Cholinergic Agonists and Antagonists PDF

Pharmacology Hussein T. Alkaisey Cholinergic agonists and cholinergic antagonists Drugs affecting the autonomic nervous system (ANS) are divided into: 1. The cholinergic drugs, which act on receptors that are activated by acety...

Pharmacology Hussein T. Alkaisey Cholinergic agonists and cholinergic antagonists Drugs affecting the autonomic nervous system (ANS) are divided into: 1. The cholinergic drugs, which act on receptors that are activated by acetylcholine (ACh). 2. Adrenergic drugs act on receptors stimulated by norepinephrine or epinephrine. Cholinergic receptors (Cholinoceptors): 1. Muscarinic receptors: These receptors bind to ACh, muscarine (present in mushrooms), but, show only a weak affinity for nicotine. five subclasses of muscarinic receptors: M1: found on gastric parietal cells. M2: on cardiac cells and smooth muscle. M3: on the bladder, exocrine glands, and smooth muscle. M4, and M5. 2. Nicotinic receptors: binds to ACh, nicotine but show a weak affinity for muscarine. -Nicotine at low concentration stimulates the receptor, and at high concentration blocks the receptor. -Nicotinic receptors are located in the CNS, adrenal medulla, autonomic ganglia, and the neuromuscular junction (NMJ). -The nicotinic receptors of autonomic ganglia are selectively blocked by hexamethonium, whereas NMJ receptors are blocked by tubocurarine. Direct-acting cholinergic agonists: Cholinergaic agonists (parasympathomimetics) binding directly to cholinoceptors. 1. Acetylcholine [ah-see-teel-KOE-leen]: it lacks therapeutic importance because it has multiple actions and its rapid inactivation by the cholinesterases. ACh acts on both muscarinic and nicotinic receptors. Its actions include decreases the heart rate, cardiac output and blood pressure, increases salivary secretion and stimulates intestinal secretions and motility, enhances bronchiolar secretions, expulsion of urine, miosis. 1 Pharmacology Hussein T. Alkaisey 2. Bethanechol [be-THAN-e-kole]: It lacks nicotinic actions but does have strong muscarinic activity. Its major actions are on bladder and GI tract. Uses: it is used to stimulate the atonic bladder (postpartum or postoperative) and megacolon. Adverse effects: sweating, salivation, flushing, hypotension, nausea, abdominal pain, diarrhea, and bronchospasm. Atropine may be administered to overcome cardiovascular or bronchoconstrictor side effects of this agent. 3. Carbachol [KAR-ba-kole]: It has muscarinic and nicotinic actions. It has profound effects on both the cardiovascular and GI systems. Uses: because of receptor non-selectivity, and long duration of action, carbachol is rarely used except in the eye as a miotic agent to treat glaucoma. Adverse effects: little or no side effects occur when used ophthalmologically. 4. Pilocarpine [pye-loe-KAR-peen]: exhibits muscarinic activity and is used primarily in ophthalmology to produces rapid miosis (for glaucoma). Adverse effects: CNS disturbances, sweating (diaphoresis) and salivation. Indirect-acting cholinergic agonists (Acetylcholinesterase inhibitors): AChE is an enzyme that cleaves ACh to acetate and choline and, thus, terminates its actions. Therefore, these drugs can provoke a response at all cholinergic receptors in the body. 1. Edrophonium [ed-row-FOE-nee-um]: is short-acting AChE inhibitor. Uses: - It is used in the diagnosis of myasthenia gravis, which is an autoimmune disease caused by antibodies to the nicotinic receptor at NMJs. Intravenous injection of edrophonium leads to a rapid increase in muscle strength. (atropine is the antidote). - for reversing the effects of nondepolarizing neuromuscular blockers after surgery. 2. Physostigmine [fi-zoe-STIG-meen]: stimulates the muscarinic and nicotinic receptors of the NMJ. It is considered to be an intermediate-acting agent. Uses: - increases intestinal and bladder motility. 2 Pharmacology Hussein T. Alkaisey - produces miosis, lowers the intraocular pressure (for glaucoma). - treatment of overdoses of anticholinergic drugs. Adverse effects: convulsions (high doses), bradycardia, paralysis of skeletal muscle. 3. Neostigmine [nee-oh-STIG-meen]: Uses: - to stimulate the bladder and GI tract. - as an antidote for tubocurarine and other competitive neuromuscular blocking agents. - to treat myasthenia gravis. 4. Pyridostigmine [peer-id-oh-STIG-meen]: - is used for myasthenia gravis. Toxicity of acetylcholinesterase inhibitors: AChE inhibitors are commonly used as insecticides which has led to many cases of accidental intoxication with these agents. Treatment of Toxicity with AChE inhibitors: 1. Pralidoxime can reactivate the inhibited AChE. 2. Atropine: to prevent increased bronchial secretion and saliva, bronchoconstriction, and bradycardia. 3. Diazepam: to reduce the persistent convulsion. 4. Maintenance of airway, oxygen supply, and artificial respiration, may be necessary. Antimuscarinic agents(antagonist): These agents (for example, atropine and scopolamine) block muscarinic receptors and the neurons that innervate salivary and sweat glands. They have little or no action at skeletal neuromuscular junctions (NMJs). 1. Atropine [A-troe-peen]: It has a high affinity for muscarinic receptors. a. Eye: atropine causes persistent mydriasis. b. Gastrointestinal (GI): reduces the activity of the GI tract (antispasmodic). c. Heart: causes bradycardia at low doses, and tachycardia at higher doses. 3 Pharmacology Hussein T. Alkaisey d. Secretions: blocks the salivary glands, sweat and lacrimal glands secretions. Adverse effects: dry mouth, blurred vision, tachycardia, urinary retention, constipation, confusion, hallucinations, and delirium. 2. Scopolamine [skoe-POL-a-meen]: produces effects similar to atropine. However, scopolamine has greater action on the CNS and a longer duration of action. Uses: anti–motion sickness, blocking short-term memory. In contrast to atropine, scopolamine produces sedation, but at higher doses it can produce excitement. 3. Ipratropium and tiotropium (Inhaled): are approved as bronchodilators for patients with chronic bronchitis and emphysema, for asthma in patients who are unable to take adrenergic agonists. 4. Tropicamide and cyclopentolate: - similar to atropine as ophthalmic solutions for mydriasis and cycloplegia. Their duration of action is shorter than that of atropine. 5. Benztropine and trihexyphenidyl: They are centrally acting antimuscarinic agents that have been used in the treatment of Parkinson disease. 6. Oxybutynin: It blocks muscarinic receptors in the bladder, so, bladder capacity is increased, and the frequency of contractions is reduced. thus, it is used for treatment of enuresis. 4