Drugs Affecting ANS

Cholinergic Agonists

CHOLINERGIC DRUGS
These drugs produce actions similar to that of Ach, either by directly interacting with cholinergic receptors (cholinergic agonists) or by increasing availablity of Ach at these sites (anticholinesterases) CHOLINERGIC DRUGS Direct acting Cholinergic agonists Choline esters Alkaloids Indirect acting Anticholinesterases Reversible Irreversible

DIRECT ACTING CHOLINERGIC AGENTS

Cholinergic agonists (also known as parasympathomimetics) mimic the effects of acetylcholine by binding directly to cholinoceptors. These agents may be broadly classified into two groups: a. Choline esters, which include acetyl-choline and synthetic esters of choline, such as carbachol and bethanechol. b. Naturally occurring alkaloids, such as pilocarpine constitue the second group. All of the direct-acting cholinergic drugs have longer durations of action than acetylcholine. Choline Esters Acetylcholine Methacholine Carbachol Bethanechol Alkaloids Muscarine Pilocarpine Arecoline

Mehcanism of Action Most drugs in this class nonselectively bind to cholinergic receptors. Some of the more therapeutically useful drugs (pilocarpine and bethanechol) preferentially bind to muscarinic receptors and are sometimes referred to as muscarinic agents. The drugs carbachol, bethananicol, metapropamide and pilocarpine cannot be destroyed by acetylcholinesterase (AchE). The drug methacholine can be destroyed by only plasma cholinesterase (one form of AchE). Therefore these compounds have a longer half-life than acetylcholine. Ach and methacholine are rapidly metabolized by AchE and plasma cholinesterase respectively. The therapeutic effects of Ach and methacholine can be extended by prior administration of anticholinesterase agent which blocks AchE.

Pharmacologic effect: Most drugs in this class produce non-specific effect via cholinergic activation in ganglia and various voluntary and involuntary muscles. Drugs with higher affinity for muscarinic receptors produce more selective effects. For example, muscarinic activation of the heart produces bradycardia; muscarine activation of sweat glands produces increase secretion However, as a group, the direct-acting agonists show little specifcity in their actions, which limits their clinical usefulness. Pilocarpine and arecoline have tertiary (unionized) structures which makes it possible to cross the blood brain barrier and enter the CNS. Pilocarpine and arecoline therefore have CNS effects. All other drugs listed above have quaternary structures (ionized ) which do not cross the blood brain barrier. Thus they do not have CNS effects.

Acetylcholine (prototype)
Acetylcholine is a quaternary ammonium compound that cannot penetrate membranes. Although it is the neurotransmitter of parasympathetic and somatic nerves as well as autonomic ganglia, it is therapeutically of no importance because of its multiplicity of actions and its rapid inactivation by the cholinesterases. Acetylcholine has both muscarinic and nicotinic activity. It acts on
1. 2. 3. 4. 5. Heart Blood Vessels Smooth Muscles Glands Eye

 Decrease in heart rate and cardiac output: The actions of acetylcholine on the heart mimic the effects of vagal stimulation. For example, acetylcholine, if injected intravenously, produces a brief decrease in cardiac rate (negative chronotropy) and stroke volume as a result of a reduction in the rate of firing at the sinoatrial (SA) node. [Note: It should be remembered that normal vagal activity regulates the heart by the release of acetylcholine at the SA node.] Cardiac Muscarinic receptors are of the M2 type Decrease in blood pressure: Injection of acetylcholine causes vasodilation and lowering of blood pressure by an indirect mechanism of action. Acetylcholine activates M3 receptors found on vascular endothelial cells lining the smooth muscles of blood vessels. Vasodilation is primarily mediated through the release of EDRF which is NO [Note: nitric oxide is also known as endotheliumderived relaxing factor.] In the absence of administered cholinergic agents, the vascular receptors have no known function, because acetylcholine is never released into the blood in any significant quantities. Atropine blocks these muscarinic receptors and prevents acetylcholine from producing vasodilation

 Smooth Muscles: In most organs smooth muscle is contracted (mainly through M3 receptors)
Tone and peristalisis of GI tract is increased and sphincters relax -- > abd. cramps and evacuation of bowel Peristalisis in ureter is increased. The detrusor muscle contracts while bladder trigone relaxes -- > voiding of bladder Bronchial muscles constricts, asthamatics are highly sensitive -- > dyspnoea, precipitation of an attack of asthma

