Drugs Acting on A. N. S

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Cholinergic & Anti-cholinergic Drugs

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Slide 1:

Drugs Acting on a. n. s Cholinergic & Anticholinergic Drugs Prepared By Prof. Pratik Maske. Dept. of Pharmaceutical Chemistry, Tatyasaheb Kore College of Pharmacy, Warananagar.

Slide 2:

Content- Introduction. Biosynthesis Metabolism Cholinergic Receptor Cholinergic Drugs. Anticholinergic Drugs .

Slide 3:

Introduction- The activities of involuntary organs like - Heart, Blood Vessels, Smooth muscles controlled by Autonomous Nervous System. Its divided into 2 category Sympathetic Nervous System. Parasympathetic Nervous System.

Slide 5:

Cholinergic Drug- Acetylcholine is neurotransmitter then nerve is cholinergic nerves. Drug or chemicals that causes the parasympathetic division to react are termed as parasympathomimetic or cholinergic drug. Cholinergic nerves are- Pre & post ganglionic fibers of parasympathetic nervous syst. Preganglionic fibres of sympathetic nervous system. Post ganglionic fibres of sympathetic nerves supplied to sweat & salivary glands. Cholinergic receptor characterised by 1) Nicotinic Receptor. 2) Muscarinic Receptor.

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Nicotinic Receptor- - Responsible for muscle contraction at neuromuscular junction. - Neuromuscular nicotinic Ach receptor target for autoimmune antibodies in Myasthenia Gravis. - Muscle relaxant during surgery. - Nicotinic receptor are divided into 2 types. 1) N 1 receptor. 2) N 2 receptor. N 1 receptor- At neuromuscular junction blocked by Succinylcholin,d-tubocurene & Stimulated by phenyltrimethylammonium. N 2 receptor- Found at autonomic ganglia, blocked by hexamethonium & Stimulated by tetramethylammonium .

Biosynthesis of acetylcholine:

Biosynthesis of acetylcholine

Metabolism of Acetylcholine :

Metabolism of Acetylcholine

Hypothetical model of synthesis, storage & release of acH:

Hypothetical model of synthesis, storage & release of acH

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Muscarinic Receptor- Play important role in maintain homeostasis of organism. Location. Inhibit contraction of heart & relaxes smooth muscles of blood vessels. They are classified into 4 types, 1) M 1 Receptor. 2) M 2 Receptor. 3) M 3 Receptor. 4) M 4 Receptor.

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M 1 Receptor- (Also called as Neural) Located in exocrine gland & autonomic ganglia. In humans these receptor affect rapid eye movement, sleep, emotional responses. Also participated in higher brain function like memory & learning. Also they are located in parietal cell of G.I tract. M 2 Receptor- They are also called as Cardiac muscarinic receptor.(located on atria & conducting tissue of heart) Stimulation causes decrease strength & rate of cardiac muscle contraction. Their effect may be produced by affecting intracellular Potassium & calcium levels in heart. Activation causes Hyperpolarization of cardiac cell causes bradycardia .

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M 3 Receptor- Referred as glandular muscarinic receptor in exocrine gland & smooth muscles. Glandular secretion from lacrimal , salivary, pancreatic & mucosal cell in G.I tract are characteristic of M 3 receptor. Contraction of visceral smooth muscles is also result of M 3 receptor stimulation. - These stimulant effect mediate through G protein activation of phospholipase C (PLC) to form IP 3 & DAG. M 4 Receptor- Act through G1 protein to inhibit adenylate cyclase . - Direct regulatory action on potassium & Calcium ion channel

Receptor with its binding sites:

Receptor with its binding sites

Sar of PARASympathomimetics:

Sar of PARASympathomimetics Modification of Quaternary ammonium group- + Replaced by Arsenic, P, S, Se etc. these analogs comp. are less active & not used clinically Compounds possessing positive charge on the atom in position of nitrogen had appreciable muscarinic activity All 3 methyl groups on the Nitrogen are replaced by larger alkyl group are inactive agonist When methyl gr replaced by 3 ethyl gr , resulting cholinergic antagonist activity Replacement of 1-CH 3 by ethyl/ propyl affords comp. active. Successive replacement of 1/2/3 of -CH 3 with H atoms afford tertiary, secondary, primary amines leads to diminishing activity

Sar of PARASympathomimetics:

Sar of PARASympathomimetics Modification of Ethylene bridge- β α β α As the chain length increases activity was rapidly decreases ( postulate Rule of Five, there should be no more than 5 atoms between N & terminal H atom for maximal activity Muscarinic ACh Receptor ( mAChR ) cant successfully accommodate molecule larger than Ach, they bind but lack of efficacy Replacement of H atom of ethylene bridge by alkyl gr larger than –CH 3 comp. are less active than ACh Introduction of –CH 3 on β carbon atom gives acetyl β - methylcholine has activity same as Ach. Introduction of –CH 3 on α carbon atom gives acetyl α – methylcholine ; activity related to Ach is reduced at both m same as mAChR & nAChR .

