congestion associated with vasomotor rhinitis and the common cold as nasal drops. They are of limited value because they cause local irritation, tachyphylaxis and rebound congestion on withdrawal. Ephedrine nasal drops are the safest decongestant and gives relief for several hours. Pseudoephedrine, an isomer of ephedrine has less potent systemic (CNS and cardiac) effects and is a poor bronchodilator. It is mainly used as a nasal decongestant.
xiii. Uterine Relaxants:
Stimulation of β2 receptors in the uterine muscles diminishes the uterine activity during pregnancy. Salbutamol and ritodrine are used by intravenous infusion in the management of premature labour between 24 and 33 weeks of pregnancy.
xiv. CNS Stimulants:
Amphetamine acts indirectly by releasing noradrenaline in the central nervous system. It produces euphoria, reduces appetite, abolishes fatigue and increases both mental and physical activity. It is no longer used because it causes dependence (drug addiction) and psychotic states. It has no place in the management of depression or obesity.
Dexamphetamine has more prominent CNS actions than amphetamine. It is used in narcolepsy and as an adjunct in the management of refractory hyperkinetic states in children.
xv. Miscellaneous Sympathomimetic:
DIPIVEFRINE is a pro-drug of adrenaline. It passes more rapidly through the cornea and is converted by intraocular enzymes to adrenaline. Adrenaline reduces the rate of production of aqueous humor, increases its outflow through the trabecular meshwork and thus lowers intraocular pressure in glaucoma. It is used as eye drops in open angle glaucoma. It is contraindicated in angle closure glaucoma. BRIMONIDINE and APRACLONIDINE are selective α2 stimulants and are used for open angle glaucoma.
2. Sympatholytic Drugs:
Sympatholytic drugs are mainly used for their actions on the blood vessels and heart in the treatment of hypertension and to decrease the work of the heart where they diminish the oxygen demand of the myocardium in coronary insufficiency.
The sympathetic nervous system can be blocked at different sites, and according to the site of action, sympatholytic can be divided into following groups:
i. α adrenergic blocking drugs.
ii. Adrenergic neuron blocking drugs.
iii. Ganglionic blocking drugs.
iv. Centrally acting sympatholytic.
v. β adrenergic blocking drugs.
3. Alpha Adrenergic Blocking Drugs:
These drugs block the vasoconstrictor action of noradrenaline and dilate arterioles.
Phenoxybenzamine is a noncompetitive and nonselective α blocker. It antagonizes both α1and α2 receptors. Its action is prolonged and irreversible and is associated with many side effects, such as profound postural hypotension. It is rarely used with a β blocker in the short term management of severe hypertensive episodes associated with pheochromocytoma.
Phentolamine is a competitive, nonselective a blocker. Because of its rapid action and short duration, phentolamine is preferred to phenoxybenzamine for the diagnosis and treatment of pheochromocytoma.
Prazosin is a selective blocker of postsynaptic α1receptors that causes vasodilatation of both the arteries and veins. Unlike nonselective α blockers, prazosin does not usually produce reflex tachycardia.
Prazosin does not increase plasma rennin activity, does not affect adversely insulin sensitivity or blood lipids. Selective α1blockers antagonize the contraction of the sphincter at the bladder trigone.
Prazosin undergoes significant first pass metabolism and has a bioavailability of about 60%. It is extensively metabolized and is excreted in the feces and bile.
Prazosin is used to treat mild to moderate hypertension. It is also used in the treatment of acute congestive heart failure as an afterload reducing agent. However, it is less effective than diuretics, ACE inhibitors, β blockers, calcium channel blockers, when used as mono-therapy. Selective α1 adrenergic blocking drugs may improve lipid profile by decreasing total cholesterol and triglyceride levels and increasing HDL cholesterol. They can improve the negative effects on lipids induced by thiazide diuretics and β blockers.
Prazosin is used in benign prostatic hyperplasia to increase urinary flow rate and relieve obstructive symptoms.
Prazosin may cause sedation, dizziness, postural hypotension and syncope, which often disappear with continued therapy. Other side effects include weakness, dry mouth, urinary frequency and incontinence.
DOXAZOSIN and TERAZOSIN are long acting selective α1 blockers and are used in the treatment of hypertension and benign prostatic hyperplasia.
