Cholinergic and Nicotinic Receptors in the Human Body

Cholinergic Receptors Ach Receptors AL-AYEN UNIVERSITY COLLEGE OF HEALTH AND MEDICAL TECHNOLOGY DEPARTMENT OF ANESTHESIA By PhD Karima Aboul Fotouh Lecturer 6

Nicotinic receptors are present in: Autonomic ganglia (NN) On skeletal muscle (NM) On the adrenal medulla (a specialised ganglia)(NN) CNS & spinal cord (NN) The nicotinic receptor is a ligand-gated ion channel designed for very rapid (within millisec) response times. Blocked by:- Ganglion blocker e.g. hexamethonium and Neuromuscular blocker e.g. curare

Receptor M1 M2 M3 Location CNS Glands: gastric, salivary . Heart Presynaptic CNS Exocrine gland: gastric ,salivary Smooth muscles: GIT, eye BV: endothelium Function CNS excitation: memory gastric secretion Cardiac inhibition CNS inhibition Presynaptic: Ach release gastric, salivary,... secretion GI smooth muscle contraction Ocular accommodation vasodilatation Agonists Ach Carbachol oxotremorine Ach Carbachol oxotremorine Ach Carbachol oxotremorine Antagonists Atropine Pirenzepine Atropine Gallamine Atropine Ipratropium

1-Muscarinic actions: a. Eye: Miosis due to stimulation of muscarinic receptors in the constrictor papillae muscle (M3). Contract ciliary muscles (M3) accommodation for near vision. Increase aqueous drainage and I.O.P.( intraocular pressure) Lacrimation and conjunctival congestion. b. Secretions: salivary, bronchial, sweat secretion (M3) and gastric(M1,3). c. Bronchi: Bronchoconstriction (M3)and increase of bronchial secretion. d. C.V.S.: Heart (M2); bradycardia (M2) delayed conduction in AV node, and hypotension, decreased contractility and refractory period in atria. Blood vessels (M3); vasodilatation (VD) in arteries & veins in all tissues ( blood vessels have no parasympathetic supply but contain muscarinic receptors) BP; hypotension due to bradycardia and VD.

e. GIT: motility (M3), tone and secretion and relaxation of pyloric and anal sphincter. f. Urinary tract: Contraction detrusor muscle of wall, relax sphincter micturation(M3). g. CNS: Learning and recent memory are muscurinic actions ( Alzheimer s dementia, due to deficient cholinergic neurons in forebrain, is treated by muscarinic agonists). Excitatory cholinergic activity in basal ganglia is also muscarinic in nature( overactivity as rigidity in parkinsonism is treated by antimuscarinics)

2- Nicotinic action: Ach stimulates nicotinic receptors in: Autonomic ganglia; both sympathetic and parasympathetic ganglia are stimulated leading to release from the postganglionic fibers of NA and ACH respectively. Adrenal medulla; leading to release of adrenaline and noradrenaline. Neuromuscular junction; leading to contraction of the skeletal muscle. CNS; release of anti-diuretic hormone (ADH) from hypothalamus.

Types of Cholinergic Agonists (Parasympathomimetics) 1)Direct-Acting Cholinergic Agonists 2)Indirect-Acting Cholinergic Agonists a)Reversible Anticholinesterases b)Irreversible Anticholinesterases

Direct Acting Cholinergic Agonists Direct Acting Cholinergic Agonists 1)Acetylcholine 2)Bethanechol 3)Carbachol 4)Pilocarpine 5)Cevimeline 6)Methacholine Therapeutically useful drugs All of the direct acting cholinergic drugs have longer durations of action than acetylcholine.

1) 1) Acetylcholine ( Acetylcholine (ACh ACh) ) Cannot penetrate membranes & BBB. Therapeutically of no importance because of a) Non selective (Multiplicity of actions) b) Rapid inactivation by the cholinesterases c)Short duration. Ach has both muscarinic and nicotinic activity.

a)Effect on heart rate and cardiac output Mimic the effects of vagal stimulation. HR ( S.A node firing) Activate M3 in endothelium lining the smooth muscles of B.V NO production VD BP b) Effect on B.P c) Other actions GIT Intestinal secretions Motility Salivary secretion Lung Urinary tract .. Eye Miosis due to contraction of iris smooth muscle

2) Bethanechol It is structurally related to Ach M agonist It is not hydrolyzed by cholinesterases Actions Primarily affects the urinary and GIT a) a) Contraction of detrusor muscle & sphincter relaxed Contraction of detrusor muscle & sphincter relaxed Expulsion of urine Expulsion of urine b) b) Directly stimulate muscarinic receptors Directly stimulate muscarinic receptors GIT motility GIT motility Therapeutic application (Uses) 1) Atonic bladder ( Non obstructive urinary retention. 2) Post operative paralytic ileus. in Postpartum, Postoperative, (

Adverse effects 1) Nausea , abdominal pain and diarrhea 2) Bronchospasm 3) Sweating & Salivation 4) Flushing & Blood pressure 3) 3) Carbachol Carbachol ( (carbamoyl Carbachol has both Muscarinic (marked on eye, GIT, urinary tract) & Nicotinic actions. carbamoyl choline choline) ) It is not hydrolyzed by cholinesterases. Action Because of nicotinic action adrenal medulla Locally into the eye mimics the effects of acetylcholine Can cause release of epinephrine and NE from Miosis Uses It is rarely used therapeutically due to a) Receptors non selectivity b) Relatively long duration of action Used as Exception in eye as Miotic agent to treat glaucoma Contraction of the constrictor pupillae muscle (circular muscle) Miosis intra ocular pressure (IOP)

