Lecture 7 Parasympathomimetic drugs PDF

12/12/2022 Lecture 7 Parasympathomimetic drugs Assoc Prof Dr Azyyati Mohd Suhaimi Adapted from Dr Zalina Zaha...

12/12/2022 Lecture 7 Parasympathomimetic drugs Assoc Prof Dr Azyyati Mohd Suhaimi Adapted from Dr Zalina Zahari 1 Introduction  Autonomic drugs  Drugs that produce their primary therapeutic effect by mimicking or altering the functions of the ANS  by stimulating or by blocking portions of the autonomic nervous system (ANS)  Autonomic nervous system  A part of the nervous system that regulates key involuntary functions of the body, including the activity of the heart muscle; the smooth muscles, including the muscles of the intestinal tract; and the glands. 2 1  12/12/2022 Introduction After the ANS receives information about the body and external environment, it responds by stimulating body processes, usually through the sympathetic division, or inhibiting them, usually through the parasympathetic division. 3 Nervous system Central nervous system Peripheral nervous system CNS Efferent division Afferent division Brain Spinal cord Autonomic Somatic nervous nervous system system ANS Sympathetic Parasympathetic 4 2  12/12/2022  Peripheral efferent neurons  2 types; preganglionic neurons & postganglionic neurons  Cell body of the 1st nerve cell (preganglionic neuron) is located within the CNS  Preganglionic neurons emerge from brainstem or spinal cord & make a synaptic connection in ganglia (an aggregation of nerve cell bodies located in the peripheral nervous system)  Ganglia function as relay stations between preganglionic & postganglionic neuron 5 6 3  12/12/2022 Parasympathetic Nervous System (Cholinergic) Acetylcholine = neurotransmitter Drugs that mimic = cholinergic drugs, parasympathomimetics Cholinergic agonists - initiates a response Drugs that block = anticholinergic, parasympatholytics Cholinergic antagonists - prevents a response 7 Sympathetic nervous system (Adrenergic) Norepinephrine = neurotransmitter Drugs that mimic = adrenergic drugs, sympathomimetics, or adrenomemetics Adrenergic agonists - initiate a response Drugs that block = adrenergic blockers, sympatholytics or adrenolytics Adrenergic antagonists - prevent a response 8 4  12/12/2022 Neurotransmitters  Communication between nerve cells, & (between nerve cells & effector organs), occurs through the release of specific chemical signals (neurotransmitters) from nerve terminals. ◼ Chemical substances that carry messages: 1- from one neuron to another ……. Or 2- from a neuron to other body tissues, such as cardiac or skeletal muscles.  Types of neurotransmitters  Norepinephrine, epinephrine, acetylcholine, dopamine, serotonin, histamine, glutamate, and GABA are commonly involved in the actions of useful drugs.  ACh & norepinephrine are primary chemical signals in ANS 9 Cholinergic Receptors 2 families cholinoceptors: Muscarinic & Nicotinic receptors - can be distinguished from each other based on their different affinities for agents that mimic the action of ACh (cholinomimetic agents) Muscarinic receptors Nicotinic receptors - Located post-synaptically at the - Located postsynaptically in parasympathetic and sympathetic autonomic ganglia and at neuro-- effector junction neuromuscular junctions - M1, M2, M3, M4, M5 - Found in different locations - Research is on-going to identify specific agonists and antagonists 10 5  12/12/2022 Muscarinic receptors (M- receptors) M-receptors belong to the class of G protein–coupled receptors (metabotropic receptors). M-receptors, bind both ACh, & muscarine (an alkaloid in some poisonous mushrooms) 11 Locations of muscarinic receptors  M-receptors show only a weak affinity for nicotine  Muscarinic drugs at high concentration, they may show some activity at nicotinic receptors  5 subclasses of muscarinic receptors, but only M1, M2, & M3 receptors have been functionally characterized  M1 receptors are also found on gastric parietal cells  M2 receptors on cardiac cells & smooth muscle  M2 found on ganglia of the peripheral nervous system & on autonomic effector organs, e.g., heart, smooth muscle, brain, & exocrine glands.  