Glands: Secretion from all parasympathetic glands is increased via M3 and some M2 receptors. This results in increased sweating, salivation, lacrimation, tracheobronchial and gastric secretions. Note: Secretion of Milk and Bile is not affected Eye: Contraction of circular (pupillae sphincter) muscles of iris, causing Miosis (marked constriction of pupil) Contraction of Ciliary muscles which results in spasm of accomodation, reduction of intraocular pressure

Bethanechol
It is structurally related to acetylcholine. It is not hydrolyzed by acetylcholinesterase (due to the addition of carbonic acid), although it is inactivated through hydrolysis by other esterases. It lacks nicotinic actions but does have strong muscarinic activity. Its major actions are on the smooth musculature of the bladder and gastro-intestinal tract. It has a duration of action of about 1 hour. Actions: Bethanechol directly stimulates muscarinic receptors, causing increased intestinal motility and tone. It also stimulates the detrusor muscles of the bladder whereas the trigone and sphincter are relaxed, causing expulsion of urine Therapeutic applications: In urologic treatment, bethanechol is used to stimulate the atonic bladder, particularly in postpartum or postoperative, nonobstructive urinary retention. Bethanechol may also be used to treat neurogenic atony as well as megacolon and gastro esophageal refulx. Adverse efects: Bethanechol causes the efects of generalized cholinergic stimulation. These include sweating, salivation, fushing, decreased blood pressure, nausea, abdominal pain, diarrhea, and bronchospasm.

Pilocarpine
The alkaloid pilocarpine is obtained from the leaves of Pilocarpus microphyllus. It is a tertiary amine and is stable to hydrolysis by acetylcholinesterase. Compared with acetylcholine and its derivatives, it is far less potent, but it is uncharged and will penetrate the CNS at therapeutic doses. Pilocarpine exhibits potent muscarinic activity and is used primarily in ophthalmology. Actions: Applied topically to the cornea, pilocarpine produces rapid miosis and contraction of the ciliary muscle. The eye undergoes miosis and a spasm of accommodation; the vision is fixed at some particular distance, making it impossible to focus. [Note the opposing effects of atropine, a muscarinic blocker, on the eye.] Pilocarpine is one of the most potent stimulators of secretions such as sweat, tears, and saliva, but its use for producing these effects has been limited due to its lack of selectivity. The drug is benefcial in promoting salivation in patients with xerostomia resulting from irradiation of the head and neck. Sjgren s syndrome, which is characterized by dry mouth and lack of tears, is treated with oral pilocarpime tablets and cevimeline, a cholinergic drug that also has the drawback of being nonspecifc.

Therapeutic use in glaucoma: Pilocarpine is the drug of choice in the emergency lowering of intraocular pressure of both narrow-angle (also called closed-angle) and wide-angle (also called open-angle) glaucoma. Pilocarpine is extremely effective in opening the trabecular meshwork around Schlemm s canal, causing an immediate drop in intraocular pressure as a result of the increased drainage of aque-ous humor. This action lasts up to 8 hours and can be repeated. The organophosphate echothiophate inhibits acetylcholinesterase and exerts the same efect for a longer duration. [Note: Carbonic anhydrase inhibitors, such as acetazolamide, as well as the -adrenergic blocker timolol, are efective in treating glaucoma chronically but are not used for emergency lowering of intraocular pressure.] Adverse efects: Pilocarpine can enter the brain and cause CNS disturbances. It stimulates profuse sweating and salivation.

Summary of adverse effects of cholinergic drugs

Arecoline: Found in betel nut Areca catechu and has both muscarinic and nicotinic actions including those on skeletal muscle end plates. It has prominent CNS effect as it has tertiary structure and therefore had been tried on dementia, but not found useful. It has no therapeutic use.

Indirect acting Anticholinesterases

Acetylcholinesterase is an enzyme that specifically cleaves acetylcholine to acetate and choline and, thus, terminates its actions. It is located both pre- and postsynaptically in the nerve terminal, where it is membrane bound. Inhibitors of acetylcholinesterase indirectly provide a cholinergic action by prolonging the lifetime of acetylcholine produced endogenously at the cholinergic nerve endings. This results in the accumulation of acetylcholine in the synaptic space. They may be reversible or irreversible acting Reversible Irreversible Carbamates Arcidine Organophosphates Carbamates Physostigmine Tacrine# Isofluorophate Carbaryl* Neostigmine Isothiophate Propoxur* Pyridostigmine Echothiophate Ambenomium Dyflos (DFP) Demecarium Malathion*, Parathion* Edrophonium Diazinon* Rivastigmine#, Donepezil#, Galantamine# Sarin^, Tabun^, Soman^ #Used in Alzhemier s Ds *Insectides ^ Nerve gases for chemical warfare

