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

Cholinergic Agonists

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.

Cholinoceptors Muscarinc Receptors 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

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

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.

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

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

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 -----------------

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)

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.

The Eye The Eye

Adverse Effects of Cholinomimetics