AUTONOMIC NERVOUS SYSTEM

Autonomic nervous system

Anti-cholinergics

A: Classification

1.      Natural alkaloids: Atropine, hyoscine,

2.      Semi-synthetic derivatives :Homatropine atropine methonitrate, hysocine butyl bromide, ipratropium bromide, iotropoium bromide

3.      Synthetic compounds

a.       Mydriatics: cyclopentolate, tropicamide

b.      Antisecretory-antispasmodics:

i.                    Quarternary compounds: propantheline, oxyphenonium, clidinium, pipenzolate, methyl bromide, isopropainde, glycopyrrolate

ii.                  Tertiary amines: dicyclomine, valethamate, pirenzepine

c.       Vasico-selective: oxybutynin, flavoxate, tolterodine

d.      Antiparkinonism: benzhexol, procyclidine, biperidin

PHARMACOLOGICAL ACTIONS of ATROPINE

Heart: Intravenous administration of low doses of atropine produces slight bradycardia, due to effect on CNS, but at higher doses produce tachycardia by directly blocking parasympathetic input to sinoatrial node. Antagonism of these presynaptic muscarinic receptors prevents feedback inhibition and increases release of ACh. Atropine can also facilitate atrioventricular (A-V) conduction and block parasympathetic effects on cardiac conduction system and on myocardial contractility.

Blood Vessels: Atropine produces minimal effects on circulation in absence of circulating muscarinic agonists. This reflects minor role of cholinergic innervations in determining vascular smooth muscle tone. Atropine can produce flushing in blush area owing to vasodilation. It is not known whether it is direct effect or response to hyperthermia induced by drug’s ability to inhibit sweating.

Gastrointestinal Tract:-Muscarinic antagonists have numerous effects on digestive system. The inhibition of salivation by low doses of atropine results in dry mouth and difficulty in swallowing. Antimuscarinic drugs also inhibit gastric acid secretion and gastrointestinal motility, because both processes are partly under control of vagus nerve.

Large doses of atropine are required to inhibit acid secretion, and side effects such as dry mouth, tachycardia, ocular disturbances, and urinary retention are drawbacks to use of muscarinic antagonists in treatment of peptic ulcers.

Bladder:-Muscarinic antagonists can cause urinary retention by blocking excitatory effect of ACh on detrusor muscle of bladder. During urination, cholinergic input to this smooth muscle is activated by a stretch reflex.

Central Nervous System:-Although atropine and scopolamine share many properties,an important difference is easier entry of scopolamine into CNS. Typical doses of atropine have minimal central effects, while larger doses produce constellation of responses collectively termed central anticholinergic syndrome. At intermediate doses, memory and concentration may be impaired, and drowsy. If doses of 10 mg or more are used, the patient may exhibit confusion, excitement, hallucinations, ataxia, asynergia, and possibly coma.

Eye:-Antimuscarinic drugs block contraction of iris sphincter and ciliary muscles of eye produced by ACh.This results in dilation of pupil and paralysis of accommodation responses that cause photophobia and inability to focus on nearby objects. Ocular effects are produced only after higher parenteral doses and produce responses lasting several days when applied directly to eyes.

Lung:-Muscarinic antagonists inhibit secretions and relax smooth muscle in respiratory system. The parasympathetic innervation of respiratory smooth muscle is abundant in large airways, where it exerts a dominant constrictor action. Muscarinic antagonists produce their bronchodilator effect at large-caliber airways. These drugs are potent inhibitors of secretions throughout respiratory system, from nose to bronchioles.

Nicotinic Receptors:-Antimuscarinic drugs are normally selective for muscarinic cholinergic receptors, high concentrations of agents with a quaternary ammonium group

(e.g., propantheline) can block nicotinic receptors on autonomic ganglia and skeletal muscles.

ABSORPTION, METABOLISM, AND EXCRETION

Well absorbed from GIT and conjunctiva and can cross blood-brain barrier. After i.v. injection of atropine, is excreted unchanged in urine. The active isomer, can undergo dealkylation, oxidation, and hydrolysis. These compounds are eliminated in feces following oral administration. The blood-brain barrier prevents quaternary ammonium muscarinic blockers from gaining significant access to CNS.

CLINICAL USES

Cardiovascular Uses of Atropine:

It is useful in patients with carotid sinus syncope.

It can be used in differential diagnosis of S-A node dysfunction.

If sinus bradycardia is due to extra cardiac causes, it can elicit a tachycardiac response, but it cannot elicit tachycardia if bradycardia results from intrinsic causes.

It is useful in treatment of acute myocardial infarction.

It is used to induce positive chronotropy during cardiopulmonary resuscitation.

As atropine sulfate is beneficial in patients whose bradycardia is accompanied by hypotension or ventricular ectopy, it is not otherwise recommended.

Uses in Anesthesiology: Atropine was routinely administered before for induction of general anesthesia to block excessive salivary and respiratory secretions induced by inhalation anesthetics (e.g., diethyl ether).

Use with Cholinesterase Inhibitors: During reversal of competitive neuromuscular blockade with neostigmine or other anticholinesterase agents and in management of myasthenia gravis with cholinesterase inhibitors, atropine should be given to prevent stimulation of muscarinic receptors that accompanies excessive inhibition of AChE.

Uses in Ophthalmology: Antimuscarinic drugs are widely used in ophthalmology to produce mydriasis and cycloplegia. These actions permit an accurate determination of the refractive state of eye, and antimuscarinics are also useful in treating specific ocular diseases and for the treatment of patients following iridectomy.

Uses in Disorders of the Digestive System: Nonselective antimuscarinic drugs have been employed in therapy of peptic ulcers, as they reduce gastric acid secretion; they also used as adjunctive therapy in treatment of irritable bowel syndrome. Antimuscarinic drugs can decrease pain associated with postprandial spasm of intestinal smooth muscle by blocking contractile responses to ACh.

Uses in Respiratory Disorders: Muscarinic receptor–blocking drugs are used in therapy of asthma, but they have displaced by adrenergic drugs. The problems associated with use of anti-muscarinic alkaloids in respiratory disorders are low therapeutic index and impaired expectoration.

Uses in Parkinsonism: Antimuscarinic agents can have beneficial effects in treatment of parkinsonism, since there is an apparent excess of cholinergic activity in striatum of patients suffering from this disorder. Antimuscarinics are sometimes employed for mild cases and in combination with other agents (e.g., levodopa) for treatment of advanced cases.

Uses in Motion Sickness: Scopolamine is useful for prevention of motion sickness when the motion is very stressful and of short duration.

Uses as Antidotes for Cholinomimetic Poisoning: Atropine is used as antidote in poisoning by overdose of a cholinesterase inhibitor. It also is used in cases of poisoning from species of mushroom that contain high concentrations of muscarine and related alkaloids.

Adrenergic drugs

Classification

1.      Adrenergic drugs used for raising blood pressure: noradrenaline, metaraminol and phenylephrine

2.      Those used for their inotropic actions on heart: dopamine, dobutamine, isoprenaline

3.      Those used as central stimulants: amphetamine, dextroamphetamine and methyphenidate

4.      Those used as smooth muscle relaxants

a.       Nonselective beta stimulants such as adrenaline, isoprenaline, isoxsuprine

b.      Selective beta-2 stimulants: salbutamol, terbutaline

5.      Those used in allergic reactions: adrenalaine, ephedrine

6.      Those used for local vasoconstrictor effect: adrenaline, naphazoline, pheylephrine, xylometazoline

7.      Those used for suppressing the appetite: fenfluramine, phenteramine

PHARMACOLOGICAL ACTIONS of Adrenaline

a.                   Vascular Effects: The blood vessels of skin and mucous membranes predominantly contain α-adrenoceptors. Epinephrine produces powerful constriction in these tissues, substantially reducing blood flow through them.