Anti-ChE s
Anti-ChEs are either esters of carbamic acid or derivatives of phosphoric acid. Some carbamates are lipid-soluble (e.g. Physostigmine) while others are lipid-insoluble (e.g. Neostigmine) All organophosphates are highly lipid soluble except Echothiophate which is water soluble. ACTIONS: Lipid-soluble agents (physostigmine and organophosphates) have more marked muscarinic and CNS effects, but action on skeletal muscles in less prominent Lipid insoluble agents (neostigmine and other quaternary ammonium compounds) produce more marked effect on skeletal muscles, but muscarinic effects are less prominent. They do not penetrate CNS and have no central effects.

Anti-ChE s
CVS: CV effects are comples. Muscarinic action would produce bradycardia and hypotension while ganglionic stimulation (through ganglionic muscarinic receptors) would tend to increase heart rate and BP. Skeletal Muscles: After treatment with anti-CHEs, the Ach released by a single nerve impulse is not immediately destroyed --- rebinds to the same receptor, diffuses to act on neighbouring receptors and activates prejunctional fibers --- > repetitive firing --- > twitching and fasciculations. Force of contraction in partially curarized (treated with curare) and myasthenic muscles is increased. Higher doses causes persistent depolarization of end plates resulting in blockade of neuromuscular transmission --- > weakness and paralysis. Others effects: These result from the stimulation of smooth muscles and glands of the GI, respiratory, UT and in the eye.

Reversible Anti-ChE s
plants) and a tertiary amine (that is why it is soluble in lipids and also has CNS effects) Actions: It has a wide range of effects not only on the muscarinic and nicotinic sites of the ANS but also on the nicotinic receptors of the neuromuscular junction. It can enter and stimulate the cholinergic sites of the CNS. Therapeutics uses:
a. b. c. d.

Physostigmine: It is an alkaloid (a nitrogenous compound present in

Increase intestinal and bladder motility in atony of bladder of intestine Placed topically in they eye, it produces miosis ans spasm of accomodation, as well as lowering of i.o.p. It is used to treat Glaucoma but pilocarpine is more effective. There fore it is used to supplement Pilocarpine. Used in the tx of overdoses of drugs with anticholinergic activity, such as atropine, phenothiazines and tricyclic antidepressants. It is used as an antidote for poisoning by muscarinic antagonists May lead to convulsions when high doses r used as it has CNS penetration. Bradycardia and fall in CO may also occur Accumulation Ach at the skeletal neuromuscular junction results in paralysis of skeletal muscles. However, these effects are rarely seen in therapeutic doses.

Adverse effects:
a) b) c)

Reversible Anti-ChE s
ester. Unlike physostigmine, neostigmine has a quaternary nitrogen; hence, it is more polar and does not enter the CNS. Actions: Its effect on skeletal muscle is greater than that of physostigmine, and it can stimulate contractility before it paralyzes. Neostigmine has a moderate duration of action, usually 30 minutes to 2 hours. It is used to stimulate the bladder and GI tract Therapeutic uses:
a) Neostigmine has found use in symptomatic treatment of myasthenia gravis, an autoimmune disease caused by anti-bodies to the nicotinic receptor at neuromuscular junctions. This causes their degradation and, thus, makes fewer receptors available for interaction with the neurotransmitter. It is also used as an antidote for tubocurarine and other competitive neuromuscular blocking agents. Neostigmine does not cause CNS side effects and is NOT used to overcome toxicity of central-acting antimuscarinic agents such as atropine.

Neostigmine: It is a synthetic compound that is also a carbamic acid

b) c)

Adverse effects: of neostigmine include those of generalized cholinergic stimulation, such as salivation, flushing, decreased blood pressure, nausea, abdominal pain, diarrhea, and bronchospasm.

Reversible Anti-ChE s
Pyridostigmine & Ambenomium: They other cholinesterase inhibitors that are used in the chronic management of myasthenia gravis. Their durations of action are inter-mediate (3-6 hrs and 4-8 hrs, respectively), but longer than that of neostigmine. Adverse effects of these agents are similar to those of neostigmine. Demecarium: It is another cholinesterase inhibitor used to treat chronic open-angle glaucoma (primarily in patients refractory to other agents) closed-angle glaucoma after irredectomy. It is also used for the diagnosis and treatment of accommodative esotropia. Demecarium is a quaternary amine that is structurally related to neostigmine. Mechanisms of actions and side effects are similar to those of neostigmine.

