Autonomic Nervous System The Autonomic Nervous System is that part of PNS consisting of motor neurons that control internal organs. It has two subsystems. The autonomic system controls muscles in the heart, the smooth muscle in internal organs such as the intestine, bladder, and uterus. The Sympathetic Nervous System is involved in the fight or flight response. The Parasympathetic Nervous System is involved in relaxation. Each of these subsystems operates in the reverse of the other (antagonism). Both systems innervate the same organs and act in opposition to maintain homeostasis. For example: when you are scared the sympathetic system causes your heart to beat faster; the parasympathetic system reverses this effect. Motor neurons in this system do not reach their targets directly (as do those in the somatic system) but rather connect to a secondary motor neuron which in turn innervates the target organ. sympathetic system ( thoracolumbar) The subdivision of the autonomic nervous system that dominates in stressful or emergency situations and prepares the body for strenuous physical activity, e.g., causing the heart to beat faster. parasympathetic system The subdivision of the autonomic nervous system that reverses the effects of the sympathetic nervous system. Part of the autonomic nervous system that controls heartbeat, respiration and other vital functions. Receptors The receipt of informational signals by a cell is a complex task. For this purpose, cells display an extraordinarily elaborate array of transmembrane proteins termed receptors that function to acquire information from the extracellular space and relay this information into the cell through the plasma membrane . In effect, cell surface receptors act as the antennae of the cell. Mammalian cells like our own have wide and diverse types of transmembrane receptors, but we will focus only on a subset of them, specifically: · Growth Factor Receptors · G Protein Receptors Neurotransmitters and Receptors Acetylcholine is released at the synaptic ends of nerve fibers in the sympathetic and parasympathetic nervous systems and results in transmission of nerve impulses that contract or dilate muscles. It also increases stomach peristalsis, urinary tract contractions; and voluntary voiding pressure on the bladder. Amphetamine is a volatile liquid, C9H13N, is a central nervous system stimulant that releases nor adrenaline neurotransmitter and activates cellular activities. Cocaine an alkaloid, C17H21NO4 is an analgesic that induces euphoria. Dopamine is a neurotransmitter that inhibits the transmission of nerve impulses--in the substantia nigra, basal ganglia, and corpus striatum of the brain. It is controlled by the enzyme Monamine Oxidase (MAO-B) which inhibits its production. Nicotine inhibits MAO and hence raises level of dopamine with euphoric results. Low levels of dopamine are associated with Parkinson's disease. Endorphins are a group of peptide hormones that bind to opiate receptors and are found mainly in the brain. Endorphins reduce the sensation of pain and affect emotions. Epinephrine (adrenaline) C9H13NO3 is a hormone secreted by the adrenal medulla, is released into the bloodstream in response to physical or mental stress, and is a vasoconstrictor that increases heart rate and blood pressure Ephedrine is an alkaloid C10H15CO that stimulates the nervous system and is used for allergies and asthma. Norepinephrine is a hormone and neurotransmitter, secreted by the adrenal medulla and the nerve endings of the sympathetic nervous system to cause vasoconstriction and increases heart rate. Serotonin is a neurotransmitter arising from emotional stimuli of the limbic system. It is an organic compound, C10 H 12 N 2 O, formed from tryptophan and found in animal and human tissue, especially the brain, blood serum, and gastric mucous membranes, and active in vasoconstriction, stimulation of the smooth muscles, transmission of impulses between nerve cells, and regulation of cyclic body processes. Low levels are associated with depression that seems to be relieved by Prozac type chemicals that act as serotonin uptake blockers Cholinergic Receptors: the receptors upon which acetylcholine acts are known as cholinergic receptors Cholinergic refers to responses in various systems to the natural transmitter molecule Acetycholine (ACh). If one looks at a set of responses where ACh is the normal transmitter, observation has shown that those same responses are differently sensitive to the extrinisic molecules Nicotine and Muscarine. Nicotine comes from tobacco, Muscarine comes from certain mushrooms. Examples of such responses are summarized in the following table: Based on the different sensitivities shown above, Cholinergic receptors are subclassified into two categories, Nicotinic and Muscarinic, named for the extrinsic compounds that stimulate only that category. The properties of the two categories are summarized as follows: Nicotinic Receptors. · Stimulated by ACh and nicotine, not stimulated by muscarine. · Found at all ganglionic synapses. · Also found at neuromuscular junctions. · Blocked by hexamethonium. The physiological responses to stimulation and block are complex since both the sympathetic and parasympathetic systems are affected. The final response of any one organ system depends on which system has a stronger tonic influence. EXAMPLE: Under normal circumstances, the heart receives more parasympathetic influence than sympathetic. Ganglionic blockade would lower the parasympathetic influence more than the sympathetic, and thus the heart rate would increase. Muscarinic Receptors. · Stimulated by ACh and muscarine, not stimulated by nicotine. · Found at target organs when ACh is released by post-ganglionic neurons (all of parasympathetic, and some sympathetic). · Stimulated selectively by Muscarine, Bethanechol. · Blocked by Atropine. · Stimulation causes: · Increased sweating. · Decreased heart rate. · Decreased blood pressure due to decreased cardiac output. · Bronchoconstriction and increased bronchosecretion. · Contraction of the pupils, and contraction of ciliary body for near vision. · Tearing and salivation. · Increased motility and secretions of the GI system. · Urination and defecation. · Engorgement of genitalia. SUMMARY of CHOLINERGIC RECEPTOR ACTION RECEPTOR nicotinic LOCATION autonomic ganglia neuromuscular junction AGONIST activates SNS post-ganglionic fibers then PNS post-ganglionic fibers (uses ?) skeletal muscle contraction (used to intensify muscle contractions in myesthenia gravis; as neuromuscular blocking agents) ANTAGONISTblocks activation of SNS pos-t ganglionic fibers then PNS fibers (treat hypertension) causes muscle relaxation/paralysis RECEPTOR muscarinic LOCATION GI smooth muscle urinary bladder smooth muscle heart blood vessels sweat glands salivary glands AGONIST increases GI tone/motility (treat constipation) increases urinary bladder tone and motility (treat urine retention) decreases heart rate decreases blood pressure increases sweating increases salivation ANTAGONIST decreases GI tone and motility (treat diarrhea) decrease urinary tone and motility increases heart rate (treat bradycardia) increases blood pressure decreases sweating decreases salivation Classification of autonomic drugs Drugs influencing the activity of the autonomic nervous system are divided into the following categories 1-Parasympathomimetics drugs (cholinergic drugs) These produce an increase in the activity of tissue innervated by chloinergic fibers . these are further divided into following sub groups *Choline esters **Cholinomimetic natural alkaloids ***Anticholinesterases ( reversible and irreversible ) 2- Parasympatholytic drugs ( anti