4. Adrenergic Neuron Blocking Drugs:
GUANETHIDINE and DEBRISOQUINE prevent the release of noradrenaline from postganglionic neurons. Guanethidine also depletes the nerve endings of noradrenaline. These drugs do not control supine blood pressure and may cause postural hypotension. They are no longer used because of their significant adverse effects. RESERPINE, a rauwolfia alkaloid, is no longer used because of serious side effects which include psychic depression that can lead to suicidal tendencies and possible increase risk of breast carcinoma.
5. Ganglionic Blocking Drugs:
These belong to different chemical groups and cause either competitive or depolarizing block and include hexamethonium, mecamylamine and trimethaphan. They block both the sympathetic as well as parasympathetic ganglia. Their therapeutic application lies in blockade of sympathetic ganglia (sympatholytic action) while blockade of parasympathetic ganglia constitutes adverse effects.
Trimethaphan is only available for clinical use. It blocks the action of acetylcholine competitively, has a very short duration of action and is rarely used by intravenous infusion for the treatment of hypertensive crisis, in the management of autonomic hyper-reflexia, and to provide controlled hypotension during surgery. The drugs of choice for hypertensive crisis are IV sodium nitroprusside and IV esmolol. Adverse effects include atropine like actions due to blockade of parasympathetic ganglia.
6. Centrally Acting Sympatholytics:
These are potent antihypertensive agents that act by stimulating presynaptic a2 adrenergic receptors in CNS, resulting in decrease peripheral sympathetic outflow which reduces sympathetic vascular resistance and causes fall in blood pressure and bradycardia.
Methyldopa is rarely used in the treatment of hypertension because of its side effects. Its main use is in the treatment of pregnancy related hypertension, since the first-line antihypertensive drugs tend to adversely affect the growth and functional development of the fetus or have toxic effects on fetal tissues.
Side effects are common. Drowsiness, depression, psychological disorders, and Parkinsonism are some of CNS disorders. Hypersensitivity reactions, haemolytic anaemia, bone marrow depression and hepatitis have also been reported.
Clonidine is used as an oral loading agent in patients with hypertensive crisis when immediate reduction in blood pressure is not indicated. It is also used to prevent unpleasant withdrawal symptoms that occur during treatment of opioid dependence. The side effects are similar to those seen with methyldopa except it does not cause haemolytic anaemia.
7. Beta Adrenergic Blocking Drugs:
This group of drugs blocks the β adreno-receptors in the heart, peripheral vasculature, bronchi, pancreas, and liver. Many β blockers are available and in general they are all equally effective but mainly differ in their cardio-selective action, lipid solubility, duration of action and sites of elimination.
Cardio-selective β blockers predominantly block β1 (cardiac) receptors and have less effect on β2 (bronchial) receptors and therefore called relatively cardio-selective, but they are not cardio- specific. Cardio-selective β blockers are used for cardiovascular disorders, while nonselective β blockers (e.g. propranolol) are used to control widespread effects of adrenergic stimulation, which occurs in thyrotoxicosis and anxiety.
ii. Partial Agonist Activity:
β blockers possessing intrinsic sympathomimetic activity (ISA) show partial agonist activity. The implication is that β blockers with partial agonist activity are associated with fewer cardio-respiratory side effects because of a compensatory agonist activity (PAA).
iii. Lipid Solubility:
This largely determines the pharmacokinetic behavior of an individual β blocker. Highly lipid soluble β blockers (e.g. metoprolol, propranolol) are well absorbed, undergo extensive pre-systemic elimination (first pass effect), cross the blood brain barrier, eliminated by liver and are short acting.
Water soluble (e.g. atenolol, sotalol, nadolol) β blockers are poorly absorbed, undergo little (if any) pre-systemic elimination, excreted unchanged in the urine and are long acting. They are less likely to enter the brain and may therefore cause less sleep disturbances and nightmares. Water soluble β blockers do not interact with drugs that influence liver metabolizing capacity. β blockers that are partly lipid soluble (e.g. acebutolol, pindolol, timolol) are eliminated by renal and hepatic routes and are less likely to accumulate in patients with liver or kidney disease.
iv. Membrane Stabilizing Activity (MSA):
Certain β blockers, notably propranolol, possess MSA, which implies that these drugs exert a local anesthetic, lignocaine like effect on cardiac conduction, but this action is only seen in doses in excess of those which produce β blockade and does not contribute to any antiarrhythmic properties. However, MSA inhibits the conversion of T4 to T3, which makes propranolol a very useful drug for symptomatic treatment of Grave’s disease, in which the hyperthyroid state is associated with widespread effects of adrenergic over stimulation.
