Adrenergic & cholinergic agents

Introduction
parasympathetic nervous system
cholinergic drugs
Anticholinergic agents
Divisions of Autonomous nervous system
Drugs acting on adrenergic nervous system
Adrenergic agents

1. ADVANCED MEDICINAL CHEMISTRY -Mr . Akshay Ramchandra Yadav ( M.pharm 1 st year) Pharmaceutical chemistry Dept. Rajarambapu College of P harmacy , Kasegaon ADRENERGIC & CHOLINERGIC AGENTS 1

2. The autonomic nervous system is a control system that acts largely unconsciously and regulates body functions such as the heart rate, digestion, respiratory rate, pupillary response, urination. The ANS is part of the peripheral nervous system and it also controls some of the muscles within the body. We are often unaware of the ANS because it functions involuntary and reflexively . For example , we do not notice when blood vessels change size or when our heart beats faster. AUTONOMIC NERVOUS SYSTEM 2

3. Divisions OF Autonomous Nervous System : 1.SYMPATHETIC NERVOUS SYSTEM :   The sympathetic nervous system primary process is to stimulate the body's fight-or-flight response . For   example - the  sympathetic nervous system can accelerate heart rate, widen bronchial passages, decrease motility of the large intestine, constrict blood vessels, increase peristalsis in the esophagus , cause pupillary dilation. 2. PARASYMPATHETIC NERVOUS SYSTEM: The  parasympathetic nervous system is one of three divisions of the autonomic nervous system. Sometimes called the rest and digest system , the parasympathetic system conserves energy as it slows the heart rate, increases intestinal and gland activity . 3

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5. PARASYMPATHETIC NERVOUS SYSTEM Acetyl choline (Ach) is neurotransmitter which porpagates impulse transmission in parasympathetic division. Ach also function as a neurotransmitters. Ach causes contraction of smooth muscles, cardiac inhibition in man or laboratory animals. Parasympathetic nerve fibers liberates acetylcholine hence this system is also called cholinergic nervous system. Ach is biosynthesized by acetylation of choline molecule in nerve terminals. The free acetylation present in blood and other tissues, get quickly hydrolysed by cholinesterase enzyme into acetic acid and choline as shown below:- 5

6. ACTION OF ACETYLCHOLINE- 6

7. CHOLINERGIC DRUGS- ( Cholinomimetic or parasympathomimetic ) 7

8. 1.CHOLINERGIC AGONIST- a. Choline esters Acetylcholine SAR- Any change in the ethylene bridge may affect the chemical stability of Ach molecule. A quaternery ammonium group is essential for manifestation of both muscarinic and nicotinic receptors. If one or more methyl group is present on nitrogen atom are replaced by hydrogen or ethyl group then both the activities i.e muscarinic and nicotinic activity is reduced. Quaternary nitrogen atom may be replaced by Arsenic, antimony , phosphorous or sulphur atom without the loss of Ach like activities . 8

9. Bethanicol - Mode of action- It has more selective muscarinic action on GIT and urinary bladder. It increases tone of contraction of intestine It causes emptying of urinary bladder due to contraction of muscle of bladder and relaxation of sphincter muscle. Use- It is used to get relief from abdominal distension (stress) after surgery. 9

10. 2 . ANTICHOLINETERASE These enzymes causes inhibition of cholinesterase enzyme which is responsible for hydrolysis of acetylcholine into acetic acid and choline. a . Reversible anticholinesterase - They having structural similarities with Ach hence they are combined with anionic and esteric sites. -They having a great affinity towards active sites but no intrensic activity. example- i . Physostigmine SAR- 1.The distance between other oxygen & nitrogen appproximately same as that of distance between other oxygen and nitrogen present in Ach. 2.Two heterocyclic rings are not essential for anticholinesterase activity during hydrolysis the phenolic fragment of these drug is eliminated , leaving the carbonyl group attach to the enzyme. Use - To treat glaucoma 10

11. ii.Neostigmine SAR- 1.In neostigmine stability is increased due to hydrolysis by using dimethyl carbamte in place of methyl carbamate group. 2.Because of charged nitrogen neostigmine cannot crosses blood brain barrier and do not causes CNS related side effects. Use- 1.It is used in treatment of mysthenia gravis . 2.It is used as an antidote to non-depolarizing neuromuscular blocking drugs. 11