M3 receptors on the bladder, exocrine glands, & smooth muscle 12 6  12/12/2022 13 The effect of acetylcholine on skeletal muscle  In skeletal muscle, acetylcholine receptors are coupled to sodium channels, causing a depolarization of the tissue. 14 7  12/12/2022 Mechanisms of ACh signal transduction – M1 and M3 Different molecular mechanisms transmit the signal generated by ACh occupation of the receptor. When M1 or M3 receptors are activated, the receptor undergoes a conformational change & interacts with a G protein, designated Gq, that in turn activates phospholipase C. This ultimately leads to the production of the 2nd messengers inositol-1,4,5-trisphosphate (IP3) & diacylglycerol (DAG). 15 Mechanisms of ACh signal transduction – M1 and M3 IP3 causes an increase in intracellular Ca 2+ Ca2+ interact to stimulate or inhibit enzymes or to cause hyperpolarization, secretion, or contraction DAG activates protein kinase C, an enzyme that phosphorylates numerous proteins within the cell. 16 8  12/12/2022 The effect of acetylcholine on cardiac muscle  In contrast, activation of the M2 subtype on the cardiac muscle stimulates a G protein, designated Gi, that inhibits adenylyl cyclase & increases K+ conductance  In cardiac muscle, acetylcholine receptors are coupled to potassium channels, which when open, cause a hyperpolarization of the tissue.  The binding of ACH to this receptor triggers dissociation of Gai-GTP from Gßg, which in this case, directly binds to and opens a K+ channel.  The movement of K+ down its concentration gradient to the outside of the cell, increases the positive charge outside the membrane, hyperpolarizing the cell.  This results in the slowing of heart rate. 17 Nicotinic receptors Bind with both ACh & nicotine but has weak affinity for muscarine Nicotinic Rc is composed of 5 subunits, & functions as a ligand- gated ion channel Binding of 2 ACh molecules elicits a conformational change that allows the entry of Na+, resulting in the depolarization of the effector cell Nicotine at low concentration stimulates the receptor, whereas at high concentration blocks the receptor. 18 9  12/12/2022 Nicotinic receptors Nicotinic Rcs R located in the CNS, adrenal medulla, autonomic ganglia, & neuromuscular junction (NMJ) in skeletal muscles. The Nicotinic Rc of autonomic ganglia differ from those of the NMJ Ganglionic receptors R selectively blocked by mecamylamine, whereas NMJ Rcs R specifically blocked by atracurium 19 Receptor signaling mechanisms: ion channel-linked receptors ▪ Nicotinic acetylcholine receptor (nAChR) When acetylcholine binds to sites on the α subunits, a conformational change occurs that results in the transient opening of a central aqueous channel through which sodium ions penetrate from the extracellular fluid into the cell. 20 10  12/12/2022 ▪ Acetylcholine causes the opening of the ion channel in the nicotinic acetylcholine receptor, which allows Na+ to flow down its concentration gradient into cells → producing a localized excitatory postsynaptic potential—a depolarization ▪ The voltage change then opens Ca2+ channels trigerring skeletal muscle contraction 21 Receptor signaling mechanisms: Nicotinic acetylcholine receptor (nAChR) Calcium ions help to synchronize the rapid contraction of skeletal muscle cells. (a) Acetylcholine (ACh, shown in pink) is released from the neuron terminal, and binds to ACh-gated Na+ channels on the surface of the muscle cell. (b) These receptors are ion channels, and so promote local depolarization (an increase in membrane potential caused by the entry of sodium ions). (c) Depolarization is propagated in the muscle cell (yellow arrows) by voltage-gated Na+ channels, which allow further Na+ ion entry. (d) This more general depolarization triggers the very rapid release of Ca2+ions into the sarcoplasm (muscle cytoplasm) through voltage- gated Ca2+ channels from stores in the sarcoplasmic reticulum; the Ca2+ions spread through the muscle cell. (e) The increase of Ca2+concentration throughout the sarcoplasm enables the rapid and synchronous contraction of the muscle filaments. Ca2+ achieves this by binding to an inhibitory protein complex of tropomyosin and troponin, which under resting conditions prevents actin and myosin filaments from interacting. 