Direct-acting Muscarinic Agonist (2) PDF

Direct-acting muscarinic agonist :- Choline Esters:- Acetylcholine (ACh) Structure Information -Ester of choline with acetate. - Quatenary ammonium compound  carry (+ve) charge polar  cannot penetrate membranes not pass BBB. Chemical...

Direct-acting muscarinic agonist :- Choline Esters:- Acetylcholine (ACh) Structure Information -Ester of choline with acetate. - Quatenary ammonium compound  carry (+ve) charge polar  cannot penetrate membranes not pass BBB. Chemical transmitter. Synthesis: Choline is transported from the extracellular fluid into the cholinergic neuron by active transport (energy- dependent carrier) system (Choline has a quaternary nitrogen and carries +ve charge and, cannot diffuse through the membrane). Synthesis, - This synthesis can be inhibited by the drug Hemicholinium. Choline acetyltransferase enzyme catalyzes the synthesis of acetylcholine from choline and acetyl-CoA. Storage Storage: - ACh is stored into presynaptic vesicles to prevent inactivation by and Release active transport. - The mature vesicle contains not only ACh but also Co- transmitters. -This Uptake (storage) can inhibited by Vesamicol. Release: -when an action potential arrives at a nerve ending Open voltage-sensitive calcium channels on the presynaptic membrane increase conc. Of intracellular Ca2+promote the fusion of synaptic vesicles with the cell membrane and release of their contents into the synaptic space by exocytosis This release can be blocked by botulinum toxin.  - Cholinesterase enzyme breakdown ACh into  Acetic acid + Choline. Inactivation - Types of Cholinesterase enzyme: 1: True (Acetyl) cholinesterase (ACHE) found in all ACh sites. 2: Pseudo (Butyryle) cholinesterase (BCHE) found in liver & plasma. Heart - (-ve) Inotropic, (-ve) Chronotropic & (-ve) Dromotropic. Blood - M3 receptor in endothelium are stimulated with ACh indirect action via (EDRF) increase NO formation vessels VDHypotension. GIT - Stimulates intestinal secretions and motility (peristalsis). - Relaxation of sphincter. Urinary - Contraction of detrusor muscle (wall). bladder - Relaxation of sphincter. Pharmacological Bronchi - Bronchoconstriction. action - Stimulates bronchial secretion. Eye - Contraction of circular muscle Miosis - Contraction of ciliary muscle accommodation for near vision. Ex. Increase all secretions e.g. lacrimation and salivation. glands Nicotinic - NN Stimulate ganglia and adrenal medulla increase release of adrenaline and nor-adrenaline Receptors from adrenal medulla. NM Stimulation of motor endplate (MEP)  Skeletal twitches. No clinical uses due to: - Multiplicity of action (Non-selective) act on all ACh receptors. -Short duration due to rapid inactivation by cholinesterase enzyme.  Carbachol (Isopto®Carbachol) Information - Ester of choline with carbamic acid. - Also known as carbamylcholine. - Totally resistant to two types of cholinesterase enzyme. Disadvantage - Rarely used therapeutically except in the eye as a miotic agent due to - Longer half-life. - Non-Selectiveact on nicotinic and muscarinic receptors. uses - Used rarely except in eye drops to treat Glaucoma Cause miosis  increase outflow of aqueous humour through canal of schlemm decrease Intraocular pressure (IOP). Bethanechol(Urotone®) Information - Ester of B-methyl choline with carbamic acid. - Totally resistant to two types of cholinesterase enzyme. - Selective to muscarinic receptor. Pharmacological Major action on GIT and Urinary bladder In GIT  Increase motility. action In U.B Contraction wall and relaxation sphincter lead to urination. - Postoperative non-obstructive GIT disorder to prevent constipation. uses - Postoperative non-obstructive urinary tension. - Gastro-paresis. - N.B: It has about a 1-hour duration of action.  Methacholine (Provocholine®) Information - Ester of beta-methyl choline with acetic acid. - Selective to muscarinic receptor. - used in bronchial challenge test (or Methacholine challenge test) to diagnose asthma (increase asthma uses when inhaled due to it act on M3 cause bronchoconstriction). Side effects - Cardiovascular effects, such as bradycardia and hypotension (M2). Choline Esters Susceptiblity to Muscarinic Nicotinic cholinestrase Action Action Ach ++++ +++ +++ Carabachol negligible ++ +++ Bethanechol negligible ++ None Methacholine + ++++ None All choline Esters are quaternary ammonium compounds.  Carry charge  polar Don’t pass BBB  NO CNS effect. Cholinomimetic Alkaloids :- Pilocarpine (Isopto®Carpine) Information - Alkaloid of plant origin (Pilocarpus leaflet). - Tertiary amine alkaloid Not carry charge non-polar lipid soluble  pass BBB  CNS side effect. - Stable to hydrolysis by cholinesterase enzyme. - It shows muscarinic effect without having significant nicotinic effect. Eye - Penetrate cornea because it is non-polar causing produces rapid miosis and (Main action) contraction of the ciliary muscle  accommodation for near vision. Pharmacological GIT Increase motility. Action U.B Increase urine excretion. Bronchi Bronchoconstriction Ex. gland - Potent stimulators of secretions such as sweat, tears, and saliva. Uses -Treatment of glaucoma. Mechanism of * It cause miosis and contracts to ciliary action muscle, it opens the trabecular meshwork pores and facilitate out flow of aqueous humour into the canal of schlemm  decrease IOP (Intraocular pressure). Side effects - CNS side effect CNS disturbance. -Sweating and salivation. Notes - The miotic action of pilocarpine is also useful in reversing mydriasis due to atropine.  Cevimeline (Evoxac®) Uses - Oral drug used in dry eye and dry mouth (xerostomia) associated with Sjögren's syndrome. - N.B: Sjögren's syndrome (SHOH-grinz) is an autoimmune disease in which immune cells attack and destroy the exocrine glands that produce tears and saliva. Side effects - Nausea, vomiting, diarrhea, excessive sweating, rash runny nose, blurred vision, difficulty breathing and headache. Contraindication - Patients with history of heart disease, asthma, kidney stones or closed angle glaucoma. ‫ي ْالقايُّو ُم ۚ اَل تاأْ ُخذُهُ ِسناةٌ او اَل ن ْاو ٌم ۚ لههُ اما فِي ال ه‬ َٰ. ‫ت او اما فِي‬ ِ ‫س ام ااوا‬ ُّ ‫َّللاُ اَل ِإلاها ِإ هَل ه اُو ْال اح‬ ‫ه‬ ‫طونا‬ُ ‫ض ۗ امن ذاا الهذِي يا ْشفا ُع ِعن ادهُ ِإ هَل ِبإِ ْذنِ ِه ۚ اي ْعلا ُم اما ابيْنا أا ْيدِي ِه ْم او اما خ ْالفا ُه ْم ۖ او اَل يُ ِحي‬ ِ ‫ْاْل ا ْر‬ ُ ‫ض ۖ او اَل ايئُو ُدهُ ِح ْف‬ ‫ظ ُه اما ۚ اوهُ او‬ ‫ت او ْاْل ا ْر ا‬ ِ ‫س ام ااوا‬ ‫ايءٍ ِِّم ْن ِع ْل ِم ِه ِإ هَل ِب اما شاا اء ۚ او ِس اع ُك ْر ِسيُّهُ ال ه‬ ْ ‫ِبش‬ ‫ي ْالعا ِظي ُم‬ُّ ‫ْالعا ِل‬