DIRECT CHOLINERGIC DRUGS Prof Hanan Hagar Prof Alhaider

DIRECT CHOLINERGIC DRUGS Prof. Hanan Hagar Prof. Alhaider Pharmacology Department

By the end of this lecture the student should know • Classification of nervous system. • Describe the various steps in cholinergic transmission. • Mention the different types, locations and actions of cholinergic receptors. • Describe the effects of acetylcholine on major organs • Classify cholinomimetic drugs. • Describe the kinetics, actions and uses of direct and indirectacting cholinomimetic drugs.

Nervous system Peripheral nervous system Central nervous system Efferent Division Autonomic nervous system Somatic system Enteric nervous system Parasympathetic nervous system Sympathetic nervous system

What are the differences between the somatic and the autonomic nervous system? Somatic N. S Control skeletal muscles Voluntary Somatic nerve is one fiber Autonomic N. S Control internal viscera Involuntary autonomic nerve is two fibers (Preganglionic & Postganglionic)

Post-ganglionic fiber ganglia Pre-ganglionic fiber One fiber

Division of Autonomic Nervous System • • • Sympathetic nervous system. Parasympathetic nervous system. Enteric nervous system.

Parasympathetic Nervous System (craniosacral outflow)

Neurotransmitter in parasympathetic or cholinergic system is acetylcholine and nerves are cholinergic

Cholinergic transmission

Cholinergic transmission • • • Synthesis Storage Release Binding to receptors Fate by acetylcholinesterase to give choline and acetate • Recycling of choline

Cholinergic transmission

Cholinergic or parasympathetic receptors n n Nicotinic (N, central cholinergic ) receptors. Muscarinic (M, peripheral cholinergic) receptors. Central nicotinic receptor Peripheral muscarinic receptor

Nicotinic receptors Type I receptors : ion channel linked receptors 1. Autonomic ganglia (Nn). 2. Adrenal medulla (Nn). 3. CNS (Nn) 3. Neuromuscular junction (Nm)

Muscarinic receptors Type II receptors : G-protein linked receptors • Five subclasses ; M 1 - M 5 • M 1, M 3, M 5 are excitatory in function (stimulation). • M 2, M 4 are inhibitory in function (inhibition).

Muscarinic receptors Receptor M 1 (Neural) Excitatory Locations Pharmacological actions CNS excitation gastric parietal cells Gastric acid secretion M 2 (Cardiac) Inhibitory Heart M 3 Glandular Excitatory Exocrine glands Smooth muscles Vascular endothelium Cardiac inhibition • Secretion of glands • Smooth muscle contraction • Vasodilatation (via nitric oxide)

Nicotinic receptors Central cholinoceptor Muscarinic receptors Peripheral cholinoceptor Ion channel linked receptors G protein linked receptors Autonomic ganglia (sympathetic & parasympathetic) stimulation ( Nn ) On all peripheral organs that receive postganglionic parasympathetic fibers Adrenal medulla (Nn) release of catecholamines (Adrenaline & Noradrenaline) Heart (M 2) inhibition exocrine glands (M 3) contraction Skeletal muscle (Neuromuscular junction) (Nm) Contraction Almost excitatory Smooth muscles (GIT, urinary tract, bronchial muscles) (M 3) contraction Excitatory or inhibitory

What are the actions of parasympathetic nervous system?

Nicotinic actions Skeletal muscles: • Low conc. muscle contraction • High conc. persistent depolarization & paralysis. Ganglia: stimulation of sympathetic& parasympathetic ganglia. Adrenal medulla release of catecholamines (A & NA).

Muscarinic actions Organs Cholinergic actions Eye Contraction of circular muscle of iris (miosis)(M 3) Contraction of ciliary muscles for near vision (M 3) Decrease in intraocular pressure bradycardia ( heart rate ) (M 2) Heart endothelium Release of NO (EDRF) Lung Constriction of bronchial smooth muscles Increase bronchial secretion M 3 GIT Increased motility (peristalsis) Increased secretion Relaxation of sphincter M 3 Urinary bladder Contraction of muscles Relaxation of sphincter M 3 Exocrine glands Increase of sweat, saliva, lacrimal, bronchial, intestinal secretions M 3

Cholinomimetics Parasympathomimetics Drugs that produce actions similar to stimulation of parasympathetic system (similar to Ach).

Types of cholinomimetics Direct cholinomimetics Act by direct stimulation of cholinergic receptors. Indirect cholinomimetics (anticholinesterases) They act indirectly by inhibiting acetylcholinesterase thus prevent the degradation of Ach and potentiate its action at cholinergic receptors.

Direct Cholinomimetics Direct cholinomimetics • Acetylcholine (M, N) • Carbachol (M, N) • Bethanechol (M) • Pilocarpine (M)

Acetylcholine (Ach) Muscarinic and nicotinic agonist Not used clinically because Ach – Is not selective (N, M) – Has short duration of action. Why? – Degradation by acetycholinesterase

Pilocarpine Natural alkaloids Tertiary amine lipophilic Pharmacokinetics • It is well absorbed • Good distribution • Can cross BBB (has central effects). • Long duration of action • Direct muscarinic agonist (mainly on eye & secretion).

Pilocarpine Adverse effects: • Profuse sweating • Salivation • CNS effects Uses: • Xerostomia (dry mouth). • Drug of choice in emergency glaucoma ( open-angle & closed-angle) applied as eye drops.

Synthetic choline esters Bethanechol, Carbachol q Quaternary ammonium compounds (polar) q Poor distribution q can not cross BBB (No CNS effects) q Not metabolized by cholinesterase. q Have longer duration of action than Ach. q. Never given I. V. or I. M BUT S. C.

Carbachol 1. Orally-SC 2. Not metabolized by cholinesterases. 3. Longer duration of action than Ach 4. Muscarinic actions on Eye, GIT, UT. 5. Has nicotinic actions (what are these actions? ). 6. Used for n Mainly in glaucoma n Urinary retention & paralytic ileus (rarely)

Bethanechol Ø Orally-SC Ø Prominent muscarinic actions on GIT, UT. Ø No nicotinic action Ø Not metabolized by cholinesterases. Ø Longer duration of action than Ach Ø Used for n In urinary retention (post-operative atony, neurogenic bladder, spinal cord injury) n In paralytic ileus

ACh Carbachol Bethanechol Pilocarpine Chemistry Quaternary Polar Tertiary non polar Absorption NOT better absorbed than Ach Complete Metabolism Hydrolyzed by cholinesterase NOT hydrolyzed by cholinesterase Duration Very short Longer (++) Administ. I. V. eye drops Oral, eye drops S. C. Oral S. C. oral, eye drops

ACh Carbachol Receptors Muscarinic Nicotinic Muscarinic +++ Selectivity NOT Nicotinic +++ Uses NO +++ Eye, GIT Urinary bladder +++ Bethanechol Pilocarpine Muscarinic +++ GIT, Urinary bladder NO Glaucoma Paralytic ileus Urinary retention +++ More on eye, secretion NO Glaucoma Xerostomia

Cevimeline –Direct acting muscarinic agonist –Used for treatment of dry mouth symptom associated with Sjogren's syndrome.

Contraindications of cholinomimetics 1. 2. 3. 4. 5. Bronchial asthma. Peptic ulcer. Angina pectoris Incontinence Intestinal obstruction

Thank you