DIRECT CHOLINERGIC DRUGS Profs Abdalqader Alhaider Hanan Hagar

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 indirectacting cholinomimetic drugs.

Nervous system Peripheral nervous system Central nervous system Efferent Division (Motor) Afferent Division (Sensory) Autonomic nervous system Somatic system (skeletal muscles) 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 Is a craniosacral outflow

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: 1) Synthesis of Ach 2) Storage of Ach in storage vesicles 3) Release of Ach 4) 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 n n 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: Ø Skeletal muscles (neuromuscular junction, Nm ) Ø Autonomic ganglia (sympathetic and parasympathetic ganglia, Nn). Ø Adrenal medulla (Nn). Ø CNS (Nn).

Muscarinic receptors Type II receptors : G-protein linked receptors • Five subclasses ; M 1, M 2, M 3, M 4 and M 5 • M 1, M 3, M 5 are excitatory or stimulatory in function (stimulation) • M 2, M 4 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 Receptor M 1 Excitatory M 2 Inhibitory M 3 Excitatory M 4 & M 5 Locations CNS gastric parietal cells Heart Pharmacological actions CNS excitation Gastric acid secretion Cardiac inhibition (Bradycardia) • Secretion of glands Exocrine glands Smooth muscles (GIT, urinary tract, • Smooth muscle contraction bronchial muscles) Vascular endothelium • Vasodilatation (via nitric oxide) CNS memory, arousal, attention and analgesia

Cholinergic or parasympathetic receptors Nicotinic receptors Central cholinoceptors Almost excitatory Autonomic ganglia Nn sympathetic & parasympathetic imulation Muscarinic receptors Peripheral cholinoceptors Excitatory or inhibitory On all peripheral organs innervated by postganglionic parasympathetic fibers Adrenal medulla Nn release of catecholamines (adrenaline & noradrenaline) Heart (bradycardia, M 2) exocrine glands (secretion, M 3) Skeletal muscles Nm contraction Smooth muscles (contraction, M 3) (GIT, urinary tract, bronchial muscles, uterus)

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 Ø Skeletal muscles: ØLow conc. of Ach muscle contraction ØHigh conc. of Ach persistent depolarization & relaxation. Ø Stimulation of Autonomic ganglia Ø Stimulation of adrenal medulla: release of catecholamines (Adrenaline & Noradrenaline).

Muscarinic actions of Ach 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 (IOP) bradycardia ( decrease in heart rate ) (M 2) Heart endothelium Release of NO (EDRF) Lung Constriction of bronchial smooth muscles Increase in bronchial secretion M 3 GIT Increase in motility (peristalsis) Increase in secretion Relaxation of sphincter -defecation M 3 Urinary bladder Contraction of muscles Relaxation of sphincter M 3 Urination Increase of secretions of exocrine glands sweat, saliva, lacrimal, bronchial, intestinal secretions M 3 Exocrine glands

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

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 q Quaternary ammonium compounds contain N+ (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. q

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

Carbachol 1. Muscarinic actions on Eye, GIT, UT. (see the previous table). 2. Has nicotinic actions (what are these actions? ) 3. Used for n Mainly in glaucoma n Urinary retention & paralytic ileus (rarely used due to its nicotinic actions)

Bethanechol Ø Prominent muscarinic actions on GIT, UT. Ø No nicotinic action Ø Used for n Paralytic ileus n 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

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

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

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

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

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