muscaanic drugs ) These block the muscaranic action of acetylcholine .these are further classified into *Natural belladonna alkaloids **Semiisynthetic and synthetic substitues 1*Tertiary amine compounds 2*Quaterrnary ammonium compounds 3-Sympathomimetic drug ( adrenergic drugs ) These are act on post ganglionic adrenergic nerve ending and structures innervated by them and classified as *Catecholamine or non-catecholamines **Acting directly or indirectly or by both mechanism ***Acting on alpha or beta receptors or both 4-Adrenergic blocking drugs These are inhibit adrenergic nerves and structures innervated by them further classified into *Alpha adrenergic receptor blocking agent **Beta adrenergic receptor blocking agent ***Adrenergic neurone blocking agent 5-Ganglion blocking agents These are impair transmission in ganglia of autonomic nervous system and classified as * Competitively blocking agent 1-Quaternary ammonium compounds 2-Secondary amines 3-Tertiary amines **Depolarizing drugs Parasympathomimetics ( Cholinergic drugs ) Parasympathomimetics drugs produce an increase in the activity of tissues innervated by cholnergic nerves . Pharmacological action of these drugs resemble as if parasympathetic nerves have been stimulated . these drugs include directly acting cholinergic agonists ( cholin esters and cholinomimetic natural alkaloids) and indirectly acting anticholinesterases Cholinergic agonists are subdivided into direct-acting and indirect-acting agonists. Direct-acting agonists bind to and activate receptors at autonomic ganglia (nicotinic), the neuromuscular junction (nicotinic), and a variety of tissues such as the GI tract, heart, exocrine glands (muscarinic). Activation of ganglionic nicotinic receptors leads to activation of SNS pathways following by PNS pathways. This is result of the greater number of post-ganglionic fibers in the SNS Thus ganglionic agonists activate SNS pathways first and antagonists block SNS responses first. Activation of nicotinic receptors at the NMJ leads to skeletal muscle contraction. Thus agonists (depolarizing neuromuscular blocking agents) lead to muscle contraction (followed by paralysis) while antagonists (non-depolarizing neuromuscular blocking agents) prevent muscle contraction and produce flaccid paralysis. Activation of muscarinic receptors produce 4 responses we're interested in in this class: increased GI tone and motility, increased urinary bladder tone and motility, increased salivation and sweating and decreased heart rate and blood pressure. Thus muscarinic receptor agonists produce all these responses and can be used to treat non-obstructive constipation and urine retention. They also cause side effects such as diarrhea, drooling and hyperhidrosis, bradycardia and hypotension. Antagonists produce the opposite effects and can be used to treat diarrhea, to dry up glandular secretions, and increase heart rate while producing side effects such as constipation, dry mouth and tachycardia. Indirect-acting agonists produce ACh-like effects by inhibiting the activity of AChE Since AChE is the primary way transmission is terminated at all cholinergic synapses (see Fig 1), these drugs act at virtually all synapses where ACh is the neurotransmitter (i.e. autonomic ganglia (if they're relatively uncharged), NMJ, and muscarinic receptors Classification of Parasympathomimetics 1-Cholin esters a)Acetylcholine b)Methacholine c)Carbachol d)Bethanechol 2-Cholinomimetic natural alkaloids a)Pilocarpine b)Arecholine c)Muscarine 3-Anticholinesterases a)Reversible 1-Carbamates Tertiary amines Physostigmine Quaternary ammonium compounds Neostigmiine , Pyridostigmine, Ambenonium, Distigmine & Tecrine 2-Alcohols edrophonium b)Irreversible Organophosphorus compounds Diilsopropyl Fluorophosphate(DFP)(Dyflos) Tetraethyl Pyrophosphate (TEPP) Sarin , Parathion ,Malathion & Ecothiopate 1- CHOLINE ESTERS This group includes acetycholine and its derivatives clinically useful derivative - methacholine, carbachol, bethanechol Acetylcholine Acetylcholine acetylcholine research acetylcholine and alzheimer's acetylcholine and choline Acetylcholine was the very first neurotransmitter to be identified back in the early 1900s. It is made simply from choline and a two-carbon molecule called acetyl. Dietary choline and phosphatidylcholine serve as the sources of free choline for acetylcholine synthesis. Acetylcholine is found in the brain and the peripheral nervous system. Acetylcholine plays numerous roles. In the brain, acetylcholine is involved in learning and memory. Supplements such as choline and CDP-choline influence levels of acetylcholine. Acetylcholine is a neurotransmitter that helps facilitate erections. Once produced, acetylcholine is stored in brain cells and released into the synaptic cleft upon stimulation. When released into the synaptic cleft, the enzyme acetylcholinesterase breaks acetylcholine back down into choline and acetyl. In Alzheimer's disease, there is a shortage of acetylcholine, and one of the ways doctors have tried to increase the levels of this neurotransmitter is by prescribing drugs, such as tacrine and galantamine, that inhibit the enzyme acetylcholinesterase. An alternative to these drugs, a Chinese herbal extract called huperzine A, can also inhibit this enzyme. Galantamine is now available without a prescription. 1-neurotransmitter in the brain, where it helps to regulate memory, and in the peripheral nervous system, where it controls the actions of skeletal and smooth muscle. 2-neurotransmitter of the central, somatomotor, and parasympathetic nervous systems and of the ganglia and the neuron-sweat gland junctions of the sympathetic nervous systems. synthesis of acetylcholine (ACh) from acetyl CoA and choline storage of ACh in synaptic vesicles release of ACh ( fusion of synaptic vesicle with presysnaptic membrane and release of ACh into the synapse) action of ACh by binding to and activating receptors (nicotinic in autonmic ganglia and NMJ and muscarinic in many sites) inactivation by enzymatic breakdown of ACh by acetylcholinesterase (AChE) located in the synapse Pharmacological actions:- actions of acetylcholine are divided into two main groups 1- muscaranic actions These actions are produced in tissues supplied by postganglionic cholinergic nerve ending ( all parasympathetic endings and sympathetic endings of sweat glands and blood vesseles ) .Theseactions occur in eyes ,smooth muscle of GIT , urinary bladder and bronchi ,CVS and exocrine glands. The actions are called muscaranic due to their close resemblance to the actions produced by the alkaloid muscaranic 2- Nicotinic actions These actions are produced by stimulation os all autonomic ganglia and the neuromuscular junction. These actions are called nicotinic because nicotinic stimulates autonomic ganglia in the same way as does acetylcholine. Muscaranic actions of acetylcholine are stronger than its nicotinic actions .The muscaranic actions are blocked by atropine wheras the nicotinic action are blocked by hexamethonium and related drugs at autonomic ganglia and by tubocurarine and other competitive blocking agents at neuromuscular junction. Muscaranic actions Muscaranic actions of acetylcholine in various organs are described below : 1- Eye : Constriction of pupil of eye (miosis) occurs due to contraction of circular fibers of the iris. spasm of accomodation occurs due to contraction of ciiary muscle . Eye is set fornear vision.Fall in itraocular pressure is produced due to better drainge through the canal of schlemm which occurs due to pulling away of the iris from the angle of the anterior chamber and opening up of the tracbecular network at the base of the ciliary muscle 2- cardiovascular system bradycardia and vasodilationare the most prominent effects of acetylcholine . This leads fall in blood pressure. increase in membrane potassium permiability in atrial muscle cells and probably in the cells of the S.A Node and A.V Node cause slowing of pace maker rateand the hyperpolarization . There is decrese in the contractile strnght of ventricles. Acetylcholine when injected produces dilatation of essentially all vascular beds including the pulmonary and coronary vessels 3- Lungs : Sooth muscle of bronchi is contract , There is increases secreation of the glands of tracheobronchial mucosa .These effects may be serious in asthmatics. 