The blood vessels in visceral organs, including kidneys, contain predominantly α-adrenoceptors, although some β2-adrenoceptors are also present. Consequently, epinephrine cause vasoconstriction and reduced blood flow through kidneys and other visceral organs.

Epinephrine has complex action on blood vessels because of its high affinity for both α- and β2-adrenoceptors.Whether epinephrine produces vasodilatation or vasoconstriction in skeletal muscle depends on dose. Low doses of epinephrine will dilate blood vessels; larger doses will constrict them.

Although several factors can influence flow of blood through coronary vessels, the most important of these is local production of vasodilator metabolites that results from stimulation-induced increased work by heart. α- and β-adrenoceptors in coronary vascular beds do not play a major role in determining  vasodilator effects of administration of epinephrine.

b.                  Effects on Intact Cardiovascular System: A small dose causes fall in mean and diastolic pressure with little or no effect on systolic pressure.This is due to net decrease in total peripheral resistance that results from vasodilatation in skeletal muscle vascular bed.

The i.v. infusion or s.c. administration increases systolic pressure, but diastolic pressure is decreased. Therefore, mean pressure may decrease, remain unchanged, or increase slightly, depending on balance between rise in systolic and fall in diastolic blood pressures.

The cardiac effects are due to its action on β-adrenoceptors in heart. The rate and contractile force of heart is increased; consequently, cardiac output is markedly increased.

Because total peripheral resistance is decreased, increase in cardiac output cause increase in systolic pressure. Since epinephrine causes little change in mean arterial blood pressure, reflex slowing of heart is not seen in humans.

c.                   Effects on Smooth Muscles: The effects of epinephrine on smooth muscles of different organs and systems depend on type of adrenergic receptor in muscle. Gastrointestinal smooth muscle is, relaxed by epinephrine. This effect is due to activation of both α and β receptors.

Intestinal tone and frequency and amplitude of spontaneous contractions are reduced. The stomach is relaxed and pyloric and ileocecal sphincters are contracted, but these effects depend on preexisting tone of muscle. If tone already is high, epinephrine causes relaxation; if low, contraction.

The responses of uterine muscle to epinephrine vary with species, phase of sexual cycle, state of gestation, and dose given. During last month of pregnancy and at parturition, epinephrine inhibits uterine tone and contractions.

Epinephrine relaxes detrusor muscle of bladder due to activation of β-receptors and contract trigone and sphincter muscles owing to its agonist activity. This can result in hesitancy in urination and may contribute to retention of urine in bladder. Activation of smooth muscle contraction in prostate promotes urinary retention.

d.                  Respiratory Effects: Epinephrine affects respiration primarily by relaxing bronchial muscle. It has powerful bronchodilator action; evident when bronchial muscle is contracted as in bronchial asthma, or in response to drugs or various autacoids. In such situations, epinephrine has therapeutic effect as a physiological antagonist to substances that cause broncho-constriction.

e.                   Central Nervous System Effects: Because of inability of polar compound to enter CNS, epinephrine in conventional therapeutic doses is not a powerful CNS stimulant. While drug may cause restlessness, apprehension, headache, and tremor in many persons, these effects in part may be secondary to effects of epinephrine on cardiovascular system, skeletal muscles, and intermediary metabolism. Some other sympathomimetic drugs readily cross blood-brain barrier.

f.                   Metabolic Effects: Epinephrine elevates concentrations of glucose and lactate in blood. Insulin secretion is inhibited through interaction with α₂ receptors and is enhanced by activation of β₂ receptors; the predominant effect seen with epinephrine is inhibition. Glucagon secretion is enhanced by an action on β receptors of α cells of pancreatic islets. It decreases uptake of glucose by peripheral tissues, because of its effects on secretion of insulin. Glycosuria rarely occurs. The effect of epinephrine to stimulate glycogenolysis in most tissues involves β receptors.

Epinephrine raises concentration of free fatty acids in blood by stimulating β-receptors in adipocytes. The result is activation of triglyceride lipase, which accelerates triglyceride breakdown to free fatty acids and glycerol.

Absorption, Fate, and Excretion: Epinephrine is not effective orally because it is rapidly conjugated and oxidized in GI mucosa and liver. Absorption from s.c. tissues occurs slowly because of local vasoconstriction and rate may be further decreased by systemic hypotension. Absorption is more rapid after i.m., injection. In emergencies, it is administered i.v.ly.

Rapidly inactivated in liver, which is rich in both enzymes (COMT and MAO) responsible for destroying circulating epinephrine. Small amounts appear in urine of normal persons, the urine of patients with pheochromocytoma may contain large amounts of epinephrine and their metabolites.

CLINICAL USES of Epinephrine

a.                   It is useful for treatment of allergic reactions that are due to liberation of histamine in body, because it produces certain physiological effects opposite to those produced by histamine.

b.                  It is primary treatment for anaphylactic shock and is useful in therapy of urticaria, angioneurotic edema, and serum sickness.

c.                   It also been used to lower intraocular pressure in open-angle glaucoma. Its use promotes an increase in outflow of aqueous humor, its use is contraindicated in angle-closure glaucoma; under these conditions the outflow of aqueous humor via filtration angle and into venous system is hindered, and intraocular pressure may rise abruptly.

d.                  The vasoconstrictor actions of epinephrine are used to prolong action of local anesthetics by reducing local blood flow in region of injection.

e.                   It is used as topical hemostatic agent for control of local hemorrhage.

Toxicity, Adverse Effects, and Contraindications:

Epinephrine may cause disturbing reactions, such as restlessness, throbbing headache, tremor, and palpitations. The effects rapidly subside with rest, quiet, recumbency, and reassurance.

More serious reactions include cerebral hemorrhage and cardiac arrhythmias. The use of large doses or accidental, rapid intravenous injection of epinephrine may result in cerebral hemorrhage from sharp rise in blood pressure. Ventricular arrhythmias may follow administration of epinephrine. Angina may be induced by epinephrine in patients with coronary artery disease.

The use of epinephrine is contraindicated in patients who are receiving nonselective β-receptor blocking drugs, since its unopposed actions on vascular α₁ receptors may lead to severe hypertension and cerebral hemorrhage.

Sympatholytics

Classification

A.    Alpha adrenergic blocking agents

a.       Non-equilibrium type: beta-haloalkylamines-phenoxybenzamine

b.      Equilibrium type

1.      Non-selective:

i.        Ergot alkaloids: ergotamine, ergotoxine

ii.      Halogenated ergot alkaloids: dihyrdoergotoxine, dihydroergotamine

iii.    Imidazodiones: tolazolidine, phentolamine

iv.    Misc: chlorpromazine

2.      Alpha1 selective: prazosin, terazosin, doxazosin, tamsulosin

3.      Alpha2 selective: yohimbine

B.     Beta adrenergic blocking agents

1.      Cardioselective beta1 blockers: acebutolol, atenolol, metoprolol, bisoprolol and esmolol

2.      Non-selective beta1 and 2 blockers:

a.       Beta blockers with membrane stabilizing activity: propranolol

b.      Beta blockers with membrane stabilizing activity and instrinsic sympathomimetic activity: oxprenolol, pindolol

c.       Selective beta blockers: timolol, nadolol.

d.      Misc: sotalol

3. beta blockers with additional alpha blocking property: labetalol, celiprolol and carvedilol

Pharmacological Actions

Effects on Respiratory Tract-Blockade of β₂ receptors in bronchial smooth muscle may lead to increase in airway resistance, in patients with asthma. Beta₁-receptor antagonists such as metoprolol and atenolol have advantage over nonselective β-antagonists when blockade of β₁ receptors in heart is desired and β₂-receptor blockade is undesirable. However, no β₁-selective antagonist is specific to completely avoid interactions with β₂ adrenoceptors. Consequently, these drugs should be avoided in patients with asthma.

