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Pharmacology-sheet #15 swewS haraF Cholinomimetic Drugs From the name we conclude that these are drugs that mimic the action of Acetylcholine, either by directly binding to a receptor or by increasing the amount of acetylcholine. They have the same structure as the Ach but with some modifications for example, substituting one hydrogen molecule on the ach for a methyl group will increase the half life of drug such as the Pilocarpine drug. The increased half-life is due to ach esterase not being able to recognize and deactivate the drug easily (it’s not a substrate for acetylcholine esterase). Also some modification to the structure of ach may enable drugs to have lipophilic qualities making it easier for them to pass membranes ex. Blood brain barrier. Parasympathomimitic drugs, are drugs or poisons (because some of them are found naturally occurring in plants especially mushrooms) that stimulate the parasympathetic system. They work as we said by: 1- directly acting agonist 2- indirectly acting inhibits endogenous enzymes that break Ach (ACH esterase) increasing Ach *We talked before about Ach esterase inhibitors (nerve gas and insecticides). So these increase amount of Ach In the Parasympathetic system: 1-Nicotinic receptors: -Located on the autonomic ganglia (both sympathetic and parasympathetic) -Located on the neuro-muscular end plate -Activated by nicotine but not muscarine -Found in certain plants |Page1 Pharmacology-sheet #15 swewS haraF 2-Muscurenic Receptors Located on the parasympathetic neoro-effector site activated by muscarine but not nicotine *Ach activates both Muscirine is a poison found certain types of mushrooms, if a patient ate these mushrooms or was subjected to cholinomimitic poisoning the symptoms would be as if the parasympathetic system were activated: Bradychardia, pin point pupil, sweating, blurred vision, excessive lacrimation, bronchoconstriction, wheezing, dyspnea, coughing, vomiting [abdominal cramping, diarrhea (because of contraction of walls and relaxation of sphincter and increase acid secretion in stomach)], urinary incontinence (also because of wall relaxation and sphincter relaxation) Atropine is an antidote, it works as an ach antagonist/muscarinic receptor antagonist which block the effects of poisoning (it is mainly a muscarinic antagonist) Another benefit of changing the structure of Ach, is the increased selectivity of the drugs. So some drugs are selective for muscarinic and some are for nicotinic, also they are selective for the subtypes of these receptors so if I want a drug to work on the heart we choose one which mainly affects the M2 receptors. Smoking (nicotine) stimulates the autonomic ganglia thus stimulating fibers of the sympathetic or parasympathetic systems. Effects are mostly related to the sympathetic system: 1-tachicardia 2-hypertension 3- dilated pupil 4-muscle fasciculation (quick unregulated contractions of the muscle which leads to weakness) That’s why nicotine Is bad for people with heart problems Tubocurarine drug is an antagonist for nicotinic receptors, old Mayan and Aztec tribes used this drug as a tool for hunting. They would use pipes and needles with the tip full of the drug to paralyze the animal’s muscles to catch it. tubocurarine won’t affect people who will consume that animal because the drug will be broken down in the GIT. |Page2 Pharmacology-sheet #15 swewS haraF Tubocurarine maybe used in anesthesia to relax the muscles for intubation and to cut through the muscles in operations (muscles relax) Receptor location of muscarinic: M1+M4 Brain and autonomic ganglia M2 Heart M3 Smooth muscle cells and endothelial cells M5 we’ll talk about them in the CNS Drugs: 1) Acetylcholine - Not used as a drug because of its short half life. - If injected into tissue: 1-activate muscarinic receptors 2-activates nicotinic receptors 3-stimulates post gang neuro-effector junction (somatic motor end plate) -Not selective, but after operations the patient may have dilated pupils so the apply Ach to cause meiosis “constriction” decreasing the amount of light entering the eye which may damage the retina (but there are better drugs for this use) 2) Ach derivatives -Selective and not degraded by Ach esterase A. Metacholine + methanicole more selective for muscarinic B. Carbapole can activate both Muscarinic and nicotinic but at therapeutic doses it only activates muscarinic. One explanation is that muscarinic receptors are much more in number than nicotinic receptors. (These are Hydrophilic drugs so they cant cross membranes easily. We don’t use them for preparation of the eye or in the CNS, although carbapole can cross the membrane and be used in the eye but there are better drugs such as pilocarpine) |Page3 Pharmacology-sheet #15 swewS haraF C. Pilocarpine: - Tertiary amine - Not polar, can cross membranes relatively easily so it can cross the cornea of the eye and bbb - It’s a pure muscarinic receptor agonist - Long half life - Uses: For glaucoma (increased intraocular pressure) accumulation in the anterior chamber of the eye. Canal of schleme is controlled by a meshwork of cords and the muscle responsible for the tone of these cords is the ciliary muscle. Parasympathetic stimulation causes its contraction, pulling/contracting the meshwork opening it up, so excess fluid leaks out decreasing the intraocular pressure. This drug also increases the accommodation of the eye. There are two types of glaucoma: 1- open angle 2-narrow angle Pilocarpine may not work in some cases but in general pilocarpin helps in decreasing glaucoma and mainly works in open angle situations. So Pilocarpine (also Carbapole) work on the cilliary muscle through parasympathetic stimulation (agonist) contracting and opening up the trabecular network releasing the excess fluid. Sympathetic nervous system antagonist treat glaucoma parasympathetic nervous system agonist treat glaucoma (also meiosis) sympathetic agonist contraction of radial muscle mydriasis by counteracting sympathetic effect on the radial muscle relaxation opening the passage for the fluids in the anterior compartment to decrease |Page4 Pharmacology-sheet #15 swewS haraF How does ach dilate the blood vessels? Blood vessel anatomy: -Endothelial layer (inner) -Smooth muscle cell layer (middle) -Adventitia layer (outer) Endothelial and SMC both have M3 receptors: Ach binds to M3 of the endothelial activation of calcium channels increase conc. of calcium activation of eNOS converts arginine to nitric oxide (easily diffusing gas with short half life) diffuses to the next cell “Smooth muscle cell” activates guanylyl cyclase wich gives produces cGMP activates multiple enzymes, PKG and certain channels --> Relaxation of the smooth muscles Vasodilation BUT! If the endothelial cell layer was absent for what ever reason (pathological ex. Atherosclerosis/endothelial dysfunction) Ach binds directly to the M3 of the SMC (skipping the endothelial cell) this causes calcium influx contraction of SMC Vasoconstriction *At low doses the first mechanism happens causing vasodilation but at an increased dose the drug binds to the SMC directly over coming the relaxation and causing vasoconstriction. *Sublingual nitrates release NO directly from the endothelial to the SMC vasodilation a low dose of muscarinic agonist can sometimes increase the heart rate why? First thing that comes to mind is Bradycardia but this is not happening here. This is because of the low dose affecting the blood vessels and causing vasodilation, so the reflex mechanism of the heart would be tachycardia increasing the heart rate but a high dose of ach or muscarinic agonist will directly activate the M2 receptors in the heart these will decrease the heart rate |Page5