4- G.I Tract: There is increse in secretory and motor activity of gut .Sphincters are relaxed.There ismarked increse in salivary and gastric secretions. 5- Urinay Bladder : The detrusor muscle trigone and sphincter are relaxed thus promoting micturition Drug Acetylcholine Action Parasympathomimetic Agent Class Choline Ester Receptor Nicotinic and Muscarinic receptors (AchE) ADME Ach is naturally at the post-junctional membranes of neurons and effector cells. (refer to class 4 of the cholinergic nerves). Readily metabolized by AchE in synapse or neuroeffector cell junction. Choline actively taken up by neurons Direct Effects Cardiovascular: vasodialation, decreased heart rate, inotropy (force of contraction). GI: increased tone, inotropy, peristalsis, and secretion. Bronchoconstriction; stimulates secretion of lacrimals, tracheobronchial, salivary, digestive, and sweat glands Side Effects If used as a drug, nicotinic side effects are the initial stimulation of autonomic ganglia and neuromuscular junction. At high doses, get blockage of autonomic ganglia and neuromuscular junction Therapeutic Use 1% ophthalmic solution for brief production of miosis Contraindications Intestinal obstruction, respiratory distress, and pregnancy Drug Interactions Effects of Ach are synergized by previous administration of AchE inhibitors; muscarinic effects antagonized selectively by atropine Toxicity Should be administered orally, SQ, intraconjunctivally. IV or IM increase incidence and severity of toxic side effects due to promt stimulation Antidotes Atropine for muscarinic and CNS effects; epinephrine for cardiovascular effects and bronchoconstriction Acetylcholinesterase Locations · Acetylcholinesterase: post-synaptic cholinergic membranes. · Inhibition of acetylcholinesterase with subsequent acetylcholine accumulation causes: enhanced muscarinic responses at parasympathetic effector sites. nicotinic receptor stimulation and then paralysis (depolarization block) at autonomic ganglia and skeletal muscle. CNS cholinergic neuronal stimulation · Effects of increased acetylcholine levels can be blocked or reduced by atropine (muscarinic antagonist) at: · parasympathetic effector sites · autonomic ganglia (muscarinic receptor population) · subcortical CNS sites. Methacholine This drug has both muscarinic and nicotinic actions but nicotinic actions are not prominent.Muscarinic actions are more preminent on cardiovascular system than on the G I Tractand urinary bladder . Drug Methacholine Action Parasympathomimetic Agent Class Choline Ester Receptor Nicotinic and Muscarinic receptors (AchE) ADME Administer orally, sub-q or intraconjunctivlly. Slowly hydrolyzed by AchE Direct Effects Cardiovascular: vasodialation, decreased heart rate, inotropy. GI: increased tone, inotropy, peristalsis, and secretion. Bronchoconstriction; stimulates secretion by glands Therapeutic Use Rarely used. Break atrial or AV junctional tachycardia; Diagnosis of atropine poisoning Dose 10 -- 30 mg Contraindications Intestinal obstruction, respiratory distress, and pregnancy Drug Interactions Effects enhanced by previous administration of AchE inhibitors; Muscarinic effects antagonized selectively by atropine Toxicity IV and IM administration increases incidence and severity of toxic side effects due to prompt stimulation Antidotes Atropine for muscarinic and CNS effects; epinephrine for cardiovascular effects and bronchoconstriction Carbachol ( Carbamylcholine ) :- This drug has both muscarinic and nicotinic actions .Carbachol is an ester of carbamic acid and a poor substrate for acetylcholine .Its biotransformed by other esterases but at much slower rate . A single adminstration can last as long as one hour . Drug Carbachol Action Parasympathomimetic Agent Class Choline Ester Receptor Muscarinic and Nicotinic ADME Administer orally or sub-q. Not hydrolyzed by AchE Direct Effects GI: increased tone, inotropy, peristalsis, secretion. Stimulates srection by glands, bronchoconstriction. Cardiovascular effects are inconspicuous Side Effects Nicotinic side effects are the initial stimulation and at high doses, get blockage of autonomic ganglia and neuromuscular junction. May cause abortion in late trimester pregnancy Therapeutic Use Used to expel afterbirth in cattle and swine if uterus is no longer responsive to oxytocin. Questionable results to counteract ruminal atony Dose Orally 1-4 mg , subcutaneously 250 to 500 mcg Contraindications Intestinal obstruction, respiratory distress, pregnancy Drug Interactions Effects enhanced by previous administration of AchE inhibitors; Muscarinic effects antagonized selectively by atropine Toxicity Get skeletal muscle, autonomic ganglia and CNS effects at high doses Antidotes Atropine for muscarinic and CNS effects Bethanechol Structurally related to acetylcholine ;the acetate is replaced by carbamate and the choline is methylated hnce its not hydrolysed by cholinestrases. It has strong muscarinic action but little or no nicotinic actions main action on musculature of the bladder and G I Tract it has duration of action about 1 hour Drug Bethanechol Action Parasympathomimetic Agent Class Choline Ester Receptor Muscarinic Only à most selective ADME Administer orally or sub-q. Not hydrolyzed by AchE Direct Effects Selectively stimulates urinary and GI Tracts (decreased tone, inotropy, peristalsis, secretion). Cardiovascular effects are inconspicuous Side Effects Will accumulate at muscarinic receptors Therapeutic Use Used to stimulate contraction of GI and urinary tracts Dose Orally 5-- 30 mg, subcutanously 2.5 -- 5 mg Contraindications Intestinal or urinary obstruction, respiratory disease, pregnancy Drug Interactions Effects enhanced by previous administration of AchE inhibitors; Muscarinic effects antagonized selectively by atropine Toxicity IV or IM administration increases incidence and severity of toxic side effects due to prompt stimulation Antidotes Atropine for muscarinic cholinomimetic alkaloids Pilocarpine Its an alkaloid obtained from Pilocarpus jaborandi leaves and composed of tertiary amine and is stable to hydrolysis by acetylcholinestrases its primarly used in Opthalmology. GENERIC NAME: pilocarpine oral BRAND NAME: Salagen DRUG CLASS AND MECHANISM: Pilocarpine is a "cholinergic" drug, that is, a drug that mimics the effects of the chemical, acetylcholine which is produced by nerve cells. Acetylcholine serves as a messenger between nerve cells and between nerve cells and the organs they control. For example, acetylcholine is responsible for causing the salivary glands to make saliva and the lacrimal glands to make tears to lubricate the eyes. In addition to its effects on the salivary and lacrimal glands, acetylcholine controls the production of fluid within the eye, and pilocarpine eye drops have been used to treat glaucoma for many years. In 1994, an oral formulation of pilocarpine was approved by the FDA for the treatment of dry mouth caused by radiation therapy for head and neck cancer, a treatment that damages the salivary glands and reduces their