Effects on Eye-Several β-blocking agents reduce intraocular pressure, especially in glaucomatous eyes. The mechanism usually reported is decreased aqueous humor production.

Effects on Cardiovascular System-Beta-blocking drugs given chronically lower blood pressure in patients with hypertension. The mechanisms involved are not fully understood but include effects on heart and blood vessels, suppression of renin-angiotensin system, and perhaps effects in CNS or elsewhere. In contrast, conventional doses of these drugs do not cause hypotension in healthy individuals.

Beta-receptor antagonists have prominent effects on heart and are valuable in treatment of angina and chronic heart failure and following myocardial infarction

Metabolic and Endocrine Effects-Beta-receptor antagonists such as propranolol inhibit sympathetic nervous system stimulation of lipolysis. The effects on carbohydrate metabolism are less clear, though glycogenolysis in liver is partially inhibited after β₂-receptor blockade. However, glucagon is primary hormone used to combat hypoglycemia. β-antagonists should be used with caution in insulin-dependent diabetic patients. Beta₁-receptor–selective drugs may be less prone to inhibit recovery from hypoglycemia. Beta-receptor antagonists are much safer in type 2 diabetic patients who do not have hypoglycemic episodes.

Effects Not Related to Beta-Blockade-Partial β-agonist activity was significant in first β-blocking drug synthesized, dichloroisoproterenol. It has been suggested that retention of some intrinsic sympathomimetic activity is desirable to prevent untoward effects such as precipitation of asthma or excessive bradycardia.

Clinical Uses

Hyperthyroidism-β-blockers significantly reduce peripheral manifestations of hyperthyroidism, particularly elevated heart rate, increased cardiac output, and muscle tremors. Although β-blockers can improve clinical status of hyperthyroid patient.They are most logically employed in management of hyperthyroid crisis, in preoperative preparation for thyroidectomy, and during initial period of administration of specific anti-thyroid drugs.

Glaucoma-β-Blockers can be used topically to reduce intraocular pressure in patients with chronic open-angle glaucoma and ocular hypertension. The mechanism by which ocular pressure is reduced appears to depend on decreased production of aqueous humor. The β-blockers also are beneficial in treatment of acute angle-closure glaucoma.

Anxiety States-Patients with anxiety have variety of psychic and somatic symptoms.The peripheral manifestations of anxiety include symptoms (e.g., palpitations).The β-blocking agents may offer benefit in treatment of anxiety.

Migraine-The β-blockers has value in prophylaxis of migraine headache, possibly because a blockade of craniovascular β-receptors results in reduced vasodilation. The painful phase of a migraine attack is believed to be produced by vasodilation.

Absorption, Metabolism, and Excretion

Absorption from GIT is extensive. The peak therapeutic effect after oral administration occurs in 1 to 1.5 hours. Plasma half-life is approximately 3 hours. Drug is concentrated in lungs and to lesser extent in liver, brain, kidneys, and heart. Binding to plasma proteins is extensive (90%). Metabolized in liver, and drug is subject to significant degree of first-pass metabolism and excreted from urine.

Adverse Effects and Contraindications

a.      Most prominent side effects are those directly attributable to their ability to block β-receptors.

b.      Although β-blockers prevent an increase in heart rate and cardiac output resulting from activation of autonomic nervous system, these effects may not be troublesome in patients with adequate or marginal cardiac reserve. However, they can be life threatening for patient with CHF.

c.       Caution must be exercised in use of β-blockers in obstructive airway disease, since these drugs promote bronch-oconstriction.

d.      Cardioselective β-blockers have fewer propensities to aggravate broncho-constriction than do nonselective β-blockers.If β-blocker therapy is required, a cardioselective β-blocker is preferred.

e.       β-Blockers potentiate hypoglycemia by antagonizing catecholamine-induced mobilization of glycogen.

f.       Whenever β-blocker therapy is employed, the period of greatest danger for asthmatics or insulin dependent diabetics is during initial period of drug administration

g.      After high doses, patients may have hallucinations, nightmares, insomnia, and depression.

Anticholinestrases

Classification:

1.      Reversible anticholinesterases

a.       Carbamates: physostigmine, neostigmine, pyridostigmine, edrophonium, rivastigmine, donepazil, galantamine

b.      Acridine: tacrine

2.      Irreversible

a.       Organophosphates: dyflor, echothiophate, parathion, malathion, dizinon, tabun

b.      Carbamates: carbaryl, propoxur

Organophosphorous compounds are the organic esters, of phosphoric acid, are potent irreversible inhibitors of cholinesterase. Unlike quaternary ammonium Anti-AChE, most of these compounds have high lipid solubility. Ex: diflos, ecothiphate, parathion, malathion, diazinon and carbamate derivatives ex: propoxure and carbaryl.

Organophosphate insecticides undergo metabolic activation to yield an oxygenated metabolite that will react with active site of AChE, resulting inirreversible enzyme inhibition. Symptoms of poisoningare due to excessive stimulation of cholinergic receptors.In cases of lethal poisoning in humans, death isfrom respiratory failure.Distal neuropathy of lowerlimbs also has been seen.The carbamate insecticides also inhibit AChE. Themechanism of inhibition is similar, but the reaction is reversible.

Treatment

The first step in treatment of anticholinesterase poisoning should be injection of increasing doses of atropine sulfate to block all adverse effects resulting from stimulation of muscarinic receptors. Since atropine will not alleviate skeletal and respiratory muscle paralysis, mechanical respiratory support may be required.

If poisoning is due to organophosphate, prompt administration of pralidoxime chloride will result in dephosphorylation of cholinesterases in periphery and decrease in degree of blockade at skeletal neuromuscular junction. Since pralidoxime is quaternary amine, it will not enter CNS and therefore cannot reactivate central cholinesterases. It is effective only if no aging of phosphorylated enzyme. Pralidoxime has greater effect at skeletal neuromuscular junction than at autonomic effector sites.

Myasthenia gravis

It is an autoimmune disease in which antibodies recognize nicotinic cholinoreceptors on skeletal muscle.This decreases number of functional receptors and consequently decreases sensitivity of muscle to ACh. Muscle weakness and rapid fatigue of muscles during use are characteristics of disease.

Anticholinesterase agents help to alleviate weakness by elevating and prolonging concentration of ACh in synaptic cleft, producing activation of remaining nicotinic receptors. By contrast, thymectomy, plasmapheresis, and corticosteroid administration are treatments directed at decreasing autoimmune response.

Anticholinesterase agents play a key role in diagnosis and therapy of myasthenia gravis, because they increase muscle strength. During diagnosis, the patient’s muscle strength is examined before and immediately after i.v. injection of edrophonium chloride.