22 11  12/12/2022 Introduction  Cholinergic drug 23 Parasympathetic nervous system (PANS) drugs ❖ Cholinergic agonist ❖ Parasympathomimetics – activate (mimic the parasympathetic neurotransmitter acetylcholine) ❖ Cholinomimetics - neurotransmitter (acetylcholine) ❖ Cholinergic antagonists (blocking agents) ❖ Muscarinic antagonists ❖ Parasympatholytics ❖ Anticholinergics 24 12  12/12/2022 Parasympathetic nervous system (PANS) drugs ❖ Cholinergic agonist ▪ direct agonists of acetylcholine receptors (ACh) act by binding directly to muscarinic or nicotinic ACh receptors are used topically in ophthalmology to induce miosis ▪ indirect agonists of ACh (also called anticholinesterase) prolong the action of endogenous acetylcholine by inhibiting acetylcholinesterase are used to treat, e.g., postoperative ileus or urinary retention and myasthenia gravis 25 Drugs affecting ANS ❑ Cholinergic drugs ❖ act on receptors that are activated by acetylcholine (ACh) two types of cholinergic receptors ✓ muscarinic receptors, which stimulate smooth muscle and slow the heart rate, ✓ nicotinic receptors (neuromuscular), which affect the skeletal muscles ❖ Many cholinergic drugs are nonselective ✓ because they can affect both the muscarinic and the nicotinic receptors ❖ Selective cholinergic agonists for the muscarinic receptors ✓ that do not affect the nicotinic receptors. ❑ Adrenergic drugs ❖ act on receptors stimulated by norepinephrine or epinephrine 26 13  12/12/2022 27 28 14  12/12/2022 29 Activation of the parasympathetic nervous system modifies organ function by two major mechanisms First, acetylcholine released from parasympathetic nerves activates muscarinic receptors on effector cells to alter organ function directly Second, acetylcholine released from parasympathetic nerves interacts with muscarinic receptors on nerve terminals to inhibit the release of their neurotransmitter  By this mechanism, acetylcholine release and circulating muscarinic agonists indirectly alter organ function by modulating the effects of the parasympathetic and sympathetic nervous systems and perhaps nonadrenergic, noncholinergic (NANC) systems 30 15  12/12/2022 31 32 16  12/12/2022 Parasympathetic responses  Stimulation of the parasympathetic nervous system  use of parasympathomimetic drugs  the pupils to constrict, known as miosis (pupil becomes smaller)  peristalsis and gastric secretions to increase,  the bladder muscle to contract,  bronchioles to constrict and bronchial secretions to increase,  heart rate to decrease,  blood vessels to dilate,  salivary glands to increase salivation 33 ❑ Direct-acting cholinergic agonists act on receptors to activate a tissue response Many drugs classified as direct-acting cholinergic agonists are primarily selective to the muscarinic receptors but are nonspecific ▪ because the muscarinic receptors are located in the smooth muscle of the GI and genitourinary tracts, glands, and heart. 