production of saliva. In 1998, the oral preparation was approved for the management of Sjogren's syndrome, an autoimmune disease that damages the salivary and lacrimal glands. Piloca pilocarpine was first isolated from the leaves of Pilocarpus microphyllus (also called jaborandi) in 1875. PREPARATIONS: Tablets, 5mg. STORAGE: Tablets should be stored at room temperature, 15-30°C (59-86°F). PRESCRIBED FOR: Oral pilocarpine is used to treat dry mouth caused by Sjogren's syndrome and radiation therapy to the head and neck. DOSING: Oral pilocarpine usually is taken three or four times daily. The maximum effect occurs in approximately one hour but may occur later if it is taken with food. The effects last three to five hours. DRUG INTERACTIONS: Medications possessing anticholinergic effects or side effects should not be used with pilocarpine since they will counter pilocarpine's cholinergic effects. Such medications include atropine, e.g., Lomotil; some antihistamines, e.g., carbinoxamine (Cardec-DM, Rondec-D), clemastine (Tavist), diphenhydramine (Benadryl), promethazine (Phenergan), trimeprazine (Temaril); some phenothiazines, e.g., mesoridazine (Serentil), promazine (Sparine), thioridazine (Mellaril), triflupromazine (Vesprin)]; clozapine (Clozaril), cyclobenzaprine (Flexeril), disopyramide Norpace); some antidepressants, e.g., amitriptyline (Elavil), amoxapine (Asendin), bupropion (Wellbutrin; Zyban), clomipramine (Anafranil), doxepin (Sinequan), maprotiline (Ludiomil), and protriptyline (Vivactil). SIDE EFFECTS: Excessive sweating (diaphoresis) is a frequent side effect of pilocarpine. Other side effects include chills, dizziness, excessive tearing, flushing, voice change, stuffy nose, tremor, increased need to urinate, visual disturbances, diarrhea, difficulty swallowing, abdominal pain, nausea, vomiting, and slow heart rate. Drug Pilocarpine Action Parasympathomimetic Agent Class Cholinomimetic Alkaliod Receptor Muscarinic and Nicotinic ADME Administer orally or sub-q. Not hydrolyzed by AchE. Inactived by metabolism and excretion Direct Effects GI: increased peristalsis and secretion. Stimulates secretion by glands; bronchoconstriction; cardiovascular: bradycardia, hypotension. Urinary: increased tone and motility. CNS Stimulation and depression Side Effects Therapeutic Use Mitotic to treat glaucoma. Used alternately with atropine to break adhesions between iris and lens. Decreases intraocular pressure to cure glaucoma Dose 3 -- 12 mg Orally or subcutaneously Contraindications Intestinal obstruction, respiratory distress, pregnancy Drug Interactions Effects enhanced by previous administration of AchE inhibitors; Muscarinic effects antagonized selectively by atropine Toxicity Get skeletal muscle, autonomic ganglia, and CNS effects at high doses Antidotes Atropine for muscarinic and CNS effects; Epinephrine for cardiovascular effects and bronchoconstriction Muscarine its an alkaloid present in mushroom amanita muscaria whose ingestion causes muscaranic poisoning .its effects are to stimulate all parasympathetic postganglionic fibers. these effects are blocked by atropine Drug Muscarine Action Parasympathomimetic Agent Class Cholinomimetic Alkaliod Receptor Muscarinic ADMEAdminister orally or sub-q. Not hydrolyzed by AchE. Inactived by metabolism and excretion. Decreased availability due to quaternary nitrogen Direct Effects GI: increased peristalsis and secretion. Stimulates secretion by glands; bronchoconstriction; cardiovascular: bradycardia, hypotension. Urinary: increased tone and motility. CNS Stimulation and depression Side Effects Therapeutic UseNot employed clinically. Found in some mushrooms Contraindications Intestinal obstruction, respiratory distress and pregnancy Drug Interactions Effects enhanced by previous administration of AchE inhibitors; Muscarinic effects antagonized selectively by atropine Toxicity Can be treated with atropine. However, animal may die from hepatotoxins in some species of mushrooms Antidotes Atropine for muscarinic and CNS effects; Epinephrine for cardiovascular effects and bronchoconstriction Arecoline its an alkaloid present in betel nut . it has mainly muscarinic actions . its not used theraputically because of high toxicity Drug Arecholine Action Parasympathomimetic Agent Class Cholinomimetic Alkaliod Receptor Muscarinic and Nicotinic ADMEAdminister orally or sub-q. Not hydrolyzed by AchE. Inactived by metabolism and excretion Direct Effects GI: increased peristalsis and secretion. Stimulates secretion by glands; bronchoconstriction; cardiovascular: bradycardia, hypotension. Urinary: increased tone and motility. CNS Stimulation and depression Side Effects Respiratory difficulties Therapeutic UseOutdated teniacide and vermifuge in dogs Contraindications Intestinal obstruction, respiratory distress and pregnancy Drug Interactions Effects enhanced by previous administration of AchE inhibitors; Muscarinic effects antagonized selectively by atropine Toxicity Get skeletal muscle, autonomic ganglia and CNS effects at high doses Antidotes Atropine for muscarinic and CNS effects; Epinephrine for cardiovascular effects and bronchoconstriction Pharmacological Effects of Cholinomimetics ( SUMMARY ) Cardiovascular: Four major effects Vasodilation: This effect is mediated by muscarinic receptor activation and is especially prominent in the salivary gland and intestines. · The vascular response is due to endothelial cell nitric oxide (NO) release following agonist interactions with endothelial muscarinic receptors. Increased NO activates guanylate cyclase which increases cyclic GMP concentrations. Subsequent activation of a Ca2+ ion pump reduces intracellular Ca2+. Reduction in intracellular Ca2+ causes vascular smooth muscle relaxation. Ca2+ complexes with calmodulin activating light-chain myosin kinase Increased cGMP promotes dephosphorylation of myosin light-chains. Smooth-muscle myosin must be phosphorylated in order to interact with actin and cause muscle contraction. · Vasodilation may also occur due to ACh inhibition of N.E. release from post-ganglionic sympathetic fibers. · Damaged endothelium can result in ACh causing vasoconstriction by direct action on vascular smooth muscle. · Negative chronotropic effect (Decrease in heart rate) · Decreases phase 4 (diastolic depolarization) · As a result, it takes longer for the membrane potential to reach threshold. · Mediated by M2 muscarinic receptors · Decreased SA nodal and AV nodal conduction velocity · Excessive vagal tone may induce bradyarrhythmias including partial or total heart block (impulses cannot pass through the AV node to drive the ventricular rate; in this case, the idioventricular or intrinsic ventricular rate must maintain adequate cardiac output) · Transmission through the AV node is especially dependent on Ca2+ currents. · ACh decreases calcium currents in the atrioventricular node. · Negative inotropism (decreased myocardial contractility) · more prominent in atrial than ventricular tissue. · due to a decrease in ICa2+ inward current · in the ventricle, adrenergic tone dominates; · at higher levels of sympathetic tone, a reduction in contractility due to muscarinic stimulation is noted. · Muscarinic stimulation reduces the response to norepinephrine by opposing increases in cAMP in addition to reducing norepinephrine release from adrenergic terminals · Effect of muscarinic receptor activation on cardiac currents · increase in I K (Ach) in atrial muscle and in SA and AV nodal tissue · decrease in slow, inward calcium (ICa2+) current (decreased atrial contractility; decreased AV nodal conduction) · decrease in diastolic depolarizing current (If)--decreases heart rate, because it takes longer for the membrane