CHOLINERGIC AGONISTS, Study Guides, Projects, Research of Medical Sciences

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CHOLINERGIC AGONISTS

• A.DIRECT ACTING MUSCARINIC AGONISTS

• (^) 1.Action and chemical structure
• (^) a.Direct acting parasympathomimetic drugs ac at muscarinic cholino-
• (^) receptors to mimic the many of the physiologiv effects that result from stimulation of the parasympathetic division of the autonomic nervous system
• (^) b.BETHANECHOL&CARBACHOL are choline esters with a quaternary ammonium group that are structurally similar to acetylcholine but more resistant to hydrolysis by acetylcholinesterase.TheBmethylgroup

b.Cardiovascular system: 1.Direct-acting muscarinic cholinoceptor agonists produce a negative chronotropic effect(reduced SA node activity). 2.These drugs decrease conduction velocity thru AV node.

• (^) 3.These drugs have no effect on force of contraction because there are no muscarinic receptors on parasympathetic of ventricles.
• (^) 4.Direct-acting muscarinic cholinoreceptor agonists produce vasodi
• (^) lation that results primarily from their action on endothelial cells to promote the release of nitric oxide(NO),which diffuses to the vascular smooth muscle and produces relaxation.Vascular smoothmuscle has
• (^) muscarinic receptors but no parasympathetic innervation.

• (^) The resulting decrease in blood pressure can result in a reflex increase in heart rate.(Intravenous infusion of low doses of Ach causes a reflex sympathetic increase in heart rate;higher doses directly inhibit heart rate.)
• (^) c.Gastrointestinal tract-1.Direct acting muscarinic cholinoreceptor agonists increase smooth muscle contractions and tone,with increased peristaltic activity and motility.
• (^) 2.These drugs increase salivation and acid secretion.
• (^) d.Urinary Tract-1.Direct-acting muscarinic cholinoreceptor agonists increase contraction of the ureter and bladder

• (^) a.Bethanechol-(Urecholine)
• (^) 1.Bethanechol is used to stimulate smooth muscle motor activity of the urinary tract to prevent urine retention.
• (^) 2.It is used occasionally to stimulate gastrointestinal smooth muscle motor activity for postoperative abdominal distention and for gastric atony following bilateral vagotomy(in the absence of obstruction).
• (^) 3.Bethanechol is administered orally or subcutaneously,not by IV or IM route,because parenteral administration may cause cardiac arrest.
• (^) 4.This drug has low lipid solubility and is poorly absorbed from the GIT.When given orally,GI effects predominate,and there are relatively

• (^) minor cardiovascular effects.
• (^) 5.Bethanechol has limited distribution to the CNS.
• (^) 6.It is resistant to hydrolysis by AchE and plasma cholinesterase and thus has longer duration of action than Ach(2-3 hours).
• (^) b.Methacholine(Mecholy) is occasionally used to diagnose bronchial hypersensitivity and asthmatic conditions.
• (^) c.Pilocarpine
• 1.Pilocarpine is occasionally used topically for open-angle

• (^) c.Pilocarpine is a tertiary amine that is well absorbed from the GIT and enters the CNS.
• (^) d.Carbachol is a rarely used med except if Pilocarpine is ineffective as a treatment for open-angle glaucoma.
• (^) 4.Adverse effects and contraindications:
• (^) a.The adverse effects associated with direct acting muscarinic cholinoceptor agonists are extensions of their pharmacologic 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.Systemic effects are
• (^) minimal for drugs applied topically to the eye.
• (^) b.These drugs are contraindicated in the presence of peptic ulcer,
• (^) because they increase acid secretion,asthma,cardiac disease,and Parkinson’s disease.They are not recommended in hyperthyroidism because they predispose to arrhythmia;they also are not recommended when there is mechanical obstruction of the gastro-
• intestinal or urinary tract.

• (^) to mimic many of the physiologic effects that result from stimulation of the parasympathetic division of the autonomic nervous system.
• (^) b.ACh interacts with AChE 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 ACh is hydrolyzed,the serine-OH side chain is acetylated and free choline is released.Acetylcholine is hydrolyzed to serine and acetate.The half-life(t 1/2 )of acetylcholine hydrolysis is
• (^) to 150 mcroseconds.
• (^) c.Edrophonium(Tensilon)acts at the same sites of AChE t competi-
• (^) tively inhibit ACh hydrolysis by the following processes:

• (^) 1.N edrophonium binds the anionic site.
• (^) 2.Phenolic hydroxyl of edrophonium interacts with histidine imida-
• (^) zolium N+ of the esteratic site.
• (^) 3.Edrophonium has a duration of action(5-15 min).
• d.NEOSTIGMINE(Prostigmin),physostigmine(Eserine,Anti lirium),and
• (^) Demecarium(Humorsol,like ACh,interact with AChE and undergo a
• (^) two step hydrolysis.

• (^) 1.These drugs differ in absorption and distribution as follows:
• (^) a.Echothiophate-is poorly absorbed from the gastrointestinal and has negligible distribution into the CNS.
• (^) b.Isoflurophate-is highly lipid soluble and is well absorbed across all membranes including skin.
• (^) f.PRALIDOXIME(Protopam)
• (^) 1.Pralidoxime is an AChE reactivator.It must be administered IV within minutes of exposure to an AChE inhibitor because it is effective

• (^) prior to “aging”.
• (^) 2.Pralidoxime acts as an antidote for insecticide and nerve gas
• (^) poisoning.It binds the anionic site and undergoes a nucleophilic reaction with P=O group of alkylphosphorylated serine to cause hydrolysis of the phosphoserine bond that is at at least 10x faster than that occuring in water.
• (^) 3.The drug is most effective at the neuromuscular junction.it is ineffective in the CNS and against carbamylated AChE.

• (^) 4.THERAPEUTIC USES:
• (^) a.Glaucoma 1.Physostigmine is often used concurrently with Pilocar-
• (^) pine for maximum effects in the treatment of acute angle glaucoma,a medical emergency.
• (^) 2.Physostigmine,demecarium,echothiophate,&other cholinesterase
• (^) inhibitors have been largely replaced for the treatment of chronic
• (^) open-angle glaucoma by topical B-adrenergic receptor antagonists such as Timolol and Betaxolol.and by prostaglandin analogues such as Latanoprost.They are used when other drugs are ineffective.

• (^) -Prolonged use may increase the possibility of cataracts.
• (^) b.Gastrointestinal and urinary tract atony can be treated with
• (^) Neostigmine,which is used much like Bethanechol.
• (^) c.Myasthenia gravis-is an autoimmune disease in which antibodies
• (^) complex with Nicotinic receptors at the neuromuscular junction to cause skeletal muscle weakness and fatigue.Neostigmine or the related AChE inhibitors Pyridostigmine,or Ambenomium is used to increase ACh levels at the NMJ to activate fully the remaining receptors.