In myasthenics, an increase in muscle strength is obtained for a few minutes. The pronounced weakness result from inadequate therapy of myasthenia gravis can be distinguished from that due to anticholinesterase overdose by use of edrophonium. In cholinergic crisis, edrophonium will cause further weakening of muscles, whereas improvement in muscle strength is seen in myasthenic patient whose anticholinesterase therapy is inadequate. Means for artificial respiration should be available when patients are being tested for cholinergic crisis.

Pyridostigmine and neostigmine are major anticholinesterase agents used in therapy of myasthenia gravis, but ambenonium can be used when these drugs are unsuitable. When it is feasible, these agents are given orally.

Pyridostigmine has a slightly longer duration of action than neostigmine, with smoother dosing, and it causes fewer muscarinic side effects. Ambenonium may act somewhat longer than pyridostigmine, but it produces more side effects and tends to accumulate.

Other therapeutic measures should be considered as essential elements in management of this disease. Controlled studies reveal that glucocorticoids promote clinical improvement in high percentage of patients. Initiation of steroid treatment augments muscle weakness; however, as patient improves with continued administration of steroids, doses of anti-ChE drugs can be reduced. Other immunosuppressive agents such as azathioprine and cyclosporineare beneficial in more advanced cases.

Ganglion blockers

These agents competitively block the action of acetylcholine and similar agonists at nicotinic receptors of both parasympathetic and sympathetic autonomic ganglia. Some members of group also block ion channel that is gated by nicotinic cholinoceptor. The ganglion-blocking drugs are important and used in pharmacologic and physiologic research because they can block all autonomic outflow.

Classification

a.       Competitive blockers:

1.      Quarternary ammonium compounds: hexamethonium, pentolinium

2.      Amines: mecamylamine, pempidine

3.      Monosulfonium compound: trimehaphan camforsulfonate

b.      Persistent depolarizing blockers; Nicotine, anticholinesterases

Mechanism of Action

Drugs can block autonomic ganglia by several mechanisms. They may act presynaptically by affecting nerve conduction or neurotransmitter synthesis, release, or reuptake. Acting postjunctionally, drugs may affect interaction between ACh and its receptor, or they may affect depolarization of ganglion cell or initiation of propagated action potential.

Ganglionic nicotinic blockers can be divided into two groups. The first group, characterized by nicotine and related drugs (e.g., lobeline, tetraethylammonium), initially stimulates ganglia and then blocks them.These agents are not therapeutically useful.

The second groups of drugs, which have some therapeutic usefulness but rarely used, inhibit postsynaptic action of ACh and do not themselves produce depolarization, thereby blocking transmission without causing initial stimulation.

The site of action of many blocking drugs is associated at ionic channel rather than at receptor. Prolonged administration of ganglionic blocking drugs leads to development of tolerance to their pharmacological effects.

Pharmacological Actions of ganglion blockers

a.                  Central Nervous System: Mecamylamine, unlike quaternary amine agents and trimethaphan, crosses blood-brain barrier and readily enters CNS. Sedation, tremor, choreiform movements, and mental aberrations are seen as effects of mecamylamine.

b.                  Eye: Ganglion-blocking drugs cause predictable cycloplegia with loss of accommodation because ciliary muscle receives innervations from parasympathetic nervous system. The effect on pupil is not easily predicted, since iris receives both sympathetic innervations (mediating pupillary dilation) and parasympathetic innervation (mediating pupillary constriction). Ganglionic blockade often causes moderate dilation of pupil because parasympathetic tone dominates this tissue.

c.                  Cardiovascular System: Blood vessels receive vasoconstrictor fibers from sympathetic nervous system; therefore, ganglionic blockade causes marked decrease in arteriolar and venomotor tone. The blood pressure may fall precipitously, because both peripheral vascular resistance and venous return are decreased. Hypotension is marked in upright position (orthostatic or postural hypotension), because postural reflexes that normally prevent venous pooling are blocked.

Cardiac effects include diminished contractility and, because sinoatrial node is dominated by parasympathetic nervous system, a moderate tachycardia.

d.                 Gastrointestinal Tract: Secretion is reduced, although not effectively to treat peptic disease. Motility is profoundly inhibited, and constipation can be marked.

e.                   Other Systems:Genitourinary smooth muscle is partially dependent on autonomic innervation for normal function. Therefore, ganglionic blockade causes hesitancy in urination and may precipitate urinary retention in men with prostatic hyperplasia. Sexual function is impaired in that both erection and ejaculation may be prevented by moderate doses.

Thermoregulatory sweating is reduced by ganglion-blocking drugs. However, hyperthermia is not a problem except in very warm environments, because cutaneous vasodilation is sufficient to maintain normal body temperature.

f.                   Response to Autonomic Drugs: Patients receiving ganglion-blocking drugs are fully responsive to autonomic drugs acting on muscarinic, α-, and β-adrenergic receptors because these effector cell receptors are not blocked. In fact, responses may be exaggerated or even reversed (eg, norepinephrine may cause tachycardia rather than bradycardia).

Absorption, Fate, and Excretion:Absorption of quaternary ammonium and sulfonium compounds from enteric tract is incomplete and unpredictable. This is due both to limited ability of these ionized substances to penetrate cell membranes and to depression of propulsive movements of small intestine and gastric emptying.

After absorption, quaternary ammonium and sulfonium-blocking agents are confined primarily to extracellular space and are excreted unchanged by kidney.

Untoward Responses and Severe Reactions observed are visual disturbances, dry mouth, conjunctival suffusion, urinary hesitancy, decreased potency, subjective chilliness, moderate constipation, occasional diarrhea, abdominal discomfort, anorexia, heartburn, nausea, eructation, and bitter taste and signs and symptoms of syncope caused by postural hypotension.

More severe reactions include marked hypotension, constipation, syncope, paralytic ileus, urinary retention, and cycloplegia.

Therapeutic Uses

a.                   Hypertensive Cardiovascular Disease: Ganglionic blockers were once widely used in management of essential hypertension. Development of tolerance to these drugs and undesirable side effects resulting from their nonselective ganglion-blocking properties led to decline in use. They have completely replaced by more effective and less toxic drugs. They do, however, retain some usefulness in emergency treatment of hypertensive crisis.

b.                  Controlled Hypotension: Ganglionic blocking agents have been used to achieve controlled hypotension in plastic, neurological, and ophthalmological surgery. They are most commonly used in surgical procedures involving extensive skin dissection.

Cholinomimetics

Classification

A.    Cholinergic agonists:

a.       Choline esters: Acetyl choline, methacholine, carbachol, bethanechol

b.      Alkaloids: Muscarine, pilocarpine, arecoline

B.     Anticholinesterases

3.      Reversible anticholinesterases

c.       Carbamates: physostigmine, neostigmine, pyridostigmine, edrophonium, rivastigmine, donepazil, galantamine

d.      Acridine: tacrine

4.      Irreversible

c.       Organophosphates: dyflor, echothiophate, parathion, malathion, dizinon, tabun

d.      Carbamates: carbaryl, propoxur

Clinical Uses

Surgery of Eye-Direct application of Ach drops to exposed iris (during surgery produces complete and prompt miosis for about 2 hours. Such an effect facilitates iridectomy and especially valuable after removal of lens because in this case rapid closure of pupil is require to prevent a forward displacement of vitreous and impending retinal detachment.

Glaucoma: Cholinomimetic drugs are useful for treating glaucoma because they can decrease resistance to movement of fluid (aqueous humor) out of eye, thereby reducing intraocular pressure.