34 17  12/12/2022 ❑ Indirect-acting cholinergic agonists ✓ cholinesterase inhibitors, acetylcholinesterase inhibitors, or anticholinesterases ✓ inhibit the action of the enzyme cholinesterase (ChE) i.e. acetylcholinesterase (AChE) ❑ How? ✓ by forming a chemical complex that allows acetylcholine to persist and attach to the receptor ✓ ChE may destroy acetylcholine before it reaches the receptor or after it has attached to the site ✓ by inhibiting or destroying the ChE, more acetylcholine is available to stimulate the receptor and to remain in contact with it longer 35 A B Cholinergic agonists resemble Cholinesterase inhibitors inactivate the acetylcholine and act directly on the enzyme acetylcholinesterase receptor (cholinesterase), thus permitting acetylcholine to react to the receptor ACh, Acetylcholine; AChE, acetylcholinesterase or cholinesterase; D, cholinergic agonist; DD, cholinesterase inhibitor (anticholinesterase) 36 18  12/12/2022 37 Cholinergic Agonists/Cholinergic Agent (Parasympathomimetics)  Acetylcholine  Bethanechol  Carbachol  Pilocarpine 38 19  12/12/2022 Cholinergic agonist  Bethanechol selective to muscarinic receptors, mimic action of acetylcholine  Pilocarpine Ophthalmic - direct acting 39 General Effects of Cholinergic Agonists  Decrease heart rate and cardiac output  Decrease blood pressure  Increases GI motility and secretion  Pupillary constriction 40 20  12/12/2022 Effects 41 Cholinomimetics are to treat diseases of  the eye (glaucoma, accommodative esotropia),  the gastrointestinal and urinary tracts (postoperative atony, neurogenic bladder),  the neuromuscular junction (myasthenia gravis, curare-induced neuromuscular paralysis),  to treat patients with Alzheimer’s disease Cholinesterase inhibitors are  occasionally used in the treatment of atropine overdosage  very rarely, in the therapy of certain atrial arrhythmias. Basic & Clinical Pharmacology/Katzung BG, Trevor AJ. — 13th ed. 42 21  12/12/2022 Direct-acting cholinergic agonists Cholinergic agonists classified broadly into two groups 1) endogenous choline esters, which include ACh and synthetic esters of choline, such as carbachol & bethanechol 2) naturally occurring alkaloids, such as nicotine & pilocarpine Direct-acting cholinergic drugs have a longer duration of action than ACh. 43 Choline esters: Ach, carbachol and bethanechol 44 22  12/12/2022  The more therapeutically useful drugs (pilocarpine and bethanechol) preferentially bind to muscarinic Rcs sometimes referred to as muscarinic agents.  Muscarinic Rcs located primarily, but not exclusively, at the NMJ of the parasympathetic nervous system.  However, as a group, the direct-acting agonists show little specificity in their actions, which limits their clinical usefulness. 45 Acetylcholine (Ach, Choline acetate, O-Acetylcholine)  ACh is a quaternary NH4+ cpd, cannot penetrate membranes.  ACh is major transmitter at neuromuscular junctions, autonomic ganglia, parasympathetic effector junctions, a subset of sympathetic effector junctions, and at many sites in the central nervous system.  It lacks therapeutic importance b/c of its multiplicity of actions (leading to diffuse effects) & its rapid inactivation by the cholinesterases.  but it is useful in some ophthalmological applications. 46 23  12/12/2022 Acetylcholine (Ach, Choline acetate, O-Acetylcholine)  ACh has both muscarinic & nicotinic activity.  Its actions include the following: 1- Decrease in heart rate & cardiac output: o The actions of ACh on the heart mimic the effects of vagal stimulation. o e.g., if injected IV, ACh produces a decrease in cardiac rate (-ve chronotropy) & stroke volume. 47 Acetylcholine (Ach, Choline acetate, O-Acetylcholine) 2- Decrease in blood pressure: o Injection of ACh causes vasodilation & lowering of blood pressure indirectly o In the absence of administered cholinergic agents, cholinergic receptors (in the vessels) have no known function, b/c ACh is not released into blood significantly. o Atropine blocks muscarinic receptors & prevents ACh - vasodilation. 