potential to reach threshold (less depolarizing If current) · Gastrointestinal and Urinary Tracts · Muscarinic agonists increase intestinal peristalsis, tone, and contraction amplitude. · Carbachol and bethanecol (not ACh or methacholine) stimulate the urinary tract by increasing ureteral peristalsis and by contraction of the urinary bladder detrusor muscle. Clinical Uses · Gastrointestinal & Genitourinary · Bethanechol (Urecholine) · GI smooth muscle stimulant · postoperative abdominal distention · paralytic ileus · esophageal reflux; promotes increased esophageal motility (other drugs are more effective, e.g. dopamine antagonist (metoclopramide) or serotonin agonists (cisapride) · Urinary bladder stimulant · post-operative; post-partum urinary retention · alternative to pilocarpine to treat diminished salivation secondary e.g. to radiation · Carbachol not used due to more prominent nicotinic receptor activation · Methacholine used for diagnostic purposes. · testing for bronchial hyperreactivity and asthma · Opthalmological Uses · Acetylcholine and Carbachol may be used for intraocular use as a miotic in surgery Carbachol may be used also in treatment of glaucoma. · Pilocarpine is used in management of glaucoma and has become the standard initial drug for treating the open-angle form. Sequential adminstration of atropine (mydriatic) and pilocarpine (miotic) is used to break iris-lens adhesions. Major contraindication to the use of muscarinic agonists Asthma: Choline esters (muscarinic agonists) can produce bronchoconstriction. In the predisposed patient, an asthmatic attack may be induced. Hyperthyroidism: Choline esters (muscarinic agonists) can induce atrial fibrillation in hyperthyroid patients. Peptic ulcer: Choline esters (muscarinic agonists), by increasing gastric acid secretion, may exacerbate ulcer symptoms. Coronary vascular disease: Choline esters (muscarinic agonists), as a result of their hypotensive effects, can further compromise coronary blood flow. · Adverse Effects: Muscarinic Agonists · salivation · diaphoresis · colic · GI hyperactivity · headache · loss of accommodation Cholinoceptor-Blocking Drugs · Introduction: Muscarinic Receptor Antagonists · Antimuscarinic agents were of plant origin. Belladonna (beautiful woman, a reference to the drug's mydriatic effects,) are found in many plants. Atropa belladonna (Solanaceae) or the deadly nightshade contains atropine (dl-hyoscyamine) as does Datura stramonium (Jamestown or jimsonweed, thorn-apple,etc. Scopolamine, also an alkaloid, is found in the shrub Hyosyamus niger and Scopolia carniolica. An alkaloid is one of a large group of organic, basic plant substances. They are usually pharmacologically active and bitter in taste · Alkaloids · atropine · caffeine · morphine · nicotine · quinine · strychnine · Tertiary and Quaternary Antimuscarinic Agents Atropine, scopolamine, and the semisynthetic agent homatropine (Isopto Homatropine) are tertiary amines, generally well-absorbed and able to penetrate the CNS. Each drug can be converted to a quaternary form by addition of a methyl group to the nitrogen, resulting in methylatropine nitrate, methscopolamine bromide and homatropine methybromide. Quaternary muscarinic receptor antagonists tend to be more potent as muscarinic blockers and have increased ganglionic blocking action. Quaternary (permanently charged) antagonists do not penetrate the CNS to a significant extent. Therefore, CNS activity is limited. Acetylcholinesterase Inhibitors Overview Three domains describe the acetylcholinesterase active site: an acyl binding region, the choline binding region, and a peripheral anionic site. There are three classes of anticholinesterase agents Reversible, Short-Acting Anticholinesterases Reversible inhibitors, edrophonium (Tensilon) and tacrine (Cognex), associate with the choline binding domain. The short duration of edrophonium (Tensilon) action is due to its binding reversibility and rapid renal clearance. Tacrine (Cognex), being more lipophillic, has a longer duration. Some reversible inhibitors, propidium and fasiculin, a toxic peptide, bind at the peripheral anionic site. Carbamylating Agents: Intermediate-Duration Acetylcholinesterase Inhibitors Physostigmine and Neostigmine are acetylcholinesterase inhibitors that form a moderately stable carbamyl-enzyme derivative. The carbamyl-ester linkage is hydrolyzed by the esterase, but much more slowly compared to acetylcholine. As a result, enzyme inhibition by these drugs last about 3 - 4 h (t ½ = 15 - 30 min). Neostigmine possesses a quaternary nitrogen and thus has a permanent positive charge. By contrast, physostigmine is a tertiary amine Phosphorylating Agents: Long-Duration Acetylcholinesterase Inhibitors Organophosphate acetylcholinesterase inhibitors, such as diisopropyl fluorophosphate (DFP) form stable phosphorylated serine derivatives. For DFP the enzyme effectively does not regenerate following inhibition. Furthermore, in the case of DFP, the loss, termed "aging", of an isopropyl group, further stabilizes the phosphylated enzyme. The application of the terms "reversible" and "irreversible" depends on the duration of enzyme inhibition rather than strictly based on mechanism. (see above) Examples of "reversible" acetylcholinesterase inhibitors that may be used clinically include both carbamylating agents and those that associate only with the choline binding domain. "Reversible" Anticholinesterases Used Clinically · edrophonium · pyridostigmine-Used in treatment of myasthenia gravis · neostigmine · physostigmine · demecarium · ambenonium-Used in treatment of myasthenia gravis Physostigmine Description Physostigmine (fi-zoe-STIG-meen )is an alkaloid ( anitrogenous compound found in plants ) and tertiary amine . Its a substrate for acetylcholiestrase and form relatively stable enzyme -substrate intermediate that reversible inactivates acetylcholiestrase .The result is potetiation of cholinergic activety throughoutthe body . It is used to treat certain types of glaucoma. Ophthalmic · Ophthalmic ointment · Ophthalmic solution (eye drops) Dosing— For glaucoma: For ophthalmic ointment dosage form: · Adults and children—Use in each eye one to three times a day. · For ophthalmic solution (eye drops) dosage form: · Adults and children—One drop in each eye up to four times a day. Side Effects of This Medicine Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention. Check with your doctor as soon as possible if any of the following side effects occur: · Symptoms of too much medicine being absorbed into the body Increased sweating; loss of bladder control; muscle weakness; nausea, vomiting, diarrhea, or stomach cramps or pain; shortness of breath, tightness in chest, or wheezing; slow or irregular heartbeat; unusual tiredness or weakness; watering of mouth Other side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. · More common · Blurred vision or change in near or distant vision; eye pain · Less common · Burning, redness, stinging, or other eye irritation; headache or browache; twitching of eyelids ; watering of eyes Neostigmine ( Prostigmine) Neostigmine is synthetic compound that reversible inhibit acetylcholineestrase and its more polad so does not enter the CNS Drug used to mimic the effects of stimulation of the parasympathetic nervous system. Along with several other drugs that have a similar mode of action, it inhibits the action of the enzyme cholinesterase, which destroys the substance acetylcholine at nerve endings. Because neostigmine increases the effective concentration of acetylcholine, it causes such body changes as contraction of the pupils, increased activity of intestinal muscles, and increased secretion by the salivary