Cholenergic Receptor Agonists PDF

💊 Cholenergic Receptor Agonists Cholinomimetic Agents Cholinomimetic agents mimic the action of acetylcholine (ACh), a neurotransmitter involved in parasympathetic nervous system functions. 1. Cholinoreceptor Stimulants...

💊 Cholenergic Receptor Agonists Cholinomimetic Agents Cholinomimetic agents mimic the action of acetylcholine (ACh), a neurotransmitter involved in parasympathetic nervous system functions. 1. Cholinoreceptor Stimulants These agents work by stimulating cholinergic receptors, either directly or indirectly. 2. Types of Cholinomimetic Agents: Cholenergic Receptor Agonists 1  Direct-Acting Drugs: Mechanism: These drugs bind directly to cholinergic receptors (either muscarinic or nicotinic) to stimulate a response. Examples: Alkaloids: Plant-based compounds that stimulate cholinergic activity. Choline esters: Synthetic or naturally occurring compounds that activate cholinergic receptors. Receptors Activated: Muscarinic Receptors: Found in smooth muscles, heart, glands, and the endothelium. Nicotinic Receptors: Found in the neuromuscular junctions and autonomic ganglia. Indirect-Acting Drugs (Cholinesterase Inhibitors): Mechanism: These drugs increase the availability of ACh by inhibiting acetylcholinesterase (AChE), the enzyme that breaks down ACh. Reversible Inhibitors: These temporarily inhibit AChE, allowing for an increase in ACh concentration. Irreversible Inhibitors: These permanently deactivate AChE, leading to prolonged cholinergic stimulation. 3. Physiological Effects: Muscarinic Activation: Effects on smooth muscle, heart rate, and glandular secretion. Nicotinic Activation: Primarily affects neuromuscular junctions and autonomic ganglia, influencing skeletal muscle and autonomic responses. 4. Clinical Application: Cholenergic Receptor Agonists 2  Cholinomimetic agents are used to treat conditions such as myasthenia gravis, glaucoma, and in certain cases, to stimulate bladder and bowel function post- surgery. Choline Esters Choline esters are a class of compounds that mimic the action of acetylcholine and are used as cholinomimetic agents. They are chemically derived from choline, with some having modifications that affect their pharmacokinetics and pharmacodynamics. Types of Choline Esters: 1. Acetylcholine (ACh): Acetic acid ester of choline. 2. Methacholine: Acetic acid ester of β- methylcholine. 3. Carbachol: Carbamic acid ester of choline. 4. Bethanechol: Carbamic acid ester of β- methylcholine. Structural Implications on Pharmacokinetics: 1. Lipid Solubility: Cholenergic Receptor Agonists 3  Conclusion: Choline esters generally have low lipid solubility. Reason: Their quaternary ammonium group (charged nitrogen atom) limits their ability to cross lipid membranes, such as the blood-brain barrier. 2. Absorption: Conclusion: Poor oral and GI tract absorption. Reason: The charged nature of these compounds leads to low membrane permeability, resulting in minimal absorption from the gastrointestinal (GI) tract when administered orally. 3. Distribution: Conclusion: Limited distribution in the body. Reason: Due to their low lipid solubility, they do not cross cell membranes easily and are largely restricted to peripheral tissues (do not enter the CNS effectively). 4. Elimination: Conclusion: Rapid elimination from the body. Reason: Choline esters are water-soluble and are quickly excreted via the kidneys due to minimal binding to plasma proteins and rapid filtration. 5. Hydrolysis by AChE (Acetylcholinesterase): Acetylcholine and Methacholine: Conclusion: Rapidly hydrolyzed by AChE. Reason: These esters of acetic acid are natural substrates for AChE, leading to quick degradation in the synaptic cleft. Carbachol and Bethanechol: Conclusion: Resistant to hydrolysis by AChE. Reason: Their carbamic acid ester structure makes them less susceptible to enzymatic breakdown, resulting in longer-lasting cholinergic effects. Cholenergic Receptor Agonists 4  Comparison of Choline Esters Susceptibility to Muscarinic Nicotinic Choline Ester Cholinesterase Action Action Acetylcholine Very High Moderate Moderate chloride Methacholine Low High None chloride Carbachol chloride Negligible Low High Bethanechol Negligible Moderate None chloride Natural Alakaloids Action Chielfy Muscarinic Action Chielfy Nicotinic Muscarine Nicotine Pilocarpine (tertiary= more lipid soluble = abdorbed & crosses Lobeline BBB) Effects of Muscarinic Receptor Agonists Organ Response Eye Sphincter muscle of iris Contraction (miosis) Ciliary muscle Contraction for near vision Heart Sinoatrial node Decrease in rate (negative chronotropy) Decrease in contractile strength (negative inotropy). Atria Decrease in refractory period Decrease in conduction velocity (negative dromotropy). Atrioventricular node Increase in refractory period Ventricles Small decrease in contractile