Myocardial oxygen demand, particularly during stress or physical exertion, is reduced as a result of slowing the heart rate (negative chronoscopic action) and a decrease in the force of contraction (negative ionotropic action) due to blockade of β1receptors. All β blockers have antiarrhythmic properties. They increase atrial refractoriness by prolonging sinus node recovery and increase the period of conduction at the A-V node.
β blockers lower blood pressure due to the reduction in cardiac output, reduction in plasma renin and aldosterone activity, release of vasodilator prostaglandins and possibly due to CNS mediated antihypertensive action. Labetalol further reduces peripheral vascular resistance due to their combined α and β adrenoreceptor blocking properties. Celiprolol has in addition, a direct vasodialating action on the arterioles.
β blockers cause bronchospasm, particularly in patients with asthma. Cardio selective β blocker possessing PAA (celiprolol) are preferred in asthmatic patients.
Hypoglycemia and impaired glucose tolerance may arise as a result of blockade of β2 receptors in the liver. β blockers are associated with increased triglyceride levels and a reduction in the ratio of high density to low density lipoprotein cholesterol. Cardio-selective are less likely to cause dyslipidemia.
Central nervous system:
Lipid soluble β blockers may cause adverse effects such as sleep disturbances and other psychotic changes.
β blockers are widely used drugs in cardiovascular disorders which include:
i. Angina pectoris:
β blockers play a major role in the prophylaxis of angina and are widely used alone or in combination with long acting nitrates or calcium antagonists. Their antiarrhythmic action may confer additional protection on ischemic myocardium.
β blockers continue to be first line drugs in the treatment of essential hypertension. Atenolol amongst others has been increasingly used and remains a drug of first choice. Celiprolol, a new generation cardio-selective β blocker has the advantage of possessing selective β2 partial agonist activity and direct vasodilator action and causing less impairment of glucose tolerance or causing hypo-glycaemia or dyslipidemia.
iii. Cardiac arrhythmias:
All β blockers are class II antiarrhythmic drugs. They are used in stress or exercise induced sinus tachycardia and paroxysmal atrial tachycardia.
iv. Cardiac failure:
Bisoprolol, carvedilol and metoprolol reduce the morbidity and mortality and are considered to be amongst the first line of drugs for treatment of heart failure.
v. Myocardial infarction:
Intravenous β blockers (e.g. atenolol, metoprolol, propranolol, sotalol) are useful in the acute stage of myocardial infarction, as they suppress ventricular fibrillation, reduce infarct size and limit early mortality and morbidity. Their routine oral use has been found to reduce mortality in myocardial infarction.
Nonselective β blockers (propranolol, nadolol) relieve the symptoms such as fine tremors, excessive sweating, palpitation, which are due to catecholamine excess in thyrotoxicosis.
vii. Portal hypertension:
Propranolol and other nonselective β blockers reduce portal pressure and prevent recurrent bleeding from varices or gastric erosions.
β blockers reduce aqueous humor production as a result of their effects on sympathetic innervations in the ciliary epithelium. Timolol is the most active and is used as 0.25% eye drops in open angle glaucoma.
β blockers without PAA (e.g. propranolol, metoprolol, timolol, nadolol) are effective in preventing migraine headache. They are less effective, once the headache has begun.
β blockers, in particular propranolol, are very effective in anxiety resulting from an acute stress (situational anxiety) such as that provoked by an examination or public performances. In chronic generalized anxiety states, benzodiazepines are more effective.
Cardiac side effects (e.g. sinus bradycardia, heart failure), bronchospasm, and cold extremities can be troublesome, but are not usually severe. Occasionally, β blockers cause sleep disturbances, vivid dreams, hallucinations and mood changes. They mask the usual warning symptoms of hypo-glycaemia and can be dangerous in patients with diabetes.
β blockers can cause adverse effects on lipid profile. Nonselective β blockers may cause an increase in triglyceride levels and decreased HDL cholesterol, which generally do not occur with β blockers possessing PAA. β blockers are contraindicated in severe, symptomatic or “brittle” asthma, uncontrolled heart failure, and cardiogenic shock.