and sweat glands. It will cause menstrual bleeding in a nonpregnant woman whose menstrual period is delayed, and it is therefore used as a pregnancy test. Neostigmine and related drugs are also used to diagnose and control the neuromuscular disease myasthenia gravis. Because neostigmine causes decreased fluid pressure in the eye it is used to treat certain types of glaucoma. The drug atropine is sometimes given along with neostigmine to prevent the latter's side effects. ephedrine often enhances the action of neostigmine. DESCRIPTION Prostigmin (neostigmine bromide), an anticholinesterase agent, is available for oral administration in 15-mg tablets. Each tablet also contains gelatin, lactose, corn starch, stearic acid, sugar and talc. Chemically, neostigmine bromide is ( m -hydroxyphenyl)trimethylammonium bromide dimethylcarbamate. It is a white, crystalline, bitter powder, soluble 1:1 in water, with a molecular weight of 303.20. CLINICAL PHARMACOLOGY Neostigmine inhibits the hydrolysis of acetylcholine by competing with acetylcholine for attachment to acetylcholinesterase at sites of cholinergic transmission. It enhances cholinergic action by facilitating the transmission of impulses across neuromuscular junctions. It also has a direct cholinomimetic effect on skeletal muscle and possibly on autonomic ganglion cells and neurons of the central nervous system. Neostigmine undergoes hydrolysis by cholinesterase and is also metabolized by microsomal enzymes in the liver. Protein binding to human serum albumin ranges from 15 to 25 percent. Neostigmine bromide is poorly absorbed from the gastrointestinal tract following oral administration. As a rule, 15 mg of neostigmine bromide orally is equivalent to 0.5 mg of neostigmine methylsulfate parenterally, due to poor absorption of the tablet from the intestinal tract. In a study in fasting myasthenic patients, the extent of absorption was estimated to be 1 to 2 percent of the ingested 30-mg single oral dose. Peak concentrations in plasma occurred 1 to 2 hours following drug ingestion, with considerable individual variations. The half-life ranged from 42 to 60 minutes with a mean half-life of 52 minutes. INDICATIONS AND USES Prostigmin is indicated for the symptomatic treatment of myasthenia gravis. Its greatest usefulness is in prolonged therapy where no difficulty in swallowing is present. In acute myasthenic crisis where difficulty in breathing and swallowing is present, the parenteral form (neostigmine methylsulfate) should be used. The patient can be transferred to the oral form as soon as it can be tolerated. SIDE EFFECTS Side effects are generally due to an exaggeration of pharmacological effects of which salivation and fasciculation are the most common. Bowel cramps and diarrhea may also occur. The following additional adverse reactions have been reported following the use of either neostigmine bromide or neostigmine methylsulfate: Allergic: Allergic reactions and anaphylaxis. Neurologic: Dizziness, convulsions, loss of consciousness, drowsiness, headache, dysarthria, miosis and visual changes. Cardiovascular: Cardiac arrhythmias (including bradycardia, tachycardia, A-V block and nodal rhythm) and nonspecific EKG changes have been reported, as well as cardiac arrest, syncope and hypotension. These have been predominantly noted following the use of the injectable form of Prostigmin. Respiratory: Increased oral, pharyngeal and bronchial secretions, and dyspnea. Respiratory depression, respiratory arrest and bronchospasm have been reported following the use of the injectable form of Prostigmin. Dermatologic: Rash and urticaria. Gastrointestinal: Nausea, emesis, flatulence and increased peristalsis. Genitourinary: Urinary frequency. Musculoskeletal: Muscle cramps and spasms, arthralgia. Miscellaneous: Diaphoresis, flushing and weakness. DRUG INTERACTIONS Certain antibiotics, especially neomycin, streptomycin and kanamycin, have a mild but definite nondepolarizing blocking action which may accentuate neuromuscular block. These antibiotics should be used in the myasthenic patient only where definitely indicated, and then careful adjustment should be made of adjunctive anticholinesterase dosage. Local and some general anesthetics, antiarrhythmic agents and other drugs that interfere with neuromuscular transmission should be used cautiously, if at all, in patients with myasthenia gravis; the dose of Prostigmin may have to be increased accordingly. OVERDOSE Overdosage of Prostigmin can cause cholinergic crisis, which is characterized by increasing muscle weakness, and through involvement of the muscles of respiration, may result in death. Myasthenic crisis, due to an increase in the severity of the disease, is also accompanied by extreme muscle weakness and may be difficult to distinguish from cholinergic crisis on a symptomatic basis. However, such differentiation is extremely important because increases in the dose of Prostigmin or other drugs in this class, in the presence of cholinergic crisis or of a refractory or "insensitive" state, could have grave consequences. The two types of crises may be differentiated by the use of Tensilon® (edrophonium chloride) as well as by clinical judgment. Treatment of the two conditions differs radically. Whereas the presence of myasthenic crisis requires more intensive anticholinesterase therapy, cholinergic crisis calls for the prompt withdrawal of all drugs of this type. The immediate use of atropine in cholinergic crisis is also recommended. Atropine may also be used to abolish or minimize gastrointestinal side effects or other muscarinic reactions; but such use, by masking signs of overdosage, can lead to inadvertent induction of cholinergic crisis. The LD 50 of neostigmine methylsulfate in mice is 0.3 ± 0.02 mg/kg intravenously, 0.54 ± 0.03 mg/kg subcutaneously, and 0.395 ± 0.025 mg/kg intramuscularly; in rats the LD 50 is 0.315 ± 0.019 mg/kg intravenously, 0.445 ± 0.032 mg/kg subcutaneously, and 0.423 ± 0.032 mg/kg intramuscularly. CONTRAINDICATIONS Prostigmin is contraindicated in patients with known hypersensitivity to the drug. Because of the presence of the bromide ion, it should not be used in patients with a previous history of reaction to bromides. It is contraindicated in patients with peritonitis or mechanical obstruction of the intestinal or urinary tract. WARNINGS Prostigmin should be used with caution in patients with epilepsy, bronchial asthma, bradycardia, recent coronary occlusion, vagotonia, hyperthyroidism, cardiac arrhythmias or peptic ulcer. As a rule, 15 mg of neostigmine bromide orally is equivalent to 0.5 mg of neostigmine methylsulfate parenterally, due to poor absorption of the tablet from the intestinal tract. Large doses should be avoided in situations where there might be an increased absorption rate from the intestinal tract. It should be used with caution when co-administered with anticholinergic drugs, in order to avoid reduction of intestinal motility. MYASTHENIA GRAVIS - A SUMMARY Myasthenia gravis (MG) is the most common primary disorder of neuromuscular transmission. The usual cause is an acquired immunological abnormality, but some cases result from genetic abnormalities at the neuromuscular junction. Much has been learned about the pathophysiology and immunopathology of myasthenia gravis during the past 20 years. What was once a relatively obscure condition of interest primarily to neurologists is now the best characterized and understood autoimmune disease. A wide range of potentially effective treatments are available, many of which have implications for the treatment of other autoimmune disorders. TREATMENT A controlled clinical trial has never been reported for any medical