Lecture 4 Cholinergic Agonists PDF

‫بسم ﷲ الرحمن الرحيم‬ Cholinergic Agonists (Cholinoceptor-Activating & Cholinesterase- Inhibiting Drugs) By Imad Addeen M. Taj Addeen Faculty of Pharmacy  Intended Learning Outcomes By the end of this lecture the stud...

‫بسم ﷲ الرحمن الرحيم‬ Cholinergic Agonists (Cholinoceptor-Activating & Cholinesterase- Inhibiting Drugs) By Imad Addeen M. Taj Addeen Faculty of Pharmacy  Intended Learning Outcomes By the end of this lecture the student should be able to: List the locations and types of acetylcholine receptors in the major organ systems (CNS, autonomic ganglia, eye, heart, vessels, bronchi, gut, genitourinary tract, skeletal muscle, exocrine glands). List the major clinical uses of cholinomimetic agonists. Describe the pharmacodynamic differences between direct-acting and indirect-acting cholinomimetic agents. List the major pharmacokinetic differences between bethanechol, pyridostigmine, and parathion. List the major signs and symptoms of (1) organophosphate insecticide poisoning and (2) acute nicotine toxicity.  Cholinoceptor-Activating Drugs Cholinoceptor-activating drugs are those with acetylcholine-like effects These are drugs that can produce some or all of the effect that acetylcholine is able to produce at muscarinic and nicotinic cholinoceptors (simply called cholinergic agonists). They are also called cholinomimetics or parasympathomimetics. The cholinergic agonists can be divided into two groups:  Direct-acting cholinergic agonists: they act directly as agonists at muscarinic and nicotinic cholinoceptors.  Indirect-acting cholinergic agonists: also called cholinesterase inhibitors. They act by inhibiting the enzymatic destruction of endogenous acetylcholine by acetylcholinesterase.  Direct-acting Cholinergic Agonists Because they act directly as agonists at muscarinic and nicotinic cholinoceptors, they are subdivided into: Muscarinic receptors agonists: also called parasympathomimetics They are located at parasympathetic neuroeffector junction Nicotinic receptors agonists such as those present in autonomic ganglia and neuromuscular junction (NMJ).  Direct-acting Muscarinic Cholinoceptor Agonists These are acetylcholine, bethanechol, carbachol, pilocarpine, cevimeline, arecoline and methacholine. The bethanechol and carbachol are choline, are structurally similar to acetylcholine. Pilocarpine is an alkaloid. Bethanechol and pilocarpine are selective agonists for muscarinic receptors. Acetylcholine, methacholine, and carbachol are capable of stimulating nicotinic and muscarinic receptors.  Direct-acting Muscarinic Cholinoceptor Agonists Pharmacological Effects in the Eye Direct-acting muscarinic cholinoceptor agonists contract the circular smooth muscle fibers of the ciliary muscle and iris to produce:  A spasm of accommodation (focusing for near vision) An increased outflow of aqueous humor into the canal of Schlemm, resulting in a reduction in intraocular pressure. These drugs contract the smooth muscle of the iris sphincter to cause miosis.  Direct-acting Muscarinic Cholinoceptor Agonists Pharmacological Action in Cardiovascular System: The Heart Direct-acting muscarinic cholinoceptor agonists produce a negative chronotropic effect (marked bradycardia) though reduction of SA node activity. They reduce the atrio-ventricular conduction velocity through the AV node. These drugs have no effect on force of contraction because there are no muscarinic receptors on, or parasympathetic innervation of ventricles  Direct-acting Muscarinic Cholinoceptor Agonists Blood vessels Direct-acting muscarinic cholinoceptor agonists produce vasodilation that results primarily from their action on endothelial cells to promote the release of NO, which produces relaxation Vascular smooth muscle has muscarinic receptors but no parasympathetic innervation. The decrease in blood pressure can result in a reflex increase in heart rate.  Direct-acting Muscarinic Cholinoceptor Agonists Pharmacological Action in GI tract Direct-acting muscarinic cholinoceptor agonists increase smooth muscle contractions and tone, with increased peristaltic activity and motility. They produce relaxation of most sphincters. These drugs increase salivation and acid secretion. Direct-acting Muscarinic Cholinoceptor Agonists Pharmacological Action on Urinary Tract Direct-acting muscarinic cholinoceptor agonists increase contraction of the ureter and detrusor bladder smooth muscle. These drugs increase trigonal and sphincter relaxation.  