Introduction to Parasympathetic: Cholinergic Agonists

Introduction of Parasympathetic  The chemical transmitter of parasympathetic is acetylcholine (Ach) and its receptor is cholinergic receptor.  Cholinergic receptor are: Muscarinic receptors Nicotinic receptors present in the heart, p...

Introduction of Parasympathetic  The chemical transmitter of parasympathetic is acetylcholine (Ach) and its receptor is cholinergic receptor.  Cholinergic receptor are: Muscarinic receptors Nicotinic receptors present in the heart, present in the neuromuscular Site smooth muscles, secretory junction, autonomic ganglia and glands, eyes and CNS. adrenal medulla. M1 NM receptors M2  at the skeletal muscle end plate subtypes M3 NN receptors M4  at the autonomic ganglia and M5 adrenal gland.  Fate of Acetylcholine:  is rapidly hydrolysed by the enzyme Acetylcholinesterase (AChE) within few milliseconds into Choline and acetate.  A part of choline is reuptaken by nerve endings and then reused in Ach synthesis. DR. M. M. Page| 1  Cholinesterase (ChE) enzyme has two isoforms: MCQ Pseudo ChE True ChE butyryl-cholinesterase (BuChE) Present in CNS, ganglia, Present in plasma and liver, so it is Site NMJ, RBCs. called plasma ChE. Specific for Specific for Ach. Not specific for Ach Ach Deficiency Deficiency is fatal. Deficiency is Not fatal. Regeneration Regenerates in 2-3 months. Regenerates in 2-3 weeks. NB: Most enzyme inhibitors used clinically do not discriminate between the two types of ChEs. Botulinum toxin blocks Ach release and causes skeletal muscle paralysis, It is used in blepharospasm, strabismus/hyperhidrosis, dystonia, and cosmetics. DR. M. M. Page| 2  Parasympatho-mimetics (Cholinergic agonists) Direct Indirect Acetylcholine, Bethanechol Reversible. Carbachol, Pilocarpine, Cevimeline Irreversible. 1) Direct-acting Parasympathomimetic drugs 1- Acetylcholine  Pharmacokinetics:  It is the prototype cholinergic agent.  Poorly absorbed from the gastric mucosa , so not given orally.  Given only parenteral.  Duration of action: very short as it is rapidly hydrolyzed by the enzyme cholinesterase into acetic acid and choline. DR. M. M. Page| 3  Pharmacodynamics: ↓ atrio-ventricular (AV) conduction and HR (M2). CVS VD of all blood vessels through release of EDRF (M3). Miosis due to contraction of constrictor pupillae ms. Eye Accommodation for near vision due to contraction of (M3) ciliary muscle ↓ IOP. Muscarinic effects: Respiratory Contraction of bronchial smooth muscle. effects ↑ bronchial secretions. (M3) ↑ Motility of wall and relaxation of sphincters (M3). GI tract ↑ HCl secretion (M1). Urinary tract Contraction of bladder smooth muscles. (M3) Relaxation of sphincters. Exocrine ↑ all exocrine secretions, salivation, lacrimation, glands (M3) sweating, etc. ↑ Autonomic ganglia (Nn). Nicotinic effects: ↑ Motor end plate (neuromuscular junction) → skeletal ms contractions (Nm). NB: ACh is not used clinically because: 1) it has very short duration of action (seconds) due to rapid hