Can bind to several receptors in the body (nicotinic, muscarinic, everywhere)

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1 Problems of acetylcholine: 1. Selectivity : Can bind to several receptors in the body (nicotinic, muscarinic, everywhere) 2. Absorption: because any drug that acts as a cholinergic agonist must have a +ve charge the absorption is poor. 3. Stability: it has an ester chemical or enzymatic hydrolysis # These three problems need to be solved when we talk about parasympathetic or cholinergic drugs. Q: What is the therapeutic indication for parasympathetic or cholinergic agonists? 1) to decrease heart rate for people with tachycardia 2) increase GI motility (main indication) 3) given before surgery to empty the urinary bladder(increased contraction) 4)sometimes after surgery, the physician might give the patient narcotics to relieve pain prolonged use of narcotics causes severe constipation using cholinergic agonists is given to treat this constipation. 5) Treatment of myasthenia gravis: is an autoimmune neuromuscular disease leading to fluctuating muscle weakness and fatigue. Muscle weakness is caused by circulating antibodies that block acetylcholine receptors at the postsynaptic neuromuscular junction, inhibiting the excitatory effects of the neurotransmitter acetylcholine on nicotinic receptors at neuromuscular junctions. since the defect is in the receptor, we give the patient cholinergic agonist to increase its abundance, that would give greater effect even if the number of functional receptors is small 1

2 in the first stages of this disease the patient will have dropped eyes the defect acetylcholine receptors of the eyelid will stop its contraction, preventing the eyelid from going up. #Note: we won t use acetylcholine itself as a drug. Cholinergic Agonists: 1. Methacholine: methyl + acetylcholine # What is the advantage of the extra methyl? the problem with acetylcholine is that it has an ester that will undergo hydrolysis, so it is not stable. But when we add the extra methyl we prevent esterases from metabolizing the ester, by blocking its binding (steric shield ). also, when chemical hydrolysis by acidic hydrolysis is to happen, protonation of the O must occur, but due to the presence of Me group steric shield will block protonation. methyl shields the drug from both types of hydrolysis. by adding an extra methyl, we solve one problem stability ((but not completely! Stability improves by 3 to 4 fold )) 2

3 Q: is it muscarinic or nicotinic selective? muscarinic receptors are bigger, since this drug has extra methyl it is selective on muscarinic receptors. By adding this methyl group we solve another problem selectivity #Note: we still have a +ve head, so the absorption is poor isn t administered orally -it is stable & selective to muscarinic receptors due to the methyl group - not used clinically due its toxicity so our approach was : enhance stability (block hydrolysis) and selectivity by adding steric shield. 2. Carbachol : (carba carbamate) We have another approach to enhance stability of the drug. in general, our problem with esters is the carbonyl for both enzymatic and chemical hydrolysis. the first thing that happens is nucleophilic attack on the carbonyl C=O (because it is electron deficient due to the electrons being pulled towards the oxygen) If we replace the R (electron withdrawing) with NH2 (electron donating) electropositivity of carbon will decrease and nucleophilic attack will decrease as well. this way we enhance stability by decreasing ester hydrolysis carbamate 3

4 Carbachol is more stable than acetylcholine. Q: how will it bind to the receptor? there is a pocket in the receptor hydrophobic interaction -We don t have steric shield because NH2 and methyl have similar size -In terms of size NH2 can fit but without interaction this makes the binding weaker -although binding is weaker, it is still more stable than acetylcholine other properties are similar to acetylcholine. -it is nonselective (50% muscarinic & 50% nicotinic) - used topically for glaucoma 3. Bethanechol: Here we have carbamate on one side enhances stability and an extra methyl on the other side enhances both stability and selectivity. -selective to muscarinic receptors -poor oral bioavailability -therapeutic indication: GI motility (because it is muscarinic) -some physicians give it orally to relieve constipation, why? because the effect needed is in the GI, the drug acts locally on GI receptors without being absorbed (poor bioavailability) orally active for constipation but not orally bioavailable. -for evacuation of the bladder it can be given either parentral or oral, why? orally it causes evacuation indirectly by GI motility applying mechanical pressure on the bladder leading to bladder emptying (no direct action because the drug won t be absorbed) 4

5 when given parentrally it causes direct effect on cholinergic receptors in the bladder which causes contractions leading to bladder emptying. No bioavailability doesn t reach blood 4. Nicotinic selective agonist : -it is similar to Methacholine, but the extra methyl is on the alpha carbon instead of the beta carbon for an unknown reason this makes it nicotinic selective instead of muscarinic. -it is still not in the market -this compound isn t stable (no protection of ester), it is only nicotinic selective. the drugs we will talk about next have these therapeutic indications: 1) treatment of myasthenia gravis 2)treatment of glaucoma 3)treatment of GI disorders 4)treatment of tachycardia glaucoma : high pressure in the eye - open glaucoma: a problem with fluid input into the eye controlled by adrenergic system not cholinergic -closed glaucoma: channels that fluid exits through are closed because the skeletal muscle is relaxed and it blocks these channels we treat it with cholinergic agonists because it is a problem with skeletal muscle that has nicotinic receptors these agonists will cause contraction of the muscle the channels will open. #Note: - the eye has channels that fluid enters through and channels that fluid exits through in order to have a balance. 5