or surgical modality used to treat myasthenia gravis. All recommended regimens are empirical and experts disagree on treatments of choice. Treatment decisions should be based on knowledge of the natural history of disease in each patient and the predicted response to a specific form of therapy. Treatment goals must be individualized according to the severity of disease, the patient's age and sex, and the degree of functional impairment. The response to any form of treatment is difficult to assess because the severity of symptoms fluctuates. Spontaneous improvement, even remissions, occur without specific therapy, especially during the early stages of the disease. Cholinesterase Inhibitors ChE inhibitors retard the enzymatic hydrolysis of ACh at cholinergic synapses, so that ACh accumulates at the neuromuscular junction and its effect is prolonged. ChE inhibitors cause considerable improvement in some patients and little to none in others. Strength rarely returns to normal. Pyridostigmine bromide (Mestinon) and neostigmine bromide (Prostigmin) are the most commonly used ChE inhibitors. No fixed dosage schedule suits all patients. The need for ACh inhibitors varies from day-to-day and during the same day in response to infection, menstruation, emotional stress, and hot weather. Different muscles respond differently; with any dose, certain muscles get stronger, others do not change, and still others become weaker. Adverse effects of ChE inhibitors may result from ACh accumulation at muscarinic receptors on smooth muscle and autonomic glands and at nicotinic receptors of skeletal muscle. Central nervous system side effects are rarely seen with the doses used to treat myasthenia gravis. Gastrointestinal complaints are common; queasiness, loose stools, nausea, vomiting, abdominal cramps, and diarrhea. Increased bronchial and oral secretions are a serious problem in patients with swallowing or respiratory insufficiency. Symptoms of muscarinic overdosage may indicate that nicotinic overdosage (weakness) is also occurring. Excessive nicotinic receptor overdosage results in Myasthenic Crisis characterized by severe generalized weakness and respiratory failure. Pyridostigmine ( Mestinon ) DESCRIPTION Mestinon (pyridostigmine bromide) is an orally active cholinesterase inhibitor. Chemically, pyridostigmine bromide is 3-hydroxy-1-methylpyridinium bromide dimethylcarbamate. Mestinon is available in the following forms: Syrup containing 60 mg pyridostigmine bromide per teaspoonful in a vehicle containing 5% alcohol, glycerin, lactic acid, sodium benzoate, sorbitol, sucrose, FD&C Red No. 40, FD&C Blue No. 1, flavors and water. Tablets containing 60 mg pyridostigmine bromide; each tablet also contains lactose, silicon dioxide and stearic acid. Timespan Tablets containing 180 mg pyridostigmine bromide; each tablet also contains carnauba wax, corn-derived proteins, magnesium stearate, silica gel and tribasic calcium phosphate. CLINICAL PHARMACOLOGY ACTIONS Mestinon inhibits the destruction of acetylcholine by cholinesterase and thereby permits freer transmission of nerve impulses across the neuromuscular junction. Pyridostigmine is an analog of neostigmine (Prostigmin®), but differs from it in certain clinically significant respects; for example, pyridostigmine is characterized by a longer duration of action and fewer gastrointestinal side effects. Mestinon is useful in the treatment of myasthenia gravis. DOSAGE AND ADMINISTRATION Mestinon is available in three dosage forms: Syrup raspberry-flavored, containing 60 mg pyridostigmine bromide per teaspoonful (5 mL). This form permits accurate dosage adjustment for children and "brittle" myasthenic patients who require fractions of 60-mg doses. It is more easily swallowed, especially in the morning, by patients with bulbar involvement. Conventional Tablets each containing 60 mg pyridostigmine bromide. Timespan Tablets each containing 180 mg pyridostigmine bromide. This form provides uniformly slow release, hence prolonged duration of drug action; it facilitates control of myasthenic symptoms with fewer individual doses daily. The immediate effect of a 180-mg Timespan Tablet is about equal to that of a 60-mg Conventional Tablet; however, its duration of effectiveness, although varying in individual patients, averages 2 1 / 2 times that of a 60-mg dose. Dosage: The size and frequency of the dosage must be adjusted to the needs of the individual patient. Syrup and Conventional Tablets The average dose is ten 60-mg tablets or ten 5-mL teaspoonfuls daily, spaced to provide maximum relief when maximum strength is needed. In severe cases as many as 25 tablets or teaspoonfuls a day may be required, while in mild cases one to six tablets or teaspoonfuls a day may suffice. Timespan Tablets One to three 180-mg tablets, once or twice daily, will usually be sufficient to control symptoms; however, the needs of certain individuals may vary markedly from this average. The interval between doses should be at least 6 hours. For optimum control, it may be necessary to use the more rapidly acting regular tablets or syrup in conjunction with Timespan therapy. SIDE EFFECTS The side effects of Mestinon are most commonly related to overdosage and generally are of two varieties, muscarinic and nicotinic. Among those in the former group are nausea, vomiting, diarrhea, abdominal cramps, increased peristalsis, increased salivation, increased bronchial secretions, miosis and diaphoresis. Nicotinic side effects are comprised chiefly of muscle cramps, fasciculation and weakness. Muscarinic side effects can usually be counteracted by atropine, but for reasons shown in the preceding section the expedient is not without danger. As with any compound containing the bromide radical, a skin rash may be seen in an occasional patient. Such reactions usually subside promptly upon discontinuance of the medication. CONTRAINDICATIONS Mestinon is contraindicated in mechanical intestinal or urinary obstruction, and particular caution should be used in its administration to patients with bronchial asthma. Care should be observed in the use of atropine for counteracting side effects, as discussed below. PRECAUTIONS Pyridostigmine is mainly excreted unchanged by the kidney. 6,7,8 Therefore, lower doses may be required in patients with renal disease, and treatment should be based on titration of drug dosage to effect. 6,7 Pediatric Use: Safety and effectiveness in pediatric patients have not been established. Distigmine ( Ubretid ) is similar to pyridostigmime .Duration of action is much longer .Its used as an adjunct to treatment in myasthenia gravis and to treat urinary retention following surgery. Dose : Initially 5 mg daily to be increased upto 20mg daily . AMBENONIUM Brand & Generic Names Mytelase Basic Information Habit forming? No Prescription needed? Yes Available as generic? No Drug class: Cholinergic, antimyasthenic Uses Diagnosis and treatment of myasthenia gravis. Treatment of urinary retention and abdominal distention. Dose : 5to 25 mg 3-4 times daily adjusted according to the response SIDE EFFECTS: Nausea may occur. headache, diarrhea, stomach pain, increased saliva, increased sweating, urinary urgency, eye changes (pinpoint pupils or increased tears). but serious side effects occur: unusually slow pulse, trouble breathing, trouble swallowing, vision changes, muscle cramps or spasms, muscle weakness, dizziness. Tell your doctor immediately if any of these highly unlikely, but very serious side effects occur: chest pain, loss of coordination, seizures, mental/mood changes. DRUG INTERACTIONS: Tmedication you may use, especially: mecamylamine, atropine, aminoglycoside antibiotics (e.g., neomycin, gentamicin, tobramycin), local