Direct-acting Muscarinic Cholinoceptor Agonists Pharmacological Action in Respiratory System Effects of direct-acting muscarinic cholinoceptor agonists include bronchoconstriction with increased resistance and increased bronchial secretions. Other Effects These drugs increase the secretion of tears from lacrimal glands and increase sweat gland secretion. These drugs produce tremor and ataxia. Actions of Direct-acting Muscarinic Cholinoceptor Agonists  Specific Drugs and their Therapeutic Uses Acetylcholine Acetylcholine is inactivated by cholinesterases to choline and acetic acid. There are two major types of cholinesterases, true acetylcholinesterase (AchE) and pseudocholinesterase (pseudo-AchE). The true acetylcholinesterase is found at pre and post-cholinergic neuroeffector junction. Pseudocholinesterase found in the liver and in the plasma. Acetylcholine is therapeutically of no importance, because of:  Its multiplicity of actions  Its rapid inactivation by acetylcholinesterase  It is orally inactive  Specific Drugs and their Therapeutic Uses These drugs are used primarily for diseases of the eye, GI tract, urinary tract, the neuromuscular junction, and the heart. Bethanechol Bethanechol is used to stimulate smooth muscle motor activity of the urinary tract to initiate urination and prevent urine retention. It is used occasionally to stimulate GI smooth muscle motor activity for postoperative abdominal distention and for gastric atony Bethanechol is administered orally or SC, not by IV or IM route, because parenteral administration may cause cardiac arrest. When given orally, GI effects predominate It is resistant to hydrolysis by acetylcholinesterase and thus has a relatively long duration of action (2–3 h).  Specific Drugs and their Therapeutic Uses Pilocarpine Pilocarpine is occasionally used topically for open-angle glaucoma, either as eye drops or as a sustained-release ocular insert. When used before surgery to treat acute narrow-angle glaucoma (a medical emergency), pilocarpine is often given in combination with an indirectly acting muscarinic agonist such as physostigmine.  Specific Drugs and their Therapeutic Uses Orally, pilocarpine is used to increase salivary secretion; it used to treat xerostomia associated with Sjögren syndrome. Cevimeline is used to treat Sjögren syndrome-associated dry mouth and lack of tears. Carbachol It is used rarely as a treatment for open-angle glaucoma. Nicotine-based products and varenicline, direct-acting nicotinic receptor agonists, are approved for use in smoking cessation It is also approved to cause miosis during ophthalmic surgery.  Adverse Effects and Contraindications The adverse effects associated with direct-acting muscarinic cholinoceptor agonists are extensions of their pharmacological activity. The most serious include nausea, vomiting, sweating, salivation, bronchoconstriction, decreased blood pressure, and diarrhea. All of which can be blocked or reversed by atropine. Precautions: These drugs are contraindicated in the presence of peptic ulcer (because they increase acid secretion), asthma, cardiac disease, and Parkinson disease. They are not recommended in hyperthyroidism because they predispose to arrhythmia; they are also not recommended when there is mechanical obstruction of the GI or urinary tract.  Indirect-acting cholinergic agonists These drugs are also known as cholinesterase inhibitors. The enzymatic destruction of endogenous acetylcholine by acetylcholinesterase inhibitors results in the accumulation of acetylcholine in the synaptic space These agents can inhibit the destruction of acetylcholine by reversible or irreversible binding to acetylcholinesterase. Reversible inhibitors: are edrophonium, ambenonium, neostigmine, physostigmine, and pyridostigmine. Irreversible inhibitors are isoflurophate and echothiophate. Other irreversible inhibitors acetylcholinesterase are insecticides (parathion and malathion) and nerve gases (sarin and tabun)  Indirect-acting cholinergic agonists Mechanism of Action Acetylcholine interacts with acetylcholinesterase at two sites: The N+ of choline (ionic bond) binds to the anionic site, and the acetyl ester binds to the esteratic site (serine residue). As acetylcholine is hydrolyzed, the serine-OH side chain is acetylated and free choline is released. Acetylserine is hydrolyzed to serine and acetate. The half-life (t1/2) of acetyl-serine hydrolysis is 100–150 microseconds.  Indirect-acting cholinergic agonists Mechanism of Action Echothiophate and isoflurophate, irreversible and toxic organophosphate cholinesterase inhibitors, result in phosphorylation of acetylcholinesterase rather than acetylation. With time, the strength of the bond increases (“aging”), and acetylcholinesterase becomes irreversibly inhibited. The enzyme can be reactivated within the first 30 minutes by pralidoxime. Hydrolysis of the covalent alkyl phosphoryl-serine bond takes days.  