Sar of PARASympathomimetics:

Sar of PARASympathomimetics Modification of Ethylene bridge - β α Addition of –CH 3 group to either 1/both ethylene carbon results chiral molecule S(+) methacholine is equipotent with Ach, whereas R(-) isomer is 20 times less potent.

Sar of Sympathomimetics:

Sar of Sympathomimetics Modification of Acyloxy group Removal of Oxygen from carbonyl gr to CH 2 leads to muscarinic activity But reduction to CH 2 -O-CH 2 increases lipophilicity; causes CNS toxicity Acetyl group is replaced with higher homologs ( propionyl or butyryl ) loss its action Replacement of O by S Decrases activity

Mechanism of action :

Mechanism of action A- Ach activates G protein in the phosholipase system to activate the membrane enzyme phospholipase C (PLC), enhancing muscle contraction. A B B- Inhibition of adenylate cyclase system through an inhibitory G protein to cause muscle relaxation.

Classification of parasympathomimetic:

Classification of parasympathomimetic Direct acting agents: e.g. Acetylcholine, Carbachol , Methacholine . Indirect acting/Cholinesterase inhibitor: Reversible Cholinesterase: e.g. Physostigmine , Neostigmine , Pyridostigmine , Tacrine , Edrophonium . Irreversible Cholinesterase e.g. Isofluorphate , Echothiophate iodide, Parathione , Malathion . Cholinesterase reactivator : e.g. Pralidoxime chloride.

Synthesis of carbechol:

Synthesis of carbechol Uses- Its miotic & has been used to reduce intraocular tension of glucoma . Also used during ocular surgery, when prolonged miosis required

Pilocarpin:

Pilocarpin Its used as miotic for open-angle glucoma . Its also used for the treatment of xerostomia (dryness of mouth) caused by radiation therapy of the head & neck chemotherapy.

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Cholinesterase inhibitor These drugs inhibit the action of the enzyme Acetylcholinesterase & increases the lifetime of Ach Acetylcholine Choline Acetic Acid

Slide 27:

Cholinesterase inhibitor

Synthesis of neostigmine:

Synthesis of neostigmine

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Uses- Its used to diagnose myasthenia gravis. To treat paralytic ileus . For post operative urinary retention. To antagonise muscular relaxation due to curare like drug.

Reversible Cholinesterase inhibitor:

Reversible Cholinesterase inhibitor Physostigmine Uses- In treatment of glaucoma. In case of poisoning with anticholinergic drugs & tricyclic antidepressant. For treatment of psychiatric & neurological disorder. As miotic .(counteract mydriasis )

Reversible Cholinesterase inhibitor:

Tacrine Its used in the treatment of Alzheimres disease. Pyridostigmine Uses- Its used to diagnose myasthenia gravis. To treat paralytic ileus . For post operative urinary retention. Reversible Cholinesterase inhibitor

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Parathion Its used as agriculture insecticide. irReversible Cholinesterase inhibitor

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Malathion Its used as agricultural insecticide irReversible Cholinesterase inhibitor

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The organophosphate compound such as methyl parathion, malathion the organophosphate insecticides act as substrate for enzyme cholinesterase. They occupy the Ach site of the enzyme, they are slowly hydrolysed. Hence the enzyme remains inactive for longer time & hydrolysis of Ach is prevented. This leads to accumulation of Ach sending signal along cholinergic nerves. This causes excessive secretion of fluids, asthma & convulsion & may result death. To prevent this, reactivation of cholinesterase is essential. The presence of nucleophilic agents such as, Hydroxylamine (NH 2 OH), Hydroxamic acid (RCONHOH) & Oximes (RCH=NOH) reactivate the enzyme more rapidly than the hydrolysis Cholinesterase Reactivator

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Pralidoxime : 2-PAM The proposed mechanism of regeneration of AChE by 2–PAM. The binding of quaternary ammonium nitrogen to 2-PAM to anionic site of phosphorylated AChE Nucleophilic attack of the oxime oxygen results in breaking of ester bond between serine oxygen atom & phosphorus atom. Used as Antidote in of poisoning cholinesterase inhibitors. Cholinesterase Reactivator

