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DRUGS acting on the PARASYMPATHATIC NERVOUS SYSTEM

DRUGS acting on the PARASYMPATHATIC NERVOUS SYSTEM. Dr. Naila Abrar. Parasympathetic Nervous System. Muscarinic Nicotinic Autonomic neuroeffector Ganglia & NMJ junctions Acetylcholine. GPCR. Ion Channels. CHOLINOCEPTORS. Nicotinic Ion channel. Muscarinic

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DRUGS acting on the PARASYMPATHATIC NERVOUS SYSTEM

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  1. DRUGS acting on the PARASYMPATHATIC NERVOUS SYSTEM Dr. Naila Abrar

  2. Parasympathetic Nervous System Muscarinic Nicotinic Autonomic neuroeffector Ganglia & NMJ junctions Acetylcholine GPCR Ion Channels

  3. CHOLINOCEPTORS Nicotinic Ion channel Muscarinic GPCR

  4. PARASYMPATHOMIMETIC DRUGSor CHOLINERGIC DRUGSor CHOLINOMIMETIC DRUGS

  5. CLASSICIFICATION • Directly Acting • Indirectly Acting

  6. A. Directly Acting Cholinergic Drugs • CHOLINE ESTERS • CHOLINOMIMETIC ALKALOIDS

  7. CHOLINE ESTERS - Acetylcholine - Methacholine - Carbachol - Bethanechol

  8. II.CHOLINOMIMETIC ALKALOIDS a. Mainly MuscarinicAgonists • Natural Alkaloids: - Muscarine - Pilocarpine - Arecholine • Synthetic Alkaloid: - Oxotremorine • Mainly Nicotinic Agonists • Natural Alkaloids: - Nicotine - Lobeline • Synthetic Alkaloids: - Dimethylphenyl-piperazinium(DMPP)

  9. B. Indirectly Acting Cholinergic Drugs(Anticholinesterases) I- REVERSIBLE II- IRREVERSIBLE Organophosphates Therapeutically useful -ecothiopate War gases -sarin, tuban, soman Insecticides -parathion, malathion, DFP, TEPP, OMPA • Carbamates • Tertiary amines-physostigmine • Quaternary ammonium compounds- neostigmine, pyridostigmine, tacrine, ambenonium, demecarium • Alcohols- edrophonium • Miscellaneous- tacrine, galantamine, rivastigmine, donepezil

  10. PHARMACOKINETICS • Esters-Quaternary ammonium gp • Choline esters are poorly absorbed and poorly distributed into CNS • Methacholine is resistant to hydrolysis by cholinesterase • Carbamic acid esters carbachol and bethanechol- most resistant-longer duration of action

  11. Pharmacokinetic (contd.) • Pilocarpine, nicotine, lobeline-tertiary natural compounds- well absorbed • Muscarine, quaternary amine is toxic when ingested present in certain mushrooms • Excretion chiefly through kidneys

  12. MECHANISM OF ACTION of directly acting cholinomimetics • Activation of muscarinic receptors on effector cells directly to alter organ function • Interaction with muscarinic receptors on nerve terminals to inhibit release of their neurotransmitter

  13. MECHANISM OF ACTION of directly acting cholinomimetics Muscarinic- GPCR • Inhibitory effects (M2 & M4) • Inhibition of adenylyl cyclase- decrease of cAMP (GPCR-Gi/Go) • Excitatory effects (M1,M3,M5) • Increase activity of IP3 & DAG (GPCR-Gq/11)

  14. MECHANISM OF ACTION of directly acting cholinomimetics Nicotinic – pentameric ion channel • Na+ & K+ move down conc. gradient • Depolarization • Skeletal muscle-Action potential propagation-contraction • Prolonged agonist occupancy-depolarizing blockade