Reversible Anti-ChE s
Edrophonium: Its actions are similar to those of neostigmine, except that it is more rapidly absorbed and has a short duration of action of 10 to 20 minutes (prototype short-acting agent). Edrophonium is a quaternary amine and is used in the diagnosis of myasthenia gravis. Intravenous injection of edrophonium leads to a rapid increase in muscle strength. Care must be taken, because excess drug may provoke a cholinergic crisis. Atropine is the antidote. Edrophonium is used to distinguish muscle weakness caused by Cholinergic crisis (worsening is seen) and Myasthenia Gravis (improvement is seen). Tacrine, Donepezil, Rivastigmine, and Galantamine: Patients with Alzheimer s disease have a deficiency of cholinergic neurons in the CNS. This observation led to the development of anticholinesterases as possible remedies for the loss of cognitive function. Tacrine was the first to become available, but it has been replaced by the others because of its hepatotoxicity. Despite the ability of donepezil, rivastigmine, and galantamine to delay the progression of the disease, none can stop its progression. Gastrointestinal distress is their primary adverse effect.

Irreversible Anti-ChE s
Echothiophate:
Mechanism of action: It is an organophosphate that covalently binds via its phosphate group to the serine-OH group at the active site of acetylcholinesterase. Once this occurs, the enzyme is permanently inactivated, and restoration of acetylcholinesterase activity requires the synthesis of new enzyme molecules. Following covalent modification of acetyl-cholinesterase, the phosphorylated enzyme slowly releases one of its ethyl groups. The loss of an alkyl group, which is called aging, makes it impossible for chemical reactivators, such as pralidoxime, to break the bond between the remaining drug and the enzyme. Actions: Actions include generalized cholinergic stimulation, paralysis of motor function (causing breathing difficulties), and convulsions. Echothiophate produces intense miosis and, thus, has found therapeutic use. Atropine in high dosage can reverse many of the muscarinic and some of the central effects of echothiophate

 Therapeutic uses: An ophthalmic solution of the drug is used directly in the eye for the chronic treatment of open-angle glaucoma. The ef ects may last for up to one week after a single administration. Echothiophate is not a f rst-line agent in the treatment of glaucoma.In addition to its other side ef ects, the potential risk for causing cataracts limits the use of echothiophate. Reactivation of acetyl cholin esterase: Pralidoxime can reactivate inhibited acetylcholinesterase. However, it is unable to penetrate into the CNS. The presence of a charged group allows it to approach an anionic site on the enzyme, where it essentially displaces the phosphate group of the organophosphate and regenerates the enzyme. If given before aging of the alkylated enzyme occurs, it can reverse the effects of echothiophate, except for those in the CNS as Pralidoxime cannot penetrate the CNS. With the newer nerve agents, which produce aging of the enzyme complex within seconds, pralidoxime is less effective. Pralidoxime is a weak acetylcholin-esterase inhibitor and, at higher doses, may cause side effects similar to other acetylcholinsterase inhibitors.

Uses of Cholinergic Agonists

In Glaucoma: Physostigmine, Demecarium and Echothiophate are commonly used in the treatment of glaucoma. In Alzheimers Ds: It is a neurodegenerative disorder characeterized by progressive dementia. It primarily affects cholinergic neurons of the brain. Various measures to augment cholinergic transmission in the brain have been tried. Tacrine, Donepezil, Rivastigmine, and Galantamine are new agents which are used in treatment of early stages of Alzheimer s Disease as they are relatively cerebroselective. In Myasthenia Gravis: It is an autoimmune disorder affecting about 1 in 10,000 population, due to development of antibodies directed to nicotinic receptors at the muscle endplate --- > reduction in number of free Nm cholinoreceptors to 1/3rd of normal or less and structural damage to the neuromuscular junction --- > weakness and easy fatigability on repeated activity, with recovery after rest.

 Edrophonium and neostigmine have short halflives and are used in the diagnosis of Myasthenia Gravis. Ambenonium, noestigmine, and pyridostigmine are used in the treatment of Myasthenia Gravis. Neostigmine and its congeners improve muscle contraction by allowing Ach released from prejunctional endings to accumulate and act on receptors over a large area, and by directly depolarizing the endplate.

CLINICAL APPLICATIONS OF CHOLINESTERASE INHIBITORS