or general anesthetics (e.g., lidocaine), heart rhythm drugs (e.g., quinidine), corticosteroids (e.g., prednisone), cholinergic drugs (e.g., bethanecol), muscle relaxants (e.g., baclofen), magnesium supplements, dexpanthenol. Do not start or stop any medicine without doctor or pharmacist approval. OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. Symptoms of overdose may include: severe breathing trouble, seizures. STORAGE: Store at room temperature between 59 and 86 degrees F (15 to 30 degrees C) away from light and moisture. Cholinergic Blockers:Adverse effects · Dry mouth (xerostromia) · Blurred vision (cycloplegia) · Photophobia (mydriasis) Irreversible Anticholinesterases ( organophosphorus compounds) These cause irreversible inactivation of the enzyme acetylcholinesterase there by exerting long lasting inhibitory activity , These have received more extensive application as toxic agent in the form of agrecultural insecticides and potential chemical war-fare nerve gases first compound was synthesized tetraethylpyrophosphate (TEPP) Pharmacological actions: as acetylcholine released in the course of normal physiological activity is not destroyed due to inactivation of cholinesterase . acetylcholine gets accumulated in the body to exert both the muscarinic and nicotinic actions . organophosphorous com. being highly lipid soluble cross blood brain barrier to produce pronounced central effects due to muscarinic action there will be miosis , increased peristalsis ,bronchoconstriction,lacrimation ,salivation ,sweating ,excessive bronchial secretions, bradycardia, vasodilation and fall in blood pressure due to nicotinic actions there are muscle twitchings in the whole body begining with eyelids,tongueand face , followed by weakness. due to central effect there is restlessness,diazziness,confusion,tremors and hallucinations. out of various organophosphorus compounds , only ecothiopate has therapeutic utility Category · Antiglaucoma agent, ophthalmic-Demecarium; Echothiophate; Isoflurophate · Cyclostimulant, accommodative esotropia-Demecarium; Echothiophate; Isoflurophate · Diagnostic aid, accommodative esotropia-Demecarium; Echothiophate; Description Demecarium, echothiophate, and isoflurophate are used in the eye to treat certain types of glaucoma and other eye conditions, such as accommodative esotropia. They may also be used in the diagnosis of certain eye conditions, such as accommodative esotropia. These medicines are available only with your doctor's prescription, in the following dosage forms: Ophthalmic Demecarium Ophthalmic solution (eye drops) Echothiophate Ophthalmic solution (eye drops) Isoflurophate Ophthalmic ointment (eye ointment) (France) Dosing-The doses of these medicines will be different for different patients. The following information includes only the average doses of these medicines. If your dose is different, do not change it unless your doctor tells you to do so. For demecarium For ophthalmic solution (eye drops) dosage form: For glaucoma: Adults and older children-Use one drop in the eye one or two times a day. Infants and young children-Use and dose must be determined by your doctor. For treatment of accommodative esotropia: Adults and older children-Use one drop in the eye once a day for two to three weeks, then one drop in the eye once every two days for three to four weeks, then use as determined by the doctor. Infants and young children-Use and dose must be determined by your doctor. For diagnosis of accommodative esotropia: Adults and older children-Use one drop in the eye once a day for two weeks, then one drop in the eye once every two days for two to three weeks. Infants and young children-Use and dose must be determined by your doctor. For echothiophate For ophthalmic solution (eye drops) dosage form: For glaucoma: Adults and older children-Use one drop in the eye one or two times a day. Infants and younger children-Use and dose must be determined by your doctor. For treatment of accommodative esotropia: Adults and older children-Use one drop in the eye once a day or one drop in the eye once every two days. Infants and young children-Use and dose must be determined by your doctor. For diagnosis of accommodative esotropia: Adults and older children-Use one drop in the eye once a day at bedtime for two to three weeks. Infants and young children-Use and dose must be determined by your doctor. For isoflurophate For ophthalmic ointment dosage form: For glaucoma: Adults and older children-Use the ointment in the eyes once every three days or as often as three times a day as directed by the doctor. Infants and young children-Use and dose must be determined by your doctor. For treatment of accommodative esotropia: Adults and older children-Use the ointment in the eyes once a day at bedtime for two weeks, then once a week or as often as once every two days as directed by the doctor. Infants and young children-Use and dose must be determined by your doctor. For diagnosis of accommodative esotropia: Adults and older children-Use the ointment in the eyes once a day at bedtime for two weeks. Infants and young children-Use and dose must be determined by your doctor Storage-To store this medicine: Keep out of the reach of children. Overdose of demecarium, echothiophate, or isoflurophate is very dangerous in young children. Store away from heat and direct light. Keep this medicine from freezing. Do not keep outdated medicine or medicine no longer needed. Be sure that any discarded medicine is out of the reach of children. Precautions While Using This Medicine Before you have any kind of surgery (including eye surgery), dental treatment, or emergency treatment , tell the medical doctor or dentist in charge and the anesthesiologist or anesthetist (the person who puts you to sleep) that you are using this medicine or have used it within the past month. These medicines should not be used if an eye infection is present, or if the eye is wounded or injured. If redness, pain, or discharge develops, or if a foreign object becomes lodged in one or both eyes, or if you suffer a blow to the eye or eye area, notify your doctor immediately. Avoid breathing in even small amounts of carbamate- or organophosphate-type insecticides or pesticides (for example, carbaryl [Sevin], demeton [Systox], diazinon, malathion, parathion, ronnel [Trolene], or TEPP). They may add to the effects of this medicine. Farmers, gardeners, residents of communities undergoing insecticide or pesticide spraying or dusting, workers in plants manufacturing such products, or other persons exposed to such poisons should protect themselves by wearing a mask over the nose and mouth, changing clothes frequently, and washing hands often. Side Effects of This Medicine Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention. Check with your doctor immediately if any of the following side effects occur: Rare Burning, redness, stinging, or other eye irritation; eye pain; veil or curtain appearing across part of vision Symptoms of too much medicine being absorbed into the body Increased sweating; loss of bladder control; muscle weakness; nausea, vomiting, diarrhea, or stomach cramps or pain; shortness of breath, tightness in chest, or wheezing; slow or irregular heartbeat; unusual tiredness or weakness; watering of mouth Other side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. However, check with your doctor if any of the following side effects continue or are bothersome: Blurred vision or change in near or distance vision; difficulty in seeing at night or in dim light; headache or browache; twitching of eyelids; watering of eyes Other side effects not listed above may also occur in some patients.