Indirect-acting cholinergic agonists Pharmacological Effects The pharmacological effects of indirect-acting parasympathomimetic agents are similar to those of direct-acting muscarinic cholinoceptor agonists. By increasing acetylcholine at the neuromuscular junction, these drugs increase the contraction strength of skeletal muscle. The effect is more pronounced if muscle contraction is already weak, as occurs in myasthenia gravis.  Indirect-acting cholinergic agonists Indications: These agents (insecticides; parathion and malathion nerve gases; sarin and tabun) are not used in a clinical setting. They are pesticides that are used in agriculture and nerve agents that may be used in terrorism or chemical warfare. Echothiophate is an irreversible and toxic organophosphate cholinesterase inhibitor; it results in phosphorylation of acetylcholinesterase rather than acetylation. It is an ophthalmic agent approved for the treatment of elevated intraocular pressure.  Indirect-acting cholinergic agonists Therapeutic Uses 1. Glaucoma Physostigmine is often used concurrently with pilocarpine for maximum effect in the treatment of acute angle-closure glaucoma, a medical emergency. 2. GI and urinary tract disorders Postoperative ileus and congenital megacolon, and urinary tract retention can be treated with direct or indirectly acting cholinomimetic drugs such as bethanechol and neostigmine.  Indirect-acting cholinergic agonists Therapeutic Uses 3. Myasthenia gravis Myasthenia gravis is an autoimmune disease in which antibodies complex with nicotinic receptors at the neuromuscular junction to cause skeletal muscle weakness and fatigue. Acetylcholinesterase inhibitors, such as pyridostigmine, are used to increase acetylcholine levels at the neuromuscular junction to fully activate the remaining receptors. Myasthenia gravis can be diagnosed by using small doses of edrophonium which improve muscle strength in untreated patients with myasthenia gravis  Indirect-acting cholinergic agonists Therapeutic Uses 4. Alzheimer disease Donepezil, galantamine, rivastigmine, and tacrine are central acetylcholinesterase inhibitors used to ameliorate the cognitive deficit associated with Alzheimer disease. 5. Atropine and hyoscine (scopolamine) poisoning.  Indirect-acting cholinergic agonists Adverse Effects and Toxicity The adverse effects associated with indirect-acting parasympathomimetic agents are an extension of pharmacological activity and arise from excessive cholinergic stimulation. Adverse effects include muscarinic effects similar to those of direct- acting cholinergic drugs and nicotinic effects such as muscle weakness, cramps and fasciculations, excessive bronchial secretions, convulsions, coma, cardiovascular collapse, and respiratory failure Many lipid-soluble organophosphates are used as insecticides (e.g., parathion, malathion) or nerve gases (e.g., sarin, warfare) and may be absorbed in sufficient quantities from the skin or lungs to cause cholinergic intoxication.  Indirect-acting cholinergic agonists Adverse effects: Parathion is a very dangerous insecticide, which can cause all parasympathetic effects, including muscle paralysis and coma (malathion is much safer).  Toxicity occurs due to cholinergic access.  DUMBBELLS is a commonly used medical mnemonic used to identity adverse effects from an overdose or poisoning due to a cholinergic agent.  Diarrhea  Urination  Miosis (pupil constriction)  Bradycardia  Bronchospasm/bronchorrhea  Emesis  Lacrimation  Lethargy  Salivation  Indirect-acting cholinergic agonists Adverse effects: Acetylcholine stimulation of nicotinic receptors at the neuromuscular junction may cause fasciculations, muscle weakness, and paralysis Since sweat glands are regulated through sympathetic activation of postganglionic muscarinic receptors, patients may experience diaphoresis.  Indirect-acting cholinergic agonists Management of Organophosphate Poisoning Patients will most likely require 100% oxygen and endotracheal intubation. Contaminated clothing should be removed to prevent further absorption. Exposed skin washed with soap and water. Atropine is an anticholinergic agent that competes with acetylcholine at muscarinic receptors. It is used to reverse symptoms of cholinergic poisoning, including bronchorrhea and bronchoconstriction.  Indirect-acting cholinergic agonists Management of organophosphate poisoning Pralidoxime is an acetylcholinesterase reactivator that must be administered IV within minutes of exposure to an acetylcholinesterase inhibitor because it is effective only prior to “aging.” Pralidoxime acts as an antidote for organophosphorus insecticide and nerve gas poisoning. It binds the anionic site and reacts with the P=O group of alkyl phosphorylated-serine to cause hydrolysis of the phosphoserine bond. Diazepam is also administered to reduce the persistent convulsion