Essay # 2. Drugs Used for Treating the Diseases of Parasympathetic Nervous System:
1. Parasympathomimetic Drugs:
These are the drugs which produce actions similar to that of Ach, either by directly interacting with cholinergic receptors or by preventing the hydrolysis of Ach by acetylcholinesterase (anticholiesterase drugs).
Ach reduces the rate of spontaneous depolarization of the sinoatrial node and decreases the heart rate. Ach delays impulse conduction within the atrial musculature shortening the effective refractory period. Delay in impulse conduction and shortening of the effective refractory period of the atrial musculature may initiate or perpetuate atrial arrhythmias.
At the A-V node and His-Purkinje fibres, Ach reduces conduction velocity, increases the effective refractory period, and thus diminishes the ventricular rate during atrial flutter or fibrillation. Ach markedly reduces the force of atrial contraction, but has no effect on ventricular muscle.
Ach causes generalized vasodilation, though only few (skin) receive cholinergic innervations. Vasodilation is primarily mediated through the release of endothelium dependent relaxing factor (EDRF), which in all probability is nitric oxide (NO). Ach, as such, is not involved in the regulation of peripheral resistance.
Ach increases the tone of GIT smooth muscle, enhances peristaltic activity, and relaxes GIT sphincters. Ach stimulates and enhances the secretion of gastrin, secretin, and insulin.
Genitourinary and respiratory systems:
Ach increases ureteral peristalsis, contracts the urinary detrusor muscle, and relaxes the trigone and sphincter and plays an important role in the coordination of urination. Ach increases tracheobronchial secretions and causes bronchial constriction.
Ach produces contraction of the circular muscle of iris, causing pupillary constriction (miosis) and that of ciliary muscle causing spasm of accommodation. Ach facilitates the outflow of aqueous into the canal of Schlemm, by pulling the root of the iris centrally and thus relieving the obstruction, if any, imposed by trabecular meshwork.
Ach stimulates the salivary, sweat, and lacrimal glands.
Ach stimulates both sympathetic and parasympathetic ganglia.
Ach stimulates the skeletal muscles resulting in muscle twitching and fasciculation.
Directly acting parasympathomimetic drugs are seldom used for systemic actions, since their widespread effects are particularly dangerous on the heart and bronchi.
Ach itself has no therapeutic role because of its rapid hydrolysis by acetyl cholinesterase and plasma cholinesterase.
Methacholine is hydrolyzed only by acetyl cholinesterase and therefore has a longer duration of action than Ach. It exerts purely muscarinic effects and not used in therapy.
Carbachol is not hydrolyzed by cholinesterase’s and its actions are more prolonged. Carbachol is mainly used in the treatment of urinary retention following surgical operation or childbirth when there is no mechanical obstruction. It causes contraction of the bladder muscles, resulting in the passage of urine. It is given by SC injection or orally. Its action lasts unto an hour. Adverse effects include colic, diarrhea and a marked fall in blood pressure which can be controlled by atropine.
Bethanechol is resistant to hydrolysis by cholinesterase and has mainly muscarinic action. It stimulates the GIT and genitourinary smooth muscles with minimal effects on CVS. It is the only directly acting parasympathomimetic, which is rarely used for urinary retention in absence of outflow obstruction and less commonly, in GIT disorders, such as postvagotomy gastric atony.
Pilocarpine has prominent muscarinic actions like methacholine and is only used as eye drops in glaucoma, especially before operation for angle closure glaucoma.
Muscarine is found in poisonous mushrooms and is only of toxicological importance.
Arecoline is found in betel nut Areca catechu. It has nicotinic as well as muscarinic actions and prominent CNS effects. It has no therapeutic use.
viii. Anticholinesterase Drugs:
These drugs prevent the breakdown by cholinesterase of Ach produced at nerve endings throughout the body. Except for quantitative differences, their actions are similar to Ach. Lipid soluble drugs (physostigmine and organophosphates) have more marked muscarinic and CNS effects, while lipid insoluble drugs (neostigmine and related other quarternary amines) have marked actions on the skeletal muscles.
All anticholinesterases produce similar adverse effects (muscarinic effects) due to the prolongation of the actions of Ach, such as intestinal colic and diarrhea, sweating and salivation, constricted pupil, bradycardia and hypotension. IV atropine blocks the muscarinic actions of anticholinesterases.
ix. Physostigmine (Eserine):
Physostigmine is a tertiary amine alkaloid, is lipid soluble, is well absorbed and penetrates into CNS and the cornea.