  15. ACETYLCHOLINE CHEMISTRY An ester of acetic acid and choline

  16. SYNTHESIS, STORAGE, RELEASE & INACTIVATION

  17. Pharmacological actions/ Organ system effects: • Muscarinic Actions • Nicotinic Actions

  18. EYE: • M3 • Miosis (constriction of pupil)- contraction of papillary sphincter ms. • Spasm of accommodation (contraction of ciliary muscle)- eye fixed for near vision • Decrease in intraocular pressure • Conjunctival hyperemia • Lacrimation

  19. CVS (Heart & Blood Vessels) • Negative chronotropic effect-bradycardia M2 -Decreases rate of spontaneous depolarization • Negative dromotropic effect- decrease in conduction velocity in AV node-(inhibiting Ca channels) • Negative inotropic effect- decreased cardiac output (hyperpolarization, decrease cAMP & epinephrine release) • Vasodilation- fall in blood pressure- NO

  20. RESPIRATORY SYSTEM • M3 • Bronchial muscle contraction • Bronchial gland stimulation- increase tracheobronchial secretions

  21. GIT • M3 • Increase motility • Relaxation of sphincters • Increase tone of LES

  22. URINARY BLADDER • M3 • Detrusor muscle contraction • Relaxation of sphincters • Promote micturition

  23. Exocrine glands- M3 - Increase in salivation, sweat, lacrimation • Central Nervous System - M1 - Cortical arousal, or activation • Peripheral nervous system - Stimulation of ganglia both the systems are activated

  24. Neuromuscular junction - Na+ and K+ entry into cell- depolarization - Skeletal muscle contraction

  25. THERAPEUTIC USES • Glaucoma (pilocarpine) • Accommodative estropia • Induction of miosis (Ach, carbachol) • Postoperative ileus (bethanechol) • Congenital megacolon (bethanechol) • Atony of urinary bladder – post op, diabetic autonomic neuropathy (bethanechol)

  26. THERAPEUTIC USES (contd.) • Dry mouth with Sjogren’s syndrome (pilocarpine, cevimeline) • Diagnosis of bronchial airway hyperreactivity (methacholine)

  27. ADVERSE EFFECTS • Signs of muscarinic excess. • Salivation, sweating • Difficulty in visual accommodation • NVD, abd. cramps • Urinary urgency • Cutaneous vasodilatation • Bronchoconstriction • Hypotension

  28. CONTRAINDICATIONS • Bronchial asthma • GI or urinary tract obstruction • Peptic ulcer • Recent myocardial infarction • Coronary insufficiency • Hyperthyroidism

  29. MUSHROOM POISONING • Signs of muscarinic excess-salivation, sweating, NVD, visual disturbances, headache, abd. Colic,urinary urgency, bradycardia, bronchospasm, hypotension, shock • Atropine (1-2mg I/M every 30mins)

  30. ACUTE NICOTINE TOXICITY • CNS stimulation, cause convulsions, coma and respiratory arrest. • Skeletal muscle depolarization and respiratory paralysis. • Hypertension and cardiac arrhythmia.

  31. CHRONIC TOBACCO USE • Increased risk of vascular disease. • Sudden coronary death. • Aggravation of peptic ulcer in smokers.

  32. Other Choline Esters Methacholine Carbachol Bethanechol

  33. METHACHOLINE • Both muscarinic and nicotinic actions. • Muscarinic actions are more prominent on CVS than on GIT and urinary bladder. • Duration of action 30 min. • Paroxymal atrial tachycardia.

  34. CARBACHOL • Not destroyed by cholinesterase. • Longer duration of action and potent than methacholine. Therapeutic uses • Post operative abdominal distention, paralytic ileus, urinary retention and glaucoma.

  35. BETHANECHOL • Weak but prolonged effect Therapeutic uses • Difficulty in micturition, gastric distention following surgery.

  36. PILOCARPINE • Pilocarpus microphyllus (jaborandi) • Tertiary amine-enters CNS • More muscarinic effects Therapeutic uses • Glaucoma (other options available) • Reverse effects of mydriatics • Xerostomia • Break adhesions

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