DIRECT CHOLINERGIC DRUGS Profs. Abdalqader Alhaider & Hanan Hagar Pharmacology Unit

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 indirect-acting cholinomimetic drugs.

Nervous system Central nervous system Peripheral nervous system Afferent Division (Sensory) Efferent Division (Motor) Autonomic nervous system Somatic system (skeletal muscles) Enteric nervous system Parasympathetic nervous system Sympathetic nervous system

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

Autonomic nerve Somatic nerve Post-ganglionic fiber ganglia Pre-ganglionic fiber Somatic nerve One fiber

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

Parasympathetic Nervous System Is a craniosacral outflow

Neurotransmitters Neurotransmitter in parasympathetic nervous system or cholinergic system is acetylcholine and nerves are called cholinergic nerves

Cholinergic transmission The release of neurotransmitter Ach from cholinergic nerves include the following steps: Synthesis of Ach Storage of Ach in storage vesicles Release of Ach Binding of Ach to postsynaptic receptors to give actions

Cholinergic transmission 5) Metabolism by acetyl cholinesterase in synaptic cleft to give choline and acetate. acetyl cholinesterase Acetylcholine acetate + choline 6) Recycling of choline

Cholinergic transmission

Cholinergic transmission

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

Nicotinic receptors Type I receptors : ion channel linked receptors Located in: Skeletal muscles (neuromuscular junction, Nm ) Autonomic ganglia (sympathetic and parasympathetic ganglia, Nn). Adrenal medulla (Nn). CNS (Nn). Nicotinic receptors

Muscarinic receptors Five subclasses ; M1, M2, M3, M4 and M5 Type II receptors : G-protein linked receptors Five subclasses ; M1, M2, M3, M4 and M5 M1, M3, M5 are excitatory or stimulatory in function (stimulation) M2, M4 are inhibitory in function (inhibition). Located at all target organs that are innervated by parasympathetic fibers (e.g, heart, CVS, eye, bladder, etc).

Muscarinic receptors Pharmacological actions Locations Receptor CNS excitation Gastric acid secretion CNS gastric parietal cells M1 Excitatory Cardiac inhibition (Bradycardia) Heart M2 Inhibitory Secretion of glands Smooth muscle contraction Vasodilatation (via nitric oxide) Exocrine glands Smooth muscles (GIT, urinary tract, bronchial muscles) Vascular endothelium M3 Excitatory memory, arousal, attention and analgesia M4 & M5

Cholinergic or parasympathetic receptors Muscarinic receptors Peripheral cholinoceptors Nicotinic receptors Central cholinoceptors Excitatory or inhibitory Almost excitatory On all peripheral organs innervated by postganglionic parasympathetic fibers Autonomic ganglia Nn sympathetic & parasympathetic stimulation Heart (bradycardia, M2) exocrine glands (secretion, M3) Adrenal medulla Nn release of catecholamines (adrenaline & noradrenaline) Smooth muscles (contraction, M3) (GIT, urinary tract, bronchial muscles, uterus) Skeletal muscles Nm contraction

Pharmacological actions of parasympathetic N.S. Actions that are due to effects of Ach on nicotinic receptors and muscarinic receptors thus divided in two actions 1) Nicotinic actions 2) Muscarinic Actions

Nicotinic actions of Ach Skeletal muscles: Low conc. of Ach  muscle contraction High conc. of Ach persistent depolarization & relaxation. Stimulation of Autonomic ganglia Stimulation of adrenal medulla: release of catecholamines (Adrenaline & Noradrenaline). Nicotinic actions of Ach

Muscarinic actions of Ach Cholinergic actions Organs Contraction of circular muscle of iris (miosis)(M3) Contraction of ciliary muscles for near vision (M3) Decrease in intraocular pressure (IOP) Eye bradycardia ( decrease in heart rate ) (M2) Release of NO (EDRF) Heart endothelium Constriction of bronchial smooth muscles Increase in bronchial secretion M3 Lung Increase in motility (peristalsis) Increase in secretion Relaxation of sphincter -defecation M3 GIT Contraction of muscles Relaxation of sphincter M3 Urination Urinary bladder Increase of secretions of exocrine glands sweat, saliva, lacrimal, bronchial, intestinal secretions M3 Exocrine glands

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

Types of cholinomimetics Direct cholinomimetics cause direct stimulation of cholinergic receptors. Indirect cholinomimetics (anticholinesterases) acts indirectly by inhibiting acetyl cholinesterase thus prevent the hydrolysis of Ach.

Direct Cholinomimetics Naturally occurring alkaloids e.g. Pilocarpine Synthetic choline esters Acetylcholine (M,N) Carbachol (M,N) Bethanechol (M) Cevimeline (M) Direct Cholinomimetics

Acetylcholine (Ach) Muscarinic and nicotinic agonist Not used clinically because Ach Is not selective as it acts on both nicotinic and muscarinic receptors Has short duration of action. Why? Due to rapid metabolism by acetycholinesterase

Synthetic choline esters include drugs as bethanechol, carbachol Quaternary ammonium compounds contain N+ (polar) Poor distribution can not cross BBB (No CNS effects) Not metabolized by cholinesterase. Have longer duration of action than Ach. Never given I.V. or I.M BUT S.C.

Carbachol Has muscarinic actions similar to ACh Has nicotinic actions similar to Ach (side effects) Longer duration of action Used for treatment of glaucoma Bethanechol Has no nicotinic actions Used for treatment of paralytic ileus & urinary retention.

Carbachol Muscarinic actions on Eye, GIT, UT. (see the previous table). Has nicotinic actions (what are these actions?) Used for Mainly in glaucoma Urinary retention & paralytic ileus (rarely used due to its nicotinic actions)

Bethanechol Prominent muscarinic actions on GIT, UT. No nicotinic action Used for Paralytic ileus Urinary retention in cases of post-operative atony & neurogenic bladder

Pilocarpine (natural alkaloids) Tertiary amine non polar = lipophilic well absorbed, good distribution Cross BBB (has central effects). Not metabolized by cholinesterase Long duration of action Direct muscarinic agonist (mainly on eye & secretion).

Pilocarpine (continue…) Uses: Xerostomia (dry mouth). Drug of choice in emergency glaucoma applied as eye drops. Adverse effects: Profuse sweating Salivation Bronchoconstriction Diarrhea CNS effects

(autoimmune disease characterized by decreased salivation). Cevimeline Direct acting muscarinic agonist Used for treatment of dry mouth symptom associated with Sjogren's syndrome (autoimmune disease characterized by decreased salivation).

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

direct Cholinomimetic More on eye, exocrine glands Cevimeline M Pilocarpine Bethanechol Carbachol M,N ACh M, N Muscarinic Nicotinic Receptors +++ Exocrine glands More on eye, exocrine glands GIT, Urinary bladder Eye, GIT Urinary bladder NOT Selectivity NO Sjogren's syndrome Glaucoma Xerostomia Paralytic ileus Urinary retention Uses

Contraindications of direct cholinomimetics Bronchial asthma. Peptic ulcer. Angina pectoris Incontinence Intestinal obstruction

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