Adverse effects:

a)                  Muscarinic side effects: include CNS stimulation, miosis, spasm of accommodation for distant vision, broncho-constriction, abdominal cramps, flushing, sweating and salivation.

b)                  Nicotinic side effects: include CNS stimulation, ganglionic stimulation and neuromuscular end plate depolarization leading to fasciculation and paralysis

c)                  Others like hyperthyroidism, bronchial asthma, peptic ulcer, myocardial infarction.

Adrenergic receptors

Receptor	Location	Function	Agonist	Antagonist
β1	Post synaptic at cardiac muscle, Juxtaglomerular apparatus; also presynaptic at adrenergic and cholinergic nerve terminal	↑ heart rate ↑ force of contraction ↑ in renin release	Dobutamine	Metoprolol   Atenolol
β2	Post and presynaptic in bronchi, coronary arteries, uterus and smooth muscles also in myocardium	↑ NE release, relaxation of smooth muscle ↑ Glycogenolysis ↑ Heart rate ↑ Force of contraction	Salbutamol, terbutalin	α-methyl propranolol
β3	Post synaptic at adipocytes	↑ Lipolysis Thermogenesis	BRL 37344	ICI 118551
α1	Post synaptic, most smooth muscles, salivary glands, liver cells	↑ calcium concentration, contraction of smooth muscle, ↑ secretion	Phenyl ephrine, Methox- -amine	Prazosin
α2	Presynaptic on adrenergic or cholinergic nerve terminals; post synaptic in brain; β-pancreatic cells, vascular smooth muscle	↓ Norepinephrine release, ↓ central sympathetic outflow, ↓ insulin release, vasoconstriction	Clonidine	Yohimdine, Rauwolscine

Cholinergic receptors

Receptor	Location	Function	Agonist	Antagonist
NM (Nicotinic muscle type)	At skeletal neuromuscular junction; post synaptic	Contraction of skeletal muscle	Ach, succinyl choline, Phenyl trimethyl ammonium	Nicotine, dimethyl phenyl pipera-zinium, Epibatidine
NN (Nicotinic neural type)	At all autonomic ganglia and at adrenal medullar; postsynaptic	Transmission of impulse through autonomic ganglia and firing of post ganglionic neuron and secretion of NE & E from adrenal medulla	d-Tubo curarine,               α-Bungaro- -toxin	Hexametho-  -nium, trimetaphan, mecamylaine
M1 (muscarinic)	Neural: ganglia, gastric paracrine cells, CNS	Gastric acid secretion, GI motility, CNS excitation	oxotremorine	Pirenzepine, telenzepine
M2	Cardiac: SA node, AV node, atrium, ventricle, neural: pre synaptic terminals	SA node: ↓ rate of impulse generation, AV node: ↓ velocity of conduction, ↓ contractility; vagal bradycardia	Methcholine	Methoctramine, tripitramine
M3	Exocrine glands, smooth muscles, vascular endothelium	↑ exocrine secretions, smooth muscle contraction	Bethenechol	4-DAMP, Hexahydro-    -siladigenidol, Darfenacin

cholinesterase enzyme

There are two major types of cholinesterases:

1. Acetylcholinesterase (AChE) and 2. Pseudocholinesterase (pseudo-ChE).

1.                  AChE (true, specific, or erythrocyte cholinesterase) is found at number of sites in body, especially in cholinergic neuroeffector junction. Here it is localized to prejunctional and postjunctional membranes, where it rapidly terminates action of synaptically released ACh. It is essential to recognize that action of ACh is terminated only by its hydrolysis. There is no reuptake system in cholinergic nerve terminals to reduce concentration of ACh in a synaptic cleft. Therefore, inhibition of AChE can greatly prolong activation of cholinoreceptors by ACh released at a synapse.

2.                  Pseudo-ChE (butyryl-, plasma, and nonspecific cholinesterase) has a widespread distribution, with enzyme especially in liver, where it is synthesized, and in plasma. In spite of abundance of pseudo-ChE, its physiological function has not been definitively identified. It does, however, play an important role in metabolism of such clinically important compounds as succinylcholine, procaine, and numerous other esters.

Parkinsonism

It is a term that refers to symptoms of Parkinson’s disease, as well as Parkinson-like symptoms that may be seen with use of certain drugs, head injuries, and encephalitis.

Parkinson’s disease, also called paralysis agitans, is a degenerative disorder of CNS. The disease is thought to be caused by a deficiency of dopamine and an excess of acetylcholine within CNS. Parkinson’s disease affects the part of brain that controls muscle movement, causing such symptoms as trembling, rigidity, difficulty walking, and problems in balance. It is characterized by fine tremors and rigidity of some muscle groups and weakness of others.

Parkinson’s disease is progressive, that is symptoms become worse over time.

a.       As disease progresses, speech become slurred, face has masklike and emotionless expression, and patient may have difficulty chewing and swallowing.

b.      The patient may have shuffling and unsteady gait, and the upper part of body is bent forward.

c.       Fine tremors begin in the fingers with a pill-rolling movement, increase with stress, and decrease with purposeful movement.

d.       Depression or dementia may occur, causing memory impairment and alterations in thinking.

e.       Parkinson’s disease has no cure, but antiparkinsonism drugs are used to relieve the symptoms and assist in maintaining patient’s mobility and functioning capability as long as possible

Treatment of parkinsonism

For years, levodopa was drug that provided mainstay of treatment. Now, there are new drugs that are used either alone or in combination with levodopa. Entacapone, pramipexole, and ropinirole are newer drugs used in the treatment of Parkinson’s disease. Drug-induced parkinsonism is treated with the anticholinergics benztropine (Cogentin) and trihexyphenidyl (Artane).

Pharmacotherapy of parkinsonism

Drugs used to treat the symptoms associated with parkinsonism are called antiparkinsonism drugs.

Classification

1.      These that increases the dopaminergic activity

a.       Precursors of dopamine: l-dopa

b.      Drugs that inhibit dopamine metabolism

i.                    MAO-B inhibitors: Selegiline

ii.                  COMT inhibitors: Tolcapone, entacopone

c.       Drugs that release dopamine: amatadine

d.      Dopamine receptor agonists: Ex: bromocriptine, lysuride, ropinirole

2.      Those that suppress the cholinergic activity: Atropine, and its substitutes such as benzhexol, procyclidine, and antihistaminics with anticholinergic properties.

ACTIONS

a.       Levodopa (L-DOPA), the most reliable and effective drug used in treatment of parkinsonism, can be considered a form of replacement therapy.

b.      Levodopa is biochemical precursor of dopamine.

c.       It is used to elevate dopamine levels in neostriatum of parkinsonian patients.

d.      Dopamine itself does not cross blood-brain barrier and therefore has no CNS effects.

e.       However, levodopa, as an amino acid, is transported into brain by amino acid transport systems, where it is converted to dopamine by enzyme L-aromatic amino acid decarboxylase.

f.        If levodopa is administered alone, it is extensively metabolized by L-aromatic amino acid decarboxylase in liver, kidney, and GIT. To prevent this peripheral metabolism, levodopa is coadministered with carbidopa (Sinemet), a peripheral decarboxylase inhibitor.

g.      The combination of levodopa with carbidopa lowers necessary dose of levodopa and reduces peripheral side effects associated with its administration.

USES

a.       Levodopa is widely used for treatment of all types of parkinsonism except those associated with antipsychotic drug therapy.

b.      The dopaminergic drugs are used to treat signs and symptoms of parkinsonism.

c.       Carbidopa is always given with levodopa, combined either as one drug or as two separate drugs.

d.      When it is necessary to titrate the dose of carbidopa, both carbidopa and levodopa may be given at same time, but as separate drugs.

e.       Sometimes response with these two drugs can be enhanced by addition of another drug. For Ex: selegiline or pergolide may be added to drug regimen of those being treated with carbidopa and levodopa.