48 24  12/12/2022 Acetylcholine (Ach, Choline acetate, O-Acetylcholine) 3- In the genitourinary tract, ACh increases the tone of the detrusor muscle, causing urination (promotes voiding of urine) 49 Acetylcholine (Ach, Choline acetate, O-Acetylcholine) 4- Other actions:  In the GIT, ACh increases salivary secretion & stimulates intestinal secretions, & motility  Enhances bronchiolar secretions  contracts bronchial smooth muscle resulting in broncospasm (may result in severe dyspnea)  enhances secretions of all glands; salivary, lacrimal, nasopharyngeal, gastric & intestinal secretions, & sweating also increased 50 25  12/12/2022 Acetylcholine (Ach, Choline acetate, O-Acetylcholine)  ACh (In eye) causes circular muscle contraction for near vision & in the constriction of the pupillae sphincter muscle (stimulating muscarinic receptors in pupillae), resulting in miosis (constriction of the pupil).  ACh (1% eye solution) is instilled into the eye during ophthalmic surgery to produce miosis. Indication: Used to obtain miosis of the iris in seconds after delivery of the lens in cataract surgery, in penetrating keratoplasty, iridectomy and other anterior segment surgery where rapid miosis may be required. 51 Acetylcholine (Ach, Choline acetate, O-Acetylcholine) Nicotinic actions: 1- NMJ: ACh leads to contraction of skeletal muscles. Large doses causes persistent depolarization of skeletal muscle resulting in paralysis. 2- Autonomic ganglia: ACh stimulates Sympathetic & ParaSymp. Ganglia & adrenal medulla. 52 26  12/12/2022 Actions of ACh 53 Bethanechol (Carbamoyl-beta-methylcholine)  a carbamoyl ester, structurally related to ACh & not hydrolyzed by AChE.  It lacks nicotinic actions but does have strong muscarinic activity.  Its major actions are on the smooth musculature of the bladder and GI tract.  Generally used to increase smooth muscle tone, as in the GI tract following abdominal surgery or in urinary retention in the absence of obstruction.  duration of action about 1-hour 54 27  12/12/2022 Bethanechol (Carbamoyl-beta-methylcholine) ❖ acts on the muscarinic (cholinergic) receptor  is used primarily to increase urination in the treatment of urinary retention and neurogenic bladder. ❖ The principal use of bethanechol  to promote urination by stimulating the muscarinic cholinergic receptors in the detrusor muscle  to contract the bladder and produce urine output  increases peristalsis in the GI tract  drug should be taken on an empty stomach 1 to 2 hours before meals to minimize nausea and vomiting Indication: For the treatment of acute postoperative and postpartum nonobstructive (functional) urinary retention and for neurogenic atony of the urinary bladder with retention. 55 Bethanechol (Carbamoyl-beta-methylcholine) Adverse effects:  Bethanechol causes the effects of generalized cholinergic stimulation. o including sweating, salivation, flushing, decreased blood pressure, nausea, abdominal pain, diarrhoea & bronchospasm. Atropine sulfate is use to overcome severe cardiovascular or bronchoconstrictor responses. 56 28  12/12/2022 Bethanechol (Carbamoyl-beta-methylcholine) Mild to severe side effects ▪ hypotension, tachycardia, blurred vision, excessive salivation, increased gastric acid secretion, abdominal cramps, diarrhea, bronchoconstriction, and, in some cases, cardiac dysrhythmias o should be prescribed cautiously for patients with low blood pressure and low heart rates o contraindicated for patients with intestinal or urinary tract obstruction, severe bradycardia, or active asthma 57 Carbachol (Carbacholine, carbamylcholine)  Carbachol has both muscarinic and nicotinic actions.  Like bethanechol, carbachol is an ester of carbamic acid & a poor substrate for AChE.  It is biotransformed by other esterases, but at a much slower rate. 58 29  12/12/2022 Carbachol (Carbacholine, carbamylcholine) Actions:  Carbachol effects both CVS & GI systems, as it stimulates ganglion activity, & it may first stimulate & later depress these systems.  It can release epinephrine from adrenal medulla by its nicotinic action.  (Instillation into the eye), it will act as ACh, causing miosis & a spasm of accommodation in which the ciliary muscle of the eye remains in a constant state of contraction. Indication: Primarily used in the treatment of glaucoma, but is also used during ophthalmic surgery. 