SYMPATHETIC Increase BP & HR, glucose Perfusion to skeletal muscles Mydriasis, bronchodilatation

2. SYMPATHETIC • Increase BP & HR, glucose • Perfusion to skeletal muscles • Mydriasis, bronchodilatation • PARASYMPATHETIC • Miosis, decreased HR, BP, bronchia secretion, • Insulin release, Digestion, excretion

3. Cholinergic Agonists

4. Sites of Cholinergic Transmission ACh is major neurohumoral transmitter at autonomic, somatic and central nervous system: • All preganglionic sites (Both Parasympathetic and sympathetic) • All Postganglionic Parasympathetic sites and sympathetic to sweat gland and some blood vessels • Skeletal Muscles • CNS: Cortex, Basal ganglia, spinal chord and others • Parasympathetic Stimulation –(Ach) synthhesis, storage, release, binding of Ach to Rs, degradation and recycling.

7. Cholinoceptors • Two families of cholinoceptors: M and N receptors, can be distinguished on the basis of their different affinities • Muscarinc Receptors • G protein–coupled receptors (metabotropic receptors) • recognize muscarine, an alkaloid /in certain poisonous mushrooms • weak affinity for nicotine • M1, M2, and M3 receptors have been functionally characterized. • ganglia of the peripheral nervous system and on the autonomic effector organs, such as the heart, smooth muscle, brain, and exocrine glands

8. There are five subclasses of muscarinic receptors: M1, M2, M3, M4, and M5. • Only M1, M2 and M3, receptors have been functionally characterized. • M1 receptors /on gastric parietal cells • M2 receptors on cardiac cells and smooth muscle • M3 receptors on the bladder, exocrine glands, and smooth muscle

12. Nicotinic Receptors • Nicotinic receptors are located in the CNS, adrenal medulla, autonomic ganglia, and the NMJ. • Those at the neuromuscular junction are sometimes designated NM and the others NN. • Nicotinic receptors of autonomic ganglia differ from those of the NMJ. E.g. ganglionic receptors selectively blocked by Hexamethonium, whereas NMJ Rs specifically blocked by Tubocurarine.

13. Signal transduction (cont.) • N Rs / composed of five subunits (a ligand-gated ion channel) • Binding of two Ach molecules elicits a conformational change that allows the entry of sodium ions, resulting in the depolarization of the effector cell. Schematic illustration of ACh receptors

15. Direct-Acting Cholinomimetics • Direct-Acting Cholinergic Agonists (N & M) • Cholinergic agonists (parasympathomimetics) mimic the effects of ACh on cholinoceptors. • These agents broadly classified into: • Endogenous choline esters, Ach • Synthetic esters of choline, carbachol and bethanechol. • Naturally occurring alkaloids, nicotine, pilocarpine • All of the direct-acting cholinergic drugs have longer durations of action than acetylcholine • As a group, the direct-acting agonists show little specificity in their actions, which limits their clinical usefulness

16. Acetylcholine (Ach) • Quaternary ammonium compound -------- • Site of action -------- • Both muscarinic and nicotinic activity • Therapeutic uses ----- • HR & CO (vagal stimulation). • Effect of IV Ach on: • Heart: ------------ due to -----------------

17. II. Blood Pressure Injection of Ach vasodilation and lowering BP ( indirect mechanism of action) activates M3 receptors on endothelial cells lining SM of BVs production of nitric oxide from arginine NO diffuses to vascular SM stimulates PK G production hyperpolarization (SM relaxation through PDE-3 inhibition)

18. III. Other Actions of ACh • GIT: increases salivary secretion & intestinal secretions and motility. • Bronchiolar secretions are also enhanced. • Genitourinary tract: the tone of the detrusor urinae muscle is increased, causing expulsion of urine. • Eye: stimulating ciliary muscle contraction for near vision • Constriction of the pupillae sphincter muscle, causing miosis • ACh (1% solution) is instilled into the anterior chamber of the eye to produce miosis during ophthalmic surgery.

19. The Eye The Eye

20. Adverse Effects of Cholinomimetics