Adverse Effects

Gastrointestinal Effects-When levodopa is given without decarboxylase inhibitor, anorexia and nausea and vomiting occurs. These can be minimized by taking drug in divided doses, with or after meals, and by increasing total daily dose very slowly; antacids taken 30–60 minutes before levodopa is beneficial. The vomiting has been attributed to stimulation of CTZ. Antiemetics (phenothiazines) should be avoided because they reduce antiparkinsonism effects of levodopa and may exacerbate disease.

When levodopa is given in combination with carbidopa, adverse GI effects are much less frequent and troublesome, occurring in less than 20% of cases, so that patients can tolerate proportionately higher doses.

Cardiovascular Effects-Cardiac arrhythmias have been described in patients receiving levodopa, including tachycardia, ventricular extrasystoles and, rarely, atrial fibrillation. This effect is due to increased catecholamine formation peripherally. The incidence of such arrhythmias is low, even in presence of established cardiac disease, and may be reduced still further if levodopa is taken in combination with peripheral decarboxylase inhibitor.

Postural hypotension is common, but often asymptomatic, and diminishes with continuing treatment. Hypertension may also occur.

Dyskinesias-occur in patients receiving levodopa therapy for long periods. The form and nature of dopa dyskinesias vary widely but tend to remain constant in character in individuals. Choreoathetosis of face and distal extremities is most common presentation. The development of dyskinesias is dose-related.

Behavioral Effects-Like depression, anxiety, agitation, insomnia, somnolence, confusion, delusions, hallucinations, nightmares, euphoria, and other changes in mood or personality. These are common in patients taking levodopa in combination with decarboxylase inhibitor rather than levodopa alone, because higher levels are reached in brain. They may be precipitated by intercurrent illness or operation. It may be necessary to reduce or withdraw the medication.

Fluctuations in Response-Certain fluctuations in clinical response to levodopa occur with increasing frequency as treatment continues. In some patients, these fluctuations relate to timing of levodopa intake, and referred to as wearing-off reactions or end-of-dose akinesia. In other instances, fluctuations in clinical state are unrelated to timing of doses (on-off phenomenon).

Miscellaneous-Mydriasis may occur and may precipitate an attack of acute glaucoma in some patients. Others include various blood dyscrasias; a positive Coombs test with evidence of hemolysis; hot flushes; aggravation or precipitation of gout; abnormalities of smell or taste; brownish discoloration of saliva, urine, or vaginal secretions; priapism; and mild—usually transient—elevations of blood urea nitrogen and of serum transaminases, alkaline phosphatase, and bilirubin.

Drug Interactions

Pyridoxine enhance extracerebral metabolism of levodopa and may therefore prevent its therapeutic effect unless peripheral decarboxylase inhibitor is also taken. Levodopa should not be given to patients taking monoamine oxidase A inhibitors or within 2 weeks of their discontinuance, because such a combination can lead to hypertensive crises.

Contraindications

Levodopa should not be given to psychotic patients because it may exacerbate mental disturbance. It is also contraindicated in patients with angle-closure glaucoma, but those with chronic open-angle glaucoma may be given levodopa if intraocular pressure is well controlled and can be monitored. It is best given combined with carbidopa to patients with cardiac disease; even so, the risk of cardiac dysrhythmia is slight.

Dopamine Agonists Ex: bromocriptine, pergolide, pramipexole, and ropinirole.

a.       Dopamine receptor agonists are considered as first approach to therapy. They have long duration of action and are less likely to cause dyskinesias than levodopa.

b.      The rationale for use of dopamine agonists is that they provide means of directly stimulating dopamine receptors and do not depend on formation of dopamine from levodopa.

c.       As monotherapy, dopamine agonists are less effective than levodopa but are often used early in disease to delay initiation of levodopa therapy.

d.      When used as adjunct to levodopa in advanced stages, the dopamine receptor agonists may contribute to clinical improvement and reduce levodopa dosage needs.

e.       Bromocriptine, an ergot derivative, is an agonist at D2-receptors and a partial D1-antagonist.

f.       Pergolide, also an ergot derivative, is an agonist at both D1- and D2-receptor subtypes.

g.      Non-ergot drugs, ropinirole and pramipexole, are selective agonists at D2-receptor sites.

h.      All four exert similar therapeutic effects and produce same adverse effects seen with levodopa.

Adverse effects Postural hypotension, nausea, somnolence, and fatigue are common of bromocriptine and pergolide therapy and limits use of these drugs. Because of these adverse effects, the drugs are first administered at low doses and then dose is gradually increased over weeks or months as tolerance to adverse effects develops.

These symptoms are less frequent and less severe with pramipexole and ropinirole, which allows for rapid achievement of therapeutic response. Also, because pramipexole and ropinirole are better tolerated, they are increasingly used as monotherapy.

Selegiline

a.       It is an irreversible inhibitor of MAO-B, an important enzyme in metabolism of dopamine.

b.      Blockade of dopamine metabolism makes more dopamine available for stimulation of its receptors.

c.       Selegiline, as monotherapy, may be effective in newly diagnosed patient with parkinsonism because its pharmacological effect enhances the actions of endogenous dopamine.

Uses

a.       It is used in conjunction with levodopa–carbidopa in later-stage parkinsonism to reduce levodopa dosage requirements and to minimize or delay onset of dyskinesias and motor fluctuations that accompany long-term treatment with levodopa.

b.      It has also been proposed that selegiline may slow progression of disease by reducing formation of toxic free radicals produced during metabolism of dopamine.

Adverse reactions are related to increased levels of dopamine. Selegiline has little effect on MAO-A and therefore does not cause hypertension associated with ingestion of tyramine-enriched foods. However, at doses higher than those recommended, MAO-A may be inhibited, which increases the risk of tyramine reaction.

Selegiline should not be co-administered with tricyclic antidepressants or selective serotonin uptake inhibitors because of possibility of severe adverse drug reaction (e.g., hyperpyrexia, agitation, delirium, coma).

Amantadine

a.       It was originally introduced as antiviral compound, but it is effective in treating symptoms of parkinsonism.

b.      It is useful in early stages of parkinsonism or as an adjunct to levodopa therapy. Its mechanism of action in parkinsonism is not clear, but amantadine may affect dopamine release and reuptake.

c.       Additional sites of action may include antagonism at muscarinic and N-methyl-D-Aspartate (NMDA) receptors.

d.      Adverse effects include nausea, dizziness, insomnia, confusion, hallucinations, ankle edema, and livedo reticularis.

e.       Amantadine and anticholinergics may exert additive effects on mental functioning.

Skeletal muscle relaxants

Classification

1.                  Agents acting by competitive blockade of ACh at motor end plate Ex: d-tubocurarine, alcuronium, atracurium, vecuronium and gallamine

2.                  Agents acting by persistent depolarization of motor end plate and muscle fiber membrane: succinycholine

3.                  Drugs which inhibit the release of Ach from motor nerve terminals: botulinium toxiun type A

4.                  Drugs acting directly on skeletal muscle: dantrolene

Pharmacological Actions of d-Tubocurarine

a.      It blocks nicotinic AChRs in muscle end plates and autonomic ganglia but has no effect on muscarinic AChRs.

b.      It does not affect nerve or muscle excitability or conduction of action potentials. Because it is charged, it penetrates cells poorly and does not enter the CNS.

c.       However, if applied directly to brain or spinal cord, it will block nicotinic AChR in those tissues.

d.      In humans, d-tubocurarine has moderate onset of action (3-4 minutes) followed by progressive flaccid paralysis.

e.       The head and neck muscles are affected initially, then limb muscles, and finally muscles of respiration. Recovery from paralysis is in the reverse order.