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Classification Anticholinergic agents e.g. Atropine, Propantheline e.g. Biperidine (amino alcohol) Tropicamide (amino amide) e.g. Benzotropane

Sar of Anticholinergic agents:

Sar of Anticholinergic agents - Substituent R 1 & R 2 should be carbocyclic & heterocyclic for maximal antagonist activity Generally more potent comp. having different rings. One ring is aromatic & other is saturated. The size of ring should be limited. Napthalene ring affords compound inactive

Sar of Anticholinergic agents:

Sar of Anticholinergic agents - Substituent R 3 can be a H, -OH, hydroxymethyl / carboxamide or one of the componant of R 1 & R 2 ring, the antagonist activity more potent than the same compound without these group

Sar of Anticholinergic agents:

Sar of Anticholinergic agents - The X substituent in the most potent anticholinergic agents is an ester . But its not essential for anti-muscarinic activity it may be ether oxygen

Sar of Anticholinergic agents:

Sar of Anticholinergic agents The N substituent is quaternary ammonium salt in the most potent anticholinergic agents. But this is not requirement because tertiary amines also possess antagonist activity. The alkyl substituent's usually methyl, ethyl, propyl , isopropyl

Sar of Anticholinergic agents:

Sar of Anticholinergic agents Muscarinic antagonist must compete with agonist for a common receptor. This ability is due to larger group at R 1 & R 2 enhance binding. The area surrounding the binding site of Ach is hydrophobic in nature, on this account in potent cholinergic antagonist groups R 1 & R 2 must be hydrophobic (like phenyl, cyclohexyl , cyclopnetyl )

Therapeutic application of anticholinergic:

Therapeutic application of anticholinergic Decreases the contraction of smooth muscle of urinary & gastrointestinal tracts. Dilation of pupil. Reduces the gastric & salivary secretion. Therapeutic value in treatment of smooth muscle spasm. Treatment of gastric ulcer Used in cold & flu remedies to reduce nasal & upper respiratory tract secretions Centrally acting Belladona alkaloids such as Scoplamine used in transdermal delivery to prevent motion sickness. Several synthetic agents used to treat parkinsonism. Certain agents used for organophosphorous poison.

atropine:

atropine Uses- It is used to treat parkinsonism to reduce muscular rigidity & salivation. In small doses, it is C.N.S. stimulant. As a mydriatic in ophthalmologic. As an antispasmodic For anaesthetic premedication. As an adjust to treat gastric & duodenal depression.

ipratropium:

ipratropium Its used to treat bronchospasm associated with asthama

hyoscymine:

hyoscymine It’s used in the treatment of acute mania & delirium & for calming excitement. It’s used for prevention & treatment of motion sickness. The butyl bromide salt used for gastrointestinal spasm. Its used in the conjunction with morphine to produce amnesia & partial analgesia, a condition known as “twilight sleep”. To the lasser extent it is used treat parkinsonism .

Scoplamine:

Scoplamine Uses- It’s used for prevention & treatment of motion sickness. It’s used for organophosphorous poison.

Amino alcohol esters:

Amino alcohol esters Dicyclomine - Binds with M 1 & M 3 receptor Its used for its spasmolytic effect on various effect on smooth muscle. Its useful in dysmenorrhea , pyroplasm & biliary disfunction .

Amino alcohol esters:

Clidinium Its used along with major tranquilizer chlordiazepoxide in treatment of anxiety with GI menifestations . Its is suggested for peptic ulcer, hyperchlorhydria , ulcerative colitis. Amino alcohol esters

Amino alcohol esters:

Cyclopentolate It can be used as mydriatic in management of Iritis , Keratitis . Its is used as antispasmodic agent. Amino alcohol esters

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Amino alcohol Procyclidine Uses Clinically its used to relieve muscle spasm. Its is used in treatment of Parkinsonism disease. Its is used to reduce muscle rigidity in arteriosclerotic & iodopathic disease.

Amino alcohol:

Biperidine Its used to treat all types of Parkinson's diseases. Its used as an adjust to treat gastric & duodenal depression. Its used To treat sialorrhoea , acute, coryza , rhinitis, hay fever etc. due to its antisecretory activity. Its used To treat poisoning by organophosphorus compounds. Amino alcohol

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Benzotropine It has anticholinergic , antihistaminics & local anaesthetic agent. Its antiparkinsonian agent. Amino alcohol ethers

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Orphenadrine It reduces voluntary muscle spasm. Its antiparkinsonian agent. Amino alcohol ethers

Amino amide:

Amino amide Tropicamide Its used as mydriasis

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