59 Carbachol (Carbacholine, carbamylcholine) Therapeutic uses:  Because of its high potency, receptor nonselectivity & relatively long duration of action, carbachol is rarely used therapeutically only in case of glaucoma/eye as a miotic agent by causing a decrease in intraocular pressure (IOP). Adverse effects:  At doses used ophthalmologically, little or no side effects occur due to lack of systemic penetration (quaternary amine). 60 30  12/12/2022 Pilocarpine  An alkaloid, is a tertiary amine & is stable to hydrolysis by AChE.  Far less potent than ACh & its derivatives, but is uncharged & can penetrate the CNS at therapeutic doses.  Pilocarpine exhibits muscarinic activity & is used primarily in ophthalmology. 61 Pilocarpine ❖ constricts the pupils of the eyes to promote drainage of aqueous humor (fluid) ❖ is used to treat glaucoma by relieving (intraocular) fluid pressure in the eye and to promote miosis in eye surgery and examinations ❖ also acts on the nicotinic receptor 62 31  12/12/2022 Pilocarpine Actions: Pilocarpine used topically to the eye, producing rapid miosis & contraction of the ciliary muscle. Such miosis in the eye, makes the subject experiences a spasm of accommodation. vision becomes fixed at some particular distance, making it impossible to focus. 63 Pilocarpine  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.  Pilocarpine enhances salivation in patients with xerostomia resulting from irradiation of the head & neck.  Pilocarpine & cevimeline (a nonspecific cholinergic drug) are used to treat Sjögren syndrome (characterized by dry mouth & lack of tears). Indication: For the treatment of radiation-induced dry mouth (xerostomia) and symptoms of dry mouth in patients with Sjögrens syndrome. 64 32  12/12/2022 Glaucoma  Glaucoma is an eye disease characterized by increased IOP.  Aqueous humor is secreted by ciliary body & it drains through channel of schlemm.  Rise of IOP>30mmHg damages optic nerve and leads to blindness. 65 Pilocarpine Therapeutic uses:  Pilocarpine is used to treat glaucoma & is drug of choice for emergency lowering of IOP of both open-angle & angle-closure glaucoma.  Pilocarpine ocusert delivers the drug constantly for 7 days. Adverse effects:  Pilocarpine can cause blurred vision, night blindness, & brow ache.  Poisoning with Pilocarpine is characterized by exaggeration of various parasympathetic effects, including profuse sweating (diaphoresis) & salivation.  The effects R similar to those produced by consumption of a specific mushroom.  Parenteral atropine, at doses that can cross BBB, is administered to counteract the toxicity of pilocarpine. 66 33  12/12/2022 67 68 34  12/12/2022 INDIRECT-ACTING CHOLINERGIC AGONISTS: ANTICHOLINESTERASE AGENTS (REVERSIBLE) 69 AChE Inhibitors AChE is an enzyme that specifically cleaves ACh to acetate & choline and, thus, terminates its actions. AChE-Inhibitors drugs which inhibit the enzyme cholinesterase. indirectly provide a cholinergic action by preventing the degradation of ACh. resulting in accumulation of ACh in the synaptic space reversible AChE inhibitors can be broadly classified as short-acting or intermediate-acting agents. 70 35  12/12/2022 71 Edrophonium is the prototype short-acting AChE inhibitor. Edrophonium binds reversibly to the active site of AChE, preventing hydrolysis of ACh. Rapidly absorbed with short duration of action of 10-20 minutes due to rapid renal elimination. Edrophonium is a quaternary amine, & its actions R limited to the periphery. 72 36  12/12/2022 Edrophonium Edrophonium is used in the diagnosis of myasthenia gravis, an autoimmune disease caused by antibodies to the nicotinic receptor at the NMJ. - causes their degradation, & decreasing number of receptors available for interaction with ACh. 73 Edrophonium 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 also used for reversing the effects of nondepolarizing neuromuscular blockers after surgery. Due to the availability of other agents, edrophonium use has become limited. 