Physostigmine has predominant effects on muscarinic receptors, autonomic ganglia and CNS.
Physostigmine has been used as eye drops, especially for simple and secondary glaucoma and parenterally for the reversal of intoxication by drugs with a central anticholinergic action such as atropine, phenothiazines and tricyclic antidepressants.
x. Neostigmine (Prostigmin):
Neostigmine, a quarternary ammonium compound, is poorly absorbed, does not penetrate CNS and has prominent action on skeletal muscles, which is both a direct action as well as due to blockade of acetylcholiesterase. It is used for the treatment of myasthenia gravis along with atropine to prevent muscarinic actions such as colic, excessive salivation or diarrhea. The actions on eye and cardiovascular system are less marked than physostigmine. Neostigmine is also used to reverse the actions of non-depolarising muscle relaxants, in paralytic ileus and atony of the bladder.
Pyridostigmine is similar to neostimine in all respects except that it is less potent and has a longer duration of action. It is preferable to neostigmine in myasthenia gravis because of its smoother action and the need of less frequent dosage.
Endrophonium has a very brief action and is used mainly for the diagnosis of myasthenia gravis and also to determine over dosage or under dosage of anticholinesterase drugs in myasthenia gravis. A single test dose of endrophonium causes substantial improvement in muscle power in myasthenia gravis (myasthenia crisis), while if the treatment with cholinergic drugs is excessive, an injection of endrophonium will intensify symptoms of the disease (cholinergic crisis).
Demearium is more potent and has a longer duration of action than neostigmine and is mainly indicated in the treatment of glaucoma.
Distigmine is a longer acting neostigmine analogue and may be used for the treatment of myasthenia gravis and urinary retention.
Ambenonium is approximately six times more potent than neostigmine, with marked direct stimulant action on skeletal muscles. It is mainly used in the treatment of myasthenia gravis.
Myasthenia Gravis (MG):
Myasthenia gravis is an autoimmune disorder that involves the postsynaptic nicotinic Ach receptors at the neuromuscular junction and is often associated with thymus tumors. It is characterized by ptosis, diplopia, dysarthria, dysphagia, extremity weakness and respiratory difficulty.
The treatment of myasthenia gravis consists of:
a. Anticholinesterase drugs
c. Immunosuppressive drugs
Anticholiesterase drugs provide symptomatic treatment. Pyridostigmine is generally give orally three or four times daily in doses of 30-60 mg. Neostigmine methylsulphate, as IV infusion is an alternative for patients who are not able to take medication orally.
Thymectomy is an effective treatment for generalised MG and provides complete remission in many patients. Thymectomy is performed electively for moderate to marked generalized MG, early in the course of the disease, and if response to medical treatment is unsatisfactory.
Immunosuppressive drug are used to supplement the effects of cholinesterase inhibitors. Prednisone is frequently used to achieve rapid improvement. Azathioprine and cyclosporine are the alternatives. Cyclophosphamide and IV human immunoglobulin may be beneficial in selected refractory patients.
Plasmapheresis (replacement of the patient’s plasma with type specific fresh frozen plasma albumin) can be used to treat acute exacerbations, impending crisis and disabling MG that is refractory to other therapies. The benefits are temporary and lack specific indications. Hypotension and thromboembolism are common complications.
xvi. Irreversible Anticholinesterases:
These are organophosphorus compounds, which are not used therapeutically, but are extensively employed as insecticides. They can be absorbed from the skin and lungs if inhaled, and may result in poisoning. The treatment of poisoning consists of atropine (1 mg) intravenously followed by a cholinesterase reactivator.
xvii. Pralidoxime (PAM):
Pralidoxime reactivates cholinesterase by separating it from irreversible anticholinesterase. It is used, as an adjunct to atropine in organophosphate poisoning, to restore neuromuscular transmission.
The adverse effects of parasympathomimetic drugs are similar. The symptoms include intestinal colic, diarrhea, sweating and salivation. The pupils are constricted, the pulse is slow and the blood pressure is low. Parasympathomimetic drugs are contraindicated in patients with coronary insufficiency, hyperthyroidism, peptic ulcer and asthma.
2. Parasympatholytic Drugs:
These are the drugs, which inhibit the actions of Ach after it has been released from parasympathetic nerve endings and are better known as antimuscarinics. They belong to the belladonna group or are its synthetic substitutes.