12. b . Irreversible Anti cholinesterase Irreversible anticholinesterase causes inhibition of anticholinesterase irreversibly. e.g - methyl parathion MOA- I . Parathion is a organophosphorous compound. ii. It inhibits cholinesterase enzyme . Use- It is used to treat glaucoma. It is used to treat mysthenia gravis. 12

13. ANTICHOLINERGIC DRUGS (MUSCARINIC RECEPTOR ANTAGONIST OR PARASYMPATHOLYATIC AGENTS) Dicyclomine MOA- These class of drugs that block neurotransmitter Ach in PNS. 13

14. moa OF ANTICHOLINERGIC DRUGS- 14

15. Cationic group- i. N-atom must be tertiary amine which undergo quaternisation at physiological Ph. ii.Highly alkyl group on nitrogen causes stearic hinderance . iii.Quaternisation increases anticholinergic action and decreases cholinergic action. 2.Hydroxyl group- i.It is important for affinity and in presence of –OH more active compound. e.g amino alcohol ester. ii.In amino alcohol ester ,hydroxyl group contain carboxylic acid which having maximum activity. e. Atropine. SAR OF ANTICHOLINERGIC DRUGS- 15

16. 3.Cyclic substituents- i . At least one cyclic substituents is a common feature in anticholinergics . ii. Introduction of large cyclic group decreases activity. Adverse effects- Tachycardia. Blurred vision. Dry mouth and skin. Use- It is used to treat parkinsonism disease. Atropine is specific antidote for mushroom poisioning . 16

17. DRUGS ACTING ON ADRENERGIC NERVOUS SYSTEM These are the drugs which produces action similar to that of action produced by adrenaline or causes sympathetic stimulants. Adrenaline and nor- adrenaline are the two transmitters- Relaxation of smooth muscles. Increases in heart activity/ tachycardia. Decreases the gland secreation . 17

18. CLASSIFICATION OF ADRENERGIC DRUGS OR SYMPATHOMIMETIC DRUGS- 18

19. DIRECTLY ACTING DRUGS Non-selective beta 1 & Beta 2 blockers . example- propranolol Propranolol belongs to the group of beta blocking agents known as acyclopropanolol amine (-OCH2) Group has been incorporated into molecule between aromatic ring and ehtylamine side chain. MOA- It blocks the action of epinephrine and nor-epinephrine on both beta 1 and beta 2 adrenergic receptor. 19

20. SAR- Nature of aromatic ring and its substituents are primary determinants of beta antagonist activity. Propranolol has high lipid solubility which allows it to penetrate nerve tissue and shows cardiodepressant effect in addition to its beta blocking activity, to avoid this problem use of polar group like methane sulphonamide . Alkyl on ortho group position on phenyl ring provides good activity. e.g - 20

21. 2 . MIXED ACTING DRUGS- SAR- Substitution of amine group R3 i.e CH3 Increased selectivity. Substitution if alpha carbon blocks metabolism by MAO. OH at beta carbon enhances adrenoreceptor properties. 21

22. They block the release action of   catecholamines  (epinephrine , norepinephrine , dopamine), which are released in response to stress. Centrally acting antiadrenergic agents make the heart beat slower and with less force, and relax the blood vessels. SYMPATHOLYTIC OR ANTIADRENERGIC AGENTS 22

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24. A. ADRENERGIC RECEPTOR ANTAGONIST- Prazosin : (i) Prazosin is a selective blocker of postsynaptic α 1   receptors, producing vasodilation of both arteries and veins. (ii) Prazosin reduces peripheral vascular resistance and lowers arterial blood pressure. SAR- Amine group present in structure is essential for the activity. If five membered ring in structure is removed then activity decreases . 24

25. 2.DRUGS INHIBITING NE SYNTHESIS- SAR- a. Methyl group is replaced with other group than activity decreases. b . Hydroxy group attached with ring structure shows activity. 25

26. 3.DRUGS INHIBITING NE STORAGE- e.g - Reserpine SAR- If methoxy group is removed then sympatholytic activity decreases. Nitrogen atom present in structure is essential for activity. Amine group present in structure shows antiadrenergic activity. MOA- Stimulate NE secreation and inhibit sympathetic activity and reduces BP. 26

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