74 37  12/12/2022 Physostigmine (Eserine, Physostol) Physostigmine a nitrogenous carbamic acid ester, found naturally in plants & is a tertiary amine. It is a substrate for AChE, and forms a relatively stable carbamoylated intermediate with the enzyme, which then becomes reversibly inactivated. The result is potentiation of cholinergic activity throughout the body. 75 Physostigmine (Eserine, Physostol) Physostigmine stimulates muscarinic & nicotinic sites of the ANS & nicotinic receptors of the NMJ. Duration of action is about 30 minutes to 2 hrs, & it is an intermediate-acting agent. Physostigmine can enter and stimulate the cholinergic sites in the CNS. 76 38  12/12/2022 Physostigmine (Eserine, Physostol) Therapeutic uses: Physostigmine increases intestinal & bladder motility, which serves as its therapeutic action in atony of either organ. Physostigmine is also used in the treatment of overdoses of drugs with anticholinergic actions, such as atropine. Side effects: ❖ high doses of physostigmine may lead to convulsions (CNS effects) ❖ Bradycardia and a fall in cardiac output may also occur. ❖ Inhibition of AChE at the skeletal NMJ causes the accumulation of ACh &, finally, results in paralysis of skeletal muscle (However, these effects are rarely seen with therapeutic doses). 77 Neostigmine (Eustigmine) Neostigmine: a synthetic carbamic acid ester compound , and it reversibly inhibits AChE similar to that of physostigmine. Unlike physostigmine, neostigmine has a quaternary nitrogen. i.e., it is more polar & absorbed poorly from the GI tract, & does not enter CNS. Its effect on skeletal muscle is greater than that of physostigmine, and it can stimulate contractility before it paralyzes. Neostigmine has intermediate duration of action, usually ½ hr-2 hours. 78 39  12/12/2022 Neostigmine (Eustigmine) Therapeutic uses: - It is used to stimulate the bladder and GI tract & also as an antidote for competitive neuromuscular-blocking agents. - Neostigmine is also used to manage symptoms of myasthenia gravis. Adverse effects of neostigmine including generalized cholinergic stimulation:- salivation, flushing, decreased blood pressure, nausea, abdominal pain, diarrhoea, & bronchospasm. Neostigmine (has a quaternary nitrogen) does not cause CNS side effects & is not used to overcome toxicity of central-acting antimuscarinic agents such atropine. - Neostigmine is contraindicated when intestinal or urinary bladder obstruction is present. 79 Pyridostigmine Pyridostigmine & ambenonium R cholinesterase inhibitors that are used in the chronic management of myasthenia gravis. Durations of action of both R intermediate (3-6 hours & 4-8 hrs respectively) but longer than that of neostigmine. Adverse effects of these agents R similar to those of neostigmine. 80 40  12/12/2022 Tacrine, donepezil, rivastigmine, galantamine Patients with Alzheimer’s disease have a deficiency of cholinergic neurons in the CNS. This observation led to the development of anticholinesterases as treatments for the loss of cognitive function. Tacrine has been replaced by others because of its hepatotoxicity. Donepezil, rivastigmine , & galantamine R able to delay the progression of Alzheimer’s disease, none can stop its progression. GI distress is their primary adverse effect 81 82 41  12/12/2022 INDIRECT-ACTING CHOLINERGIC AGONISTS: ANTICHOLINESTERASE AGENTS (IRREVERSIBLE) - many organophosphate cpds able to bind covalently to AChE - Leading to a long-lasting increase in Ach - many of these drugs are extremely toxic & were developed by the military as nerve agents - Related compounds, e.g., parathion and malathion, R used as insecticides. 