Atropine is an alkaloid derived from the plant Atropa belladonna. Atropine is well absorbed when given orally. The liver largely breaks it down.
Atropine increases the heart rate and enhances A-V conduction, due to blockade of inhibitory vagal impulses to the SA node. There is no significant effect on blood pressure.
Central nervous system:
Atropine has an overall CNS stimulant action, which is not seen with therapeutic doses. It possesses anti-tremor activity due to blocking of the relative cholinergic over-activity in basal ganglia. High doses can produce hallucinations and ultimately coma.
Atropine relaxes all smooth muscles. Tone, amplitude and frequency of contraction of stomach and intestines are decreased. It relaxes the ureter and urinary bladder, but increases the tone of the vesical sphincter. Relaxation of biliary tract is less marked. Atropine produces slight bronchodilation.
Atropine markedly decreases the sweat, salivary, tracheobronchial and lachrymal secretions. Larger doses decrease gastric secretions.
Topical instillation of atropine blocks the Ach response of the ciliary muscle and the circular smooth muscles of the iris, producing paralysis of accommodation (cycloplegia) and dilation of pupil (mydriasis). Its action lasts for 7-10 days. The intraocular tension tends to rise, especially in narrow angle glaucoma.
The use of atropine, because of its widespread effects, is restricted to topical instillation or for short-term treatment of certain acute conditions.
The principal uses of atropine are:
a. For refraction procedures in children and for treatment of uveitis to prevent posterior synechia (eye ointment 1 % or drops 0.5-1%).
b. For intestinal, biliary or renal colic (600 microgram parenterally).
c. Bradycardia, particularly, if complicated by hypertension after myocardial infarction.
d. To reverse muscarinic actions in organ phosphorus poisoning (2 mg IM or IV) every 20 to 30 minutes until the skin becomes flushed and dry, the pupils dilate and tachycardia develops.
These are dose related. Dry mouth, constipation, urinary urgency and retention, dilatation of pupil with loss of accommodation, reduced bronchial secretions; flushing and dryness of the skin are common. Higher doses of atropine cause restlessness, hallucinations and delirium. Parasympatholytics are contraindicated in glaucoma, paralytic ileus, pyloric stenosis and prostatic enlargement.
ii. Hyoscine (Scopolamine):
Hyoscine is an alkaloid, has anti-muscarinic actions like atropine. Hyoscine has more potent action on the eye and exocrine glands, but is less potent than atropine in its actions on the heart and smooth muscles. Unlike atropine, hyoscine is a CNS depressant. Hyoscine, even in small doses, causes drowsiness and sleep. Hyoscine is the most effective drug for the prevention of motion sickness. It is often used in children for premedication to allay the apprehension in the preoperative period.
iii. Atropine Substitutes:
Many semisynthetic derivatives of belladonna alkaloids and synthetic substitutes are available and in general, they are all capable of producing atropine like side effects. There are, however, differences between them which may affect choice in treating a particular disease.
Atropine substitutes can be grouped according to their clinical indication based on selectivity of action.
Dicycloverine (tertiary amine) and quaternary ammonium compounds such as propantheline and hyoscine butylbromide are used to relieve the spasm of GIT smooth muscles in irritable bowel syndrome and in diverticular disease. The quaternary ammonium compounds are lipid insoluble, less liable to cross the blood brain barrier and may not produce atropine like CNS side effects, but the peripheral atropine like effects are common.
Alverine and mebeverine:
Alverine and mebeverine are direct relaxants of intestinal muscle and relieve pain in irritable bowel syndrome and diverticular disease without causing any serious atropine like side effects. Oxybutynin, flavoxate and tolteridine are the antimuscarinic drugs which are used as urinary antispasmodics in patients with frequency and other urinary problems. Oxybutynin has high incidence of side effects and may cause convulsions in children.
b. Mydriatics and Cycloplegics:
Homatropine (1 and 2% eye drops) is much less potent than atropine; mydriasis lasts for 1-3 days while accommodation recovers in 1 day. It is used in the treatment of anterior segment inflammation and is preferred for its short duration of action.
Cyclopentolate (0.5 and 1% eye drops) is a potent and rapidly acting drug. Mydriasis and cycloplegia last for a day. It is preferred for producing cycloplegia for refraction in young children. Tropicamide (0.5 and 1% eye drops) is a relatively weak and short acting mydriatic and is commonly used for the examination of the fundus of the eye.