4) 4) Pilocarpine Pilocarpine Stable to hydrolysis by acetylcholinesterase. It exhibits muscarinic activity and is used primarily in ophthalmology but also has actions on exocrine glands and smooth muscles. Actions 1) Eye (Topically it produces ) a) Miosis b) Contraction of the ciliary muscle. 2) Exocrine glands Potent stimulators of secretions (secretagogue) such as sweat, tears, and saliva 3) Smooth muscle Urine excretion Motility of the bowel Defecation

Therapeutic applications It is the drug of choice in lowering of IOP of glaucoma Treatment of Xerostomia (due to sialagogue effect) Diaphoretic fever Promotion of hair growth. Adverse effects Pilocarpine can enter the brain and cause CNS disturbances. It stimulates profuse sweating and salivation 1) 2) 3) 4) 5 5) ) Cevimeline Cevimeline (synthetic) (synthetic) Selective M3 agonist in lacrimal and salivary glands Has sialogogue effect Used in treatment of a) Xerostomia after head and neck radiation b) Sjogren's syndrome Has less side effects than pilocarpine

6) Methacholine It is acetyl - methyl choline Actions: Acts directly on muscarinic receptor, which are more prominent on C.V.S. and has insignificant nicotinic actions. Contraindications of choline esters 1) Bronchial asthma. 2) Peptic ulcer 3) Angina pectoris (can reduce coronary flow due to hypotension). 4) Never given I.M. or I.V. (produce sever bradycardia and hypotension and atropine is the antidote).

Indirect Acting Cholinergic Agonists Indirect Acting Cholinergic Agonists Anticholinesterases Anticholinesterases A. Reversible Anticholinesterases B. Irreversible Anticholinesterases Lifetime of Ach (Endogenously) at the cholinergic nerve endings accumulation of Ach in the synaptic space at M &N receptors of 1) ANS 2) Neuromuscular junctions

a) a)Reversible indirect Reversible indirect- -Acting Cholinergic Agonists Acting Cholinergic Agonists 1) Physostigmine 2) Neostigmine Carbamate derivatives 3) Pyridostigmine & Ambenomium 4) Edrophonium (quaternary ammonium alcohol) 5) Donepezil, Rivastigmine and galantamine (Alzheimer s disease)

Reversible anticholinesterases Physostigmine (Eserine) Neostigmine (Prostigmine) Sourse Natural (plant origin) (calabar beans) synthetic Oral absorption Complete Incomplete Passage through lipid barrier Passes BBB to CNS Can not pass CNS Action a. Muscarinic (eye, bronchi, heart, gut, urinary .) b. Nicotinic c. CNS stimulation(convulsions) a. Muscarinic b. Nicotinic c. Direct skeletal muscle stimulant Uses 1-Locally on eye (0.5-1%)in Glaucoma (muscarinic effect), antagonize mydriatics. 2- Systemically it is used in treatment of atropine poisoning. 3- Eye drops it may produce twitches of the eye lids (nicotinic effect). 1. Diagnosis and treatment of myathenia gravis. 2. Antidote to non depolarizing neuromuscular blockers. 3. Antidote to atropine (antagonist of peripheral action). 4.Postoperative urine retention and paralytic ileus. 5.Paroxysmal atrial tachycardia. 6. Glaucoma

N.B Myasthenia Gravis It is auto-immune disease. Caused by antibodies that bind to nicotinic receptors of skeletal muscle Characterized by weakness of skeletal muscles. E.g. o Eye muscle (ptosis) o Limb muscle o Respiratory muscle

3)Pyridostigmine and ambenomium Used in the chronic management of myasthenia gravis Adverse effects of these agents are similar to those of neostigmine. 4) Edrophonium (quaternary amine) Used in the Diagnosis of myasthenia gravis. I.V injection of edrophonium Atropine is used as an antidote for edrophonium overdose and toxicity. Rapid in muscle strength.

5) Donepezil, Rivastigmine and Galantamine Used to delay the progression of the Alzheimer's disease o Patients with Alzheimer s disease have a deficiency of cholinergic neurons in CNS. Irreversible indirect Acting Cholinergic Agonists Irreversible anticholinesterase (organophosphorus compounds) They are used as: 1) Insecticides: Parathion and malathion. 2) War gas: Tabun, sarin, Soman 3) Metrifonate is an oral antibilharzial drug. 4)Echothiophate (eye drops in glaucoma) 5) Isofliurophtae (eye ointment in glaucoma)

Irreversible anticholinesterase The enzyme is permanently inactivated (aging of the enzyme) o Restoration of acetyl cholinesterase requires the synthesis of new enzyme ( 3 weeks for .., 3 months for .(. Cholinesterase reactivation for management of poisoning + ATROPINE Cholinesterase reactivation for management of poisoning + ATROPINE Pralidoxime (PAM) (not pass BBB)can reactivate inhibited cholinesterase. Di Acetyl Monoxime (DAM) (pass BBB) Displaces the organophosphate and regenerates the enzyme. Treatment must be within hrs. o Because the phosphorylated enzyme slowly changes to a form that cannot be reversed. Manifestations DUMBELS (muscarinic) Nicotinic Manifestations due to prolonged depolarization. muscle twitches followed by paralysis CNS failure). convulsions followed by coma (cardiac arrest & respiratory