Uses of d-Tubocurarine

Surgical Relaxation-The most important application of neuromuscular blockers is in facilitating intracavitary surgery. This is especially important in intra-abdominal and intrathoracic procedures.

Tracheal Intubation-By relaxing pharyngeal and laryngeal muscles, neuromuscular blocking drugs facilitate laryngoscopy and placement of tracheal tube. Placement of a tracheal tube ensures an adequate airway and minimizes risk of pulmonary aspiration during general anesthesia.

Control of Ventilation-In critically ill patients who have ventilatory failure from various causes (eg, severe bronchospasm, pneumonia, chronic obstructive airway disease), it may be necessary to control ventilation to provide adequate gas exchange and to prevent atelectasis. Muscle paralysis is produced by neuromuscular blocking drugs to reduce chest wall resistance and ineffective spontaneous ventilation.

Treatment of Convulsions -Neuromuscular blocking drugs are used to attenuate peripheral manifestations of convulsions associated with status epilepticus or local anesthetic toxicity. Although this approach is effective in eliminating muscular manifestations of seizures, it has no effect on central processes because neuromuscular blocking drugs do not cross blood-brain barrier.

Adverse Effects and Precautions

a.      d-Tubocurarine may cause bronchospasms and hypotension by release of histamine from mast cells. This may be counteracted by prior treatment with antihistamines.

b.      d-Tubocurarine produces partial block of sympathetic ganglia and the adrenal medulla, which may also contribute to hypotension.

c.       Inhalation anesthetics, such as isoflurane, enflurane, halothane, and nitrous oxide, potentiate the action of nondepolarizing blockers. The extent of potentiation depends on anesthetic and depth of anesthesia. The dose of muscle relaxant should be reduced when used with these anesthetics.

d.      Certain antibiotics (e.g., aminoglycosides, macrolides, polymyxins, lincomycin) enhance neuromuscular blockade by either decreasing ACh release or blocking postjunctional response.

e.       Procainamide and phenytoin also increase effects of d-tubocurarine-like drugs.The amount of neuromuscular blocker should be decreased accordingly.

Anticholinesterases

Classification

1.      Reversible anticholinesterases

a.       Carbamates: physostigmine, neostigmine, pyridostigmine, edrophonium, rivastigmine, donepazil, galantamine

b.      Acridine: tacrine

1.      Irreversible

a.       Organophosphates: dyflor, echothiophate, parathion, malathion, dizinon, tabun

b.      Carbamates: carbaryl, propoxur

Pharmacological Actions of anticholinesterases

a.                  Eye: When applied locally to conjunctiva, anti-ChE agents cause conjunctival hyperemia and constriction of pupillary sphincter muscle around pupillary margin of iris and ciliary muscle. Miosis is apparent in few minutes and last several hours to days. Although pupil may be "pinpoint" in size, it contracts further when exposed to light. The block of accommodation is more transient and disappears before termination of miosis. Intraocular pressure, when elevated, falls as a result of facilitation of outflow of aqueous humor.

b.                 Central Nervous System: In low concentrations, lipid-soluble cholinesterase inhibitors cause diffuse activation on electroencephalogram and subjective alerting response. In higher concentrations, they cause generalized convulsions, followed by coma and respiratory arrest.

c.                  Cardiovascular System: The cardiovascular actions of anti-ChE agents are complex, since they reflect both ganglionic and postganglionic effects of accumulated ACh on heart and blood vessels and actions in CNS. The predominant effect on heart from peripheral action of accumulated ACh is bradycardia, resulting in fall in cardiac output. Higher doses usually cause fall in blood pressure, as consequence of effects of anti-ChE agents on medullary vasomotor centers of CNS. Anti-ChE agents increase contraction of smooth muscle fibers of bronchioles and ureters, and ureters may show increased peristaltic activity.

d.                 Neuromuscular Junction: Most of effects of potent anti-ChE drugs on skeletal muscle are explained on basis of their inhibition of AChE at neuromuscular junctions. However, there is good evidence for an accessory direct action of neostigmine and other quaternary ammonium anti-ChE agents on skeletal muscle. For example, intra-arterial injection of neostigmine into chronically denervated muscle, or muscle in which AChE has been inactivated by prior administration of DFP, evokes an immediate contraction, whereas physostigmine does not.

e.                  Actions at Other Sites. Secretory glands that are innervated by postganglionic cholinergic fibers include bronchial, lacrimal, sweat, salivary, gastric, intestinal, and pancreatic acinar glands. Low doses of anti-ChE agents augment secretory responses to nerve stimulation, and higher doses actually produce an increase in resting rate of secretion.

Absorption, Fate, and Excretion. Physostigmine is absorbed readily from GIT, subcutaneous tissues, and mucous membranes. The conjunctival instillation of drug may result in systemic effects if measures are not taken to prevent absorption from nasal mucosa. Parenterally administered physostigmine is largely destroyed within 2 hours, mainly by hydrolytic cleavage by plasma esterases; renal excretion plays only a minor role in its elimination.

Neostigmine and pyridostigmine are absorbed poorly after oral administration; hence, larger doses are needed than by parenteral route. These are destroyed by plasma esterases, and quaternary aromatic alcohols and parent compounds are excreted in urine; half-life is 1 to 2 hours.

Clinical Uses

a.                  Myasthenia Gravis: Anticholinesterase agents help to alleviate weakness by elevating and prolonging concentration of ACh in synaptic cleft, producing activation of remaining nicotinic receptors. By contrast, thymectomy, plasmapheresis, and corticosteroid administration are treatments directed at decreasing autoimmune response.

Anticholinesterase agents play a key role in diagnosis and therapy of myasthenia gravis, because they increase muscle strength. During diagnosis, the patient’s muscle strength is examined before and immediately after intravenous injection of edrophonium chloride.

b.                  Smooth Muscle Atony: Anticholinesterase agents can be employed in treatment of dynamic ileus and atony of urinary bladder, both of which may result from surgery. Neostigmine is most commonly used, administered subcutaneously or intramuscularly in these conditions. Cholinesterase inhibitors are, of course, contraindicated if mechanical obstruction of intestine or urinary tract is known to be present.

c.                   Antimuscarinic Toxicity: Drugs like atropine and scopolamine have antimuscarinic properties.These include tricyclic antidepressants, phenothiazines, and antihistamines. Physostigmine has been used in treatment of acute toxicity produced by these compounds. However, physostigmine can produce cardiac arrhythmias and other serious toxic effects of its own, and therefore, it should be considered as antidote only in life-threatening cases of anticholinergic drug overdose.

d.                  Alzheimer’s Disease: The four cholinesterase inhibitors that have been approved for use in palliative treatment of Alzheimer’s disease are tacrine, donepezil, rivastigmine, and galanthamine. These agents can cross blood-brain barrier to produce reversible inhibition of AChE in CNS.These compounds produce modest but significant improvement in cognitive function of patients with mild to moderate Alzheimer’s disease, but they do not delay progression of disease.

e.                   Glaucoma: Long-lasting AChE inhibitors, such as demecarium, echothiophate, and physostigmine are effective in treating open-angle glaucoma, although they are replaced by less toxic drugs. Topical application of long-acting cholinesterase inhibitors to eye not only presents risk of systemic effects, but they cause cataracts; this is primary reason for reluctance to use these drugs even in resistant cases of glaucoma. Pilocarpine should be used rather than AChE inhibitors for treating angle-closure glaucoma.

f.                   Strabismus: Drug treatment of strabismus (turning of one or both eyes from normal position) is largely limited to certain cases of accommodative esotropia (inward deviation). Long-acting anticholinesterase agents, such as echothiophate or demecarium, are employed to potentiate accommodation by blocking ACh hydrolysis at ciliary muscle and decreasing activity of extraocular muscles of convergence. This results in reduced accommodative convergence.