6 -nicotinic selective drugs are few, we only have carbachol (50% nicotinic selective) -the rest of the drugs we will take this lecture are muscarinic selective 5. Pilocarpine (idoptocarpine) : eyedrops -it is a natural product -wherever you see iso it means: isotonic because eye preparations must be isotonic ( conc. Of salt in sol.1 = conc. Of salt in sol.2) - But orally or IV : Not necessary to be isotonic. -If we increase salt concentration in our eyes; it will explode. From structure : [A] we have imidazole We have 2N (Sp2,Sp3), Sp2 (Pka=6) is more basic PH of Eye around 7, 90% Unionized, 10% ionized [B] Ester: 2 HBA, We have 3D structure, We have 2 cycles : So we have rigidity not a lot of conformation Space between N ( head, 10% ionized ) and Ester = 4.4 A, It binds to muscarinic receptor in the same way acetylcholine binds. we have only 10% ionized ; If we take 100 mg only 10 mg will be ionized and bind to receptor, The presence of Methyl will improve the stability, so it s stable to hydrolysis we solve stability problem. Bulkiness + distance between 2 head: Selectivity to muscarinic. 6

7 Orally active due to 90% unionized will be absorbed. If I take it taken orally absorption is very important but in eye drops ; we don t need absorption. here : 1) +ve charge of N replaced quaternary amine. 2) Spacer not necessary to be 2 carbon, but it necessary to be 4.4 A. Therapeutic indications : 1) If it s eye drop : Treat Glaucoma. TCA : Antidepressant to increase secretion of serotonin and 2) If it s orally : To reverse effect of atropine 3) We give it to reverse TCA overdose. Why? Because : A) Atropine and TCA act on CNS and pilocarpine enter CNS because it s 90% non ionized B) Catecholamine will stimulate adrenergic system, someone take overdose so activation of adrenergic system is high ; So we give him cholinergic agonist. 6. Edrophonium ( Enlon) # Note: not necessary to use cholinergic agonist directly ( Not necessary to use acetylcholine directly ). - If we need cholinergic effect we can either : 1) use cholinergic agonist directly. OR 2) Use cholinesterase inhibitor ; because if I inhibit this enzyme increase the duration of acetylcholine in the receptor. -It s easier to make research on cholinesterase inhibitor group than cholinergic agonist because it has a lot of advantages. 7

8 BACK to edrophonium : It is a cholinesterase inhibitor : It has the same effect of acetylcholine. Acetylcholine binds to the receptor and to cholinesterase enzyme so active site is the same. +ve head is necessary, spacer, HBA or HBD important. The same basic requirements but more flexibility with enzyme. #Note: wherever you see +ve head separated from H-bonding by benzene ring ; it will have cholinesterase inhibitor effect not direct agonist. Not potent agent ; so if we have acetylcholine more binding and cholinesterase inhibitor which is more potent? acetylcholine : more binding Used for diagnosis of Myasthenia gravis : the Doctor give the patient this preparation as eye drops, IF the patient opens his eye the Doctor will make decision, If he can t open his eye we will take another decision, How? If I give him cholinesterase inhibitor ; I increase acetylcholine abundance in his eye but if he doesn t have receptor he can t open his eye. -Myasthenia graves: receptor of acetylcholine is broken. but it has level A, B, C, D. 7. Neostigmine (stigmin ) : 8

9 -Synthetic compound, +ve head, benzene ring, ester (HB) -It s cholinesterase inhibitor, more potent than Edrophonium, because it s more similar to acetylcholine ( it has methyl on N, and on ester ). So we don t use it for diagnoses; we use it for treatment of Myasthenia gravis because it s more potent. 8. Physostigmine : Ester Benzene ring The side which is similar to acytylcholine -Natural compound, because it has a lot of cyclization. -It s a parent compound of stigmine, It has 3D structure. Q: what are the binding requirements? +ve charge of pyrrolidine because N is a secondary amine, Pka =9.8 at our PH it s ionized all the time. ## Organophosphate : - Sarin : Agents developed during World War 2,Nerve gas األعصاب السام,غاز It has simple structure but it s very toxic ((Sarin, is an organophosphorus compound with the formula *(CH₃)₂CHO+CH₃PF. It is a colorless, odorless liquid, used as a chemical weapon owing to its extreme potency as a nerve agent)) 9

10 Q: What is the mechanism of action of Sarine? It is irreversible inhibitor of cholinesterase. We said that I expanded my hand, I make contraction, What make me able to do contraction? acetylcholine. What make me able to do relaxation another time? Cholinesterase. If I inhibit cholinesterase; contraction remains: at the end my hand will be paralyzed. When Nerve gas is spread between people, it will give these manifestation : Muscle spasm then paralysis then difficulty in breathing due to permanent inhibition of cholinesterase. Why it s permanent or irreversible inhibition of cholinesterase? we know that cholinesterase contain serine, it will make Nu attack on carbonyl of acetylcholine, but when the sarin enter to cholinesterase it will make Nu attack with phosphate not carbonyl, so it will produce phosphorylated enzyme. * Very stable nothing can dissociated it. * Irreversible phosphorylation, so it will deteriorate the enzyme. * P-O bond is very stable ## Ecothiopate : something similar to sarin and acetylcholine but we use it as drug. spacer 10

11 It s very similar to acetylcholine from head and spacer., Thiol is a Bioasoster to O, N, C. Phosphate is a Bioasoster to ester. So it is a Bioasoester compound to acetylcholine. It is a cholinesterase inhibitor. Q:why it s not toxic like sarin and doesn t cause death? In sarin it will enter to enzyme and make phosphate bond but in this drug it will enter to active site, the active site contain cysteine so it will make disulfide bond with the active site, and the sarine is still available for Nu attack but the active site becomes smaller because it contains a blocker : acetylcholine will enter to the cholinesterase but slowly, because the active site becomes occupied #Note : cysteine contain thiol group. Therapeutically : used to treat glaucoma. Not used orally. Done By : Ala a Jaghbeer 11