strength Blood vessels Cholenergic Receptor Agonists 5  Organ Response Dilation (via EDRF). Constriction (high-dose direct Arteries, veins effect) Lung Bronchial muscle Contraction (bronchoconstriction) Bronchial glands Stimulation Gastrointestinal tract Motility Increase Sphincters Relaxation Secretion Stimulation Urinary bladder Detrusor Contraction Trigone and sphincter Relaxation Glands Sweat, salivary, lacrimal, Secretion nasopharyngeal Note: If muscarinic receptor agonists are introduced from an external source (exogenously) rather than naturally through the parasympathetic nervous system (PNS) stimulation, they trigger the endothelium (the inner lining of blood vessels) to release nitric oxide (NO). NO then causes blood vessels to relax and dilate, lowering blood pressure. Therapeutic Uses of Cholinomimetic Agents 1. Bethanechol: Used to treat urinary and gastrointestinal tract hypotony (i.e., reduced muscle tone and motility). Conditions Treated: Post-operative urinary retention or ileus (inability of the intestine to contract). Diabetic autonomic neuropathy, which can affect the bladder and intestines. Cholenergic Receptor Agonists 6  Important Consideration: Ensure there is no obstruction in the urinary or GI tract before using. 2. Carbachol and Pilocarpine: Administered locally for glaucoma and to induce miosis (constriction of the pupil) during eye surgeries or to relieve intraocular pressure. 3. Pilocarpine: Used to manage xerostomia (dry mouth), especially in patients with: Head and neck irradiation (e.g., cancer treatment). Sjogren's Syndrome, an autoimmune disorder that causes dryness of the mouth and eyes. Contraindications for Cholinomimetic Agents 1. Asthma or Chronic Pulmonary Disease: These agents can increase bronchoconstriction, exacerbating respiratory issues. 2. Urinary or GI Obstruction: Cholinomimetic agents stimulate muscle contractions, which could worsen the obstruction and cause damage. 3. Peptic Ulcer: Cholinomimetic agents increase gastric acid secretion, which could aggravate ulcers. 4. Cardiovascular Disease & Bradycardia: These drugs lower heart rate and could cause or worsen bradycardia (abnormally slow heart rate). 5. Hypotension: They can lower blood pressure further, making hypotension more dangerous. Glaucoma 1. Development of Glaucoma Cholenergic Receptor Agonists 7  Healthy Eye: Aqueous humor, a clear fluid, is produced in the eye and drains through the drainage canal at a balanced rate, maintaining normal intraocular pressure (IOP). Glaucoma: Stage 1: Drainage canal blocked: In glaucoma, the drainage canal becomes blocked, leading to a build-up of aqueous humor. This blockage causes fluid accumulation and increases pressure inside the eye. Stage 2: Increased pressure: The increased intraocular pressure (IOP) starts to damage blood vessels and the optic nerve, which can lead to gradual vision loss if left untreated. 2. Aqueous Humor Flow in the Eye Cholenergic Receptor Agonists 8  Normal Flow Pathway of Aqueous Humor: Aqueous humor is produced by the ciliary body (3) and flows through the posterior chamber, moving between the iris and the lens. It passes through the pupil (controlled by the sphincter pupillae muscle - 1) into the anterior chamber. Aqueous humor drains primarily through the trabecular meshwork (5) into Schlemm's canal and leaves the eye through venous drainage (called uveo-scleral outflow - 4). The ciliary muscle (2) plays a role in regulating the tension in the trabecular meshwork, aiding in the outflow of the aqueous humor. Key Points: Glaucoma results from impaired drainage, leading to elevated pressure and potential optic nerve damage. Pilocarpine, as seen in the therapeutic uses, is used to treat glaucoma by enhancing the outflow of aqueous humor to reduce intraocular pressure. Muscarine Poisoning Symptoms: 1. Facial Flushing Reddening of the face due to increased blood flow to the skin. 2. Sweating, Salivation, Lacrimation Cholenergic Receptor Agonists 9  Excessive sweating, salivation, and tear production due to overstimulation of muscarinic receptors. 3. Gastrointestinal Symptoms: Vomiting, abdominal cramps, and diarrhea caused by increased smooth muscle activity in the GI tract. 4. Urination: Increased bladder contractions leading to frequent urination. 5. Respiratory Symptoms: Bronchoconstriction (narrowing of airways) and dyspnea (difficulty breathing). 6. Eye Symptoms: Miosis (pupil constriction) due to overactivity of the parasympathetic nervous system. 7. Gastric Secretion: Excessive gastric acid secretion, leading to potential digestive discomfort. 8. Cardiovascular Effects: Bradycardia (slow heart rate) and hypotension (low blood pressure) due to vagal stimulation. 9. Neurological Symptoms: Convulsions may occur in severe cases due to the overstimulation of the nervous system. Cholenergic Receptor Agonists 10