ADVERSE REACTIONS

Unless applied topically, as in treatment of glaucoma, cholinergic drugs are not selective in action. Therefore, they may affect many organs and structures of body, causing variety of adverse effects like temporary reduction of visual acuityand headache may occur. Oral or parenteral administration can result in nausea, diarrhea, abdominal cramping, salivation, flushing of skin, cardiac arrhythmias, and muscle weakness.

Dopamine

Dopamine is the immediate metabolic precursor of norepinephrine and epinephrine; it is a central neurotransmitter important in regulation of movement and possesses important intrinsic pharmacological properties. In the periphery, it is synthesized in epithelial cells of the proximal tubule and is thought to exert local diuretic and natriuretic effects. Dopamine is a substrate for both MAO and COMT and thus is ineffective when administered orally.

Dopamine is a unique adrenomimetic drug in that it exerts its cardiovascular actions by (1) releasing norepinephrine from adrenergic neurons, (2) interacting with α-and β1-adrenoceptors, and (3) interacting with specific dopamine receptors.

Therapeutic Uses

It is used in treatment of shock owing to inadequate cardiac output, which may be due to myocardial infarction or congestive heart failure. It is also used in treatment of septic shock, since renal circulation is compromised in this condition. The duration of action of dopamine is brief, and hence the rate of administration can be used to control the intensity of effect.

Adverse effects: it includes nausea, vomiting, tachycardia, ectopic beats, hypertension and cardiac arrhythmias.

Reason why L-dopa is always given in combination with carbidopa

If levodopa is administered alone, it is extensively metabolized by L-aromatic amino acid decarboxylase in liver, kidney, and gastrointestinal tract. To prevent this peripheral metabolism, levodopa is coadministered with carbidopa (Sinemet), a peripheral decarboxylase inhibitor. The combination of levodopa with carbidopa lowers necessary dose of levodopa and reduces peripheral side effects associated with its administration.

Pancuronium

It is a non-depolarizing muscle relaxants produce some cardiovascular effects that are mediated by autonomic or histamine receptors or both

Mechanism of Action-These agents preventexcitation of end plate AChRs by acting as reversiblecompetitive antagonists at binding sites.The prototype for this group is d-tubocurarine. In general,these compounds have two charged heads (e.g., quaternaryammonium) separated by a “thick” organic moiety(e.g., steroid nucleus). These heads enable attachmentof drug to two AChR binding sites. However, becauseof large intervening moiety, the channel is occludedsuch that flow of cations is prevented.Because of competitive nature of this blockade, theeffect of nondepolarizing blockers can be reversed byanti-AChE agents and other procedures that increase synaptic concentration of ACh.

Pancuronium bromide is synthetic bisquaternaryagent containing a steroid nucleus (aminosteroid). It is fivetimes as potent as d-tubocurarine. Unlike d-tubocurarine,it does not release histamine or block ganglionictransmission. Like d-tubocurarine, it has a moderatelylong onset (2.9 minutes) and duration of action (110minutes).

Clinical Uses: Non-depolarizing blockers are used to relax skeletalmuscle for surgical procedures, to prevent dislocationsand fractures associated with electroconvulsive therapy,and to control muscle spasms in tetanus.

Dale’s vasomotor reversal

The rise in systolic blood pressure produced by moderate doses of adrenaline is often followed by a fall. By stimulating α-receptors, it produces a rise in blood pressure. However action of adrenaline on beta receptors is more persistent and hence, when actionon alpha receptors wears off, the action of beta receptors is unmasked producing a fall of blood pressure. The blood pressure response to moderate doses of adrenaline is termed biphasic response. This biphasic response was converted to depressor response by prior administration of ergot extract due to alpha receptor blocking actionof ergot alkaloids, leading to stimulationof peripheral beta2 receptors by adrenaline and thus causing a fall in blood pressure This phenomenon is termed as Dale’s Vasomotor reversal.

Catecholamines

Classification:

a.       Endogenous: these are sympathomimetic amines that contain 2 adjacent OH groups in benzene nucleus. Ex: Epinephrine, norepinephrine, dopamine

b.      Synthetic: These are synthetic catecholamines containing 2 adjacent OH roups in benzene nucleus. Ex: Isoprenaine, dipivefrine, dobutamine, ibopamine, dopexamine, fenoldopam.

The clinical uses of catecholamines are based on theiractions on bronchial smooth muscle, blood vessels, and heart.

Epinephrine is useful for treatmentof allergic reactions that are due to liberation of histaminein body, because it produces certain physiologicaleffects opposite to those produced by histamine.It is primary treatment for anaphylactic shock and isuseful in therapy of urticaria, angioneurotic edema,and serum sickness.Epinephrine also has been used to lower intraocularpressure in open-angle glaucoma.

Norepinephrine is infused intravenously to combatsystemic hypotension during spinal anesthesia orother hypotensive conditions. The vasoconstrictor actions of epinephrine and norepinephrine have been used to prolong action of local anesthetics by reducing local blood flow in regionof injection.

Dopamine is used in treatment of shock owingto inadequate cardiac output,which may be due to myocardial infarction or congestiveheart failure. It is also used in treatment ofseptic shock, since renal circulation is compromisedin this condition.

Trimetharphan

It is an ultra-short acting ganglionic blocker. It is orally ineffective and given by slow I.V. infusion. It does not cross blood brain barrier significantly

Therepeutic uses: It used ot produce controlled hypotension and in hypertensive emergency due to aortic dissection. It can stimulate the realse of histamine. It should be used with caution in paitents having bronchial asthma and in those who is having history of allergy.

Uses of isoprenaline

Isoproterenol is a very potent β-receptor agonist and has little effect on α-receptors. The drug has positive chronotropic and inotropic actions; it activates β-receptors almost exclusively, it is a potent vasodilator.Isoproterenol may be used in emergencies to stimulate heart rate in patients with bradycardia or heart block, particularly in anticipation of inserting an artificial cardiac pacemaker or in patients with the ventricular arrhythmia torsades de pointes. In disorders such as asthma and shock, isoproterenol largely has been replaced by other sympathomimetic drugs.

Is neostigmine preferred in myasthenia gravis?

Neostigmine, is the standard anti-ChE drugs used in symptomatic treatment of myasthenia gravis. As it can increase response of myasthenic muscle to repetitive nerve impulses, primarily by preservation of endogenous ACh. Following AChE inhibition, receptors over a greater cross-sectional area of the endplate presumably are exposed to concentrations of ACh that are sufficient for channel opening and production of a postsynaptic endplate potential.

Reason why acetyl choline is not used clinically

Acetyl choline is a quaternary compound and hence it is not absorbed if give by oral or subcutaneous route. Its half-life is few second (rapidly metabolized by AChE) its actions are of very short duration, that too if given intravenously. It has poor diffusion through cornea, rapidly broke down by AChE before it reaches its site of action.