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Week 10 lec 2 hCholinergic agonists.pptx
- 1. Week 10 lec2 Cholinergic agonists Dr. Mohamoud Essa MD
- 2. Cholinergic Receptors (Cholinoceptors) 1.Muscarinic receptors These receptors bind Ach. Muscarinic receptors show only a weak affinity for nicotine. There are five subclasses of muscarinic receptors. However, only M1, M2, and M3 receptors have been functionally characterized.
- 3. Cont. Locations of muscarinicreceptors These receptors are found on ganglia of the peripheral nervous system and on the autonomic effector organs, such as the heart, smooth muscle, brain, and exocrine glands. M1 receptors are also found on gastric parietal cells, M2 receptors on cardiac cells and smooth muscle, and M3 receptors on the bladder, exocrine glands, and smooth muscle.
- 4. Cont. Muscarinic agonists Pilocarpine isan example of a nonselective muscarinic agonist used in clinical practice to treat xerostomia and glaucoma.
- 5. Cont. Nicotinic receptors These receptors,in addition to binding ACh, also recognize nicotine. The nicotinic receptor is composed of five subunits, and it functions as a ligand-gated ion channel. Binding of two ACh molecules elicits a conformational change that allows the entry of sodium ions, resulting in the depolarization of the effector cell.
- 6. Cont. Nicotine at lowconcentration stimulates the receptor, whereas nicotine at high concentration blocks the receptor. Nicotinic receptors are located in the CNS, the adrenal medulla, autonomic ganglia, and the neuromuscular junction (NMJ) in skeletal muscles.
- 7. Direct acting CholinergicAgonists Cholinergic agonists mimic the effects of ACh by binding directly to Cholinoceptors (muscarinic or nicotinic). These agents may be broadly classified into two groups 1. Endogenous choline esters: ACh, synthetic esters carbachol and bethanechol. 2. Naturally occurring alkaloids: nicotine, pilocarpine
- 8. Cont. All of thedirect-acting cholinergic drugs have a longer duration of action than ACh. The more therapeutically useful drugs ( pilocarpine and bethanechol) preferentially bind to muscarinic receptors and are sometimes referred to as muscarinic agents.
- 9. Cont. Acetylcholine Although it isthe neurotransmitter of parasympathetic and somatic nerves as well as autonomic ganglia, it lacks therapeutic importance because of its multiplicity of actions (leading to diffuse effects) and its rapid inactivation by the cholinesterases.
- 10. Cont. Actions of AChinclude the following. 1. Decrease in heart rate and cardiac output. 2. Decrease in blood pressure 3. In the gastrointestinal (GI) tract, acetylcholine increases salivary secretion and stimulates intestinal secretions and motility 4. It also enhances bronchiolar secretions. 5. ACh increases the tone of the detrusor muscle, causing urination. 6. Causes miosis (marked constriction of the pupil).
- 11. Cont. Bethanechol Its major actionsare on the smooth musculature of the bladder and GI tract. It has about a 1-hour duration of action. It lacks nicotinic actions Does have strong muscarinic activity.
- 12. Cont. Actions Bethanechol directly stimulatesmuscarinic receptors, causing increased intestinal motility and tone. It also stimulates the detrusor muscle of the bladder and produces urination.
- 13. Cont. Therapeutic applications: In urologictreatment, bethanechol is used to stimulate the atonic bladder, particularly in postpartum or postoperative, nonobstructive urinary retention. Bethanechol may also be used to treat neurogenic atony as well as megacolon.
- 14. Cont. Adverse effects Sweating Salivation Flushing decreased bloodpressure Nausea, abdominal pain, diarrhea, and bronchospasm. Atropine sulfate may be administered to overcome severe cardiovascular or bronchoconstrictor responses to this agent.
- 15. Cont. Carbachol Carbachol has bothmuscarinic and nicotinic actions. Actions Carbachol has profound effects on both the cardiovascular and GI systems. It can cause release of epinephrine from the adrenal medulla by its nicotinic action.
- 16. Cont. Therapeutic uses Because ofit high potency, receptor nonselectivity, and relatively long duration of action, carbachol is rarely used therapeutically. It is used as miotic agent to treat glaucoma. Adverse effects: At doses used ophthalmologically, little or no side effects occur.
- 17. Cont. Pilocarpine Pilocarpine exhibits muscarinicactivity and is used primarily in ophthalmology. Actions Rapid miosis and contraction of ciliary muscle Promoting salivation in patients with xerostomia
- 18. Cont. Therapeutic uses glaucoma:to lower intraocular pressure in emergency conditions. Useful in reversing mydriasis due to atropine. Adverse effects: Pilocarpine can cause blurred vision, night blindness, and brow ache.
- 19. Indirect acting Cholinergicagonists: Anticholinesterase agent AChE is an enzyme that specifically cleaves ACh and, thus, terminates its actions. Inhibitors of AChE (anticholinesterase agents or cholinesterase inhibitors) indirectly provide a cholinergic action by preventing the degradation of ACh. The reversible AChE inhibitors can be broadly classified as short-acting or intermediate-acting agents.
- 20. Cont. Edrophonium Edrophonium is shortacting AChE inhibitor. Edrophonium binds reversibly to the active center of AChE, preventing hydrolysis of ACh. It is used in the diagnosis of myasthenia gravis. Intravenous injection of Edrophonium leads to a rapid increase in muscle strength.
- 21. Cont. Physostigmine Actions: Physostigmine hasa wide range of effects as a result of its action and stimulates not only the muscarinic and nicotinic sites of the ANS but also the nicotinic receptors of the NMJ. Therapeutic uses To increase intestinal motility Treatment of atropine overdose Adverse effects: Convulsions at high doses, Bradycardia, paralysis of skeletal muscle.
- 22. Cont. Neostigmine Neostigmine has anintermediate duration of action, usually 30 minutes to 2 hours. is absorbed poorly from the GI tract, and does not enter the CNS. Therapeutic uses: Stimulate bladder and GI tract, Manage symptoms of Myasthenia gravis. Adverse effects: salivation, flushing, decreased blood pressure, nausea, abdominal pain, diarrhea, and bronchospasm.
- 23. Cont. Pyridostigmine and ambenonium Theirdurations of action are intermediate (3 to 6 hours and 4 to 8 hours, respectively) but longer than that of neostigmine. Tacrine, donepezil, rivastigmine, and galantamine delay the progression of Alzheimer’s disease
- 24. Indirect acting Cholinergicagonists: Anticholinesterase agents (Irreversible) Echothiophate This drug permanently inactivates the enzyme and restoration of AChE activity requires the synthesis of new enzyme molecules. Therapeutic uses: A topical ophthalmic solution of the drug is available for the treatment of open-angle glaucoma.
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