83 Echothiophate (Phospholine) Mechanism of action: - Echothiophate (is organophosphate) covalently binds via its phosphate group at the active site of AChE. - After that, the enzyme is permanently inactivated, & restoration of AChE activity requires the synthesis of new enzyme molecules. - Following covalent modification of AChE, the phosphorylated enzyme slowly releases one of its ethyl groups. - Loss of an alkyl group, (called aging), makes it impossible for chemical reactivators, such as pralidoxime, to break the bond I.I the remaining drug and the enzyme. 84 42  12/12/2022 Echothiophate (Phospholine) Echothiophate actions include generalized cholinergic stimulation, paralysis of motor function (causing breathing difficulties), & convulsions. Echothiophate produces intense miosis and, thus, has found therapeutic use IOP falls BCZ of outflow of aqueous humor. Atropine in high dosages reverse many peripheral & some of the central muscarinic effects of echothiophate. 85 Echothiophate (Phospholine) Therapeutic uses: A topical ophthalmic solution of the drug is indicated for the Rx of open-angle glaucoma. Echothiophate is rarely used due to its side effect profile, which includes the risk of causing cataracts. 86 43  12/12/2022 87 INDIRECT-ACTING CHOLINERGIC AGONISTS: ANTICHOLINESTERASE AGENTS (IRREVERSIBLE) Irreversible AChE inhibitors (mostly organophosphate cpds) R used as:- agricultural insecticide, are frequently used for suicidal and homicidal purposes. Organophosphate nerve gases such as sarin are used as agents of warfare and chemical terrorism. Toxicity with these agents is manifested as nicotinic and muscarinic signs and symptoms (cholinergic crisis). Depending on the agent, the effects can be peripheral or can affect the whole body. 88 44  12/12/2022 89 90 45  12/12/2022 Cholinergic crisis (cholinergic syndrome) Cause: in most cases as a result of poisoning with organophosphates Clinical presentation: severe and life-threatening constellation of side effects of indirect parasympathomimetics Antidotes: antimuscarinic agents atropine, pralidoxime 91 Side effects of indirect parasympathomimetics Cardiovascular symptoms: bradycardia, hypotension – Due to slowing down of AV conduction Gastrointestinal symptoms: ↑ salivation, diarrhea, abdominal pain, uncontrolled urination Increased sweating, salivation, and gastric secretion Nausea Ocular symptoms: miosis, lacrimation CNS-related symptoms: restlessness, anxiety, ataxia, tremor possibly culminating in coma Musculoskeletal symptoms: fasciculations, weakness, spasms, paralysis → peripheral neuromuscular respiratory failure 92 46  12/12/2022 93 Treating the effects of organophosphates Atropine is administered to prevent muscarinic side effects of these agents. Such effects include increased bronchial and salivary secretion, bronchoconstriction, & bradycardia. Diazepam is also administered to reduce the persistent convulsion caused by these agents. General supportive measures, such as maintenance of patent airway, oxygen supply, and artificial respiration, may be necessary as well. 94 47  12/12/2022 Reactivation of acetylcholinesterase Pralidoxime (2-PAM) can reactivate inhibited AChE. Unable to penetrate into the CNS & therefore is not useful in treating the CNS effects of organophosphates. The presence of a charged group allows it to approach an anionic site on the enzyme, where it essentially displaces phosphate group of the organophosphate & regenerates the enzyme. If given b4 aging of alkylated enzyme occurs, it can reverse both muscarinic & nicotinic peripheral effects of organophosphates, but not ….the CNS effects. With the newer nerve agents that produce aging of the enzyme complex within seconds, pralidoxime is less effective. 95 Pralidoxime (2-PAM) Pralidoxime is a weak AChE inhibitor and, at higher doses, may cause side effects similar to other AChE inhibitors. In addition, it cannot overcome toxicity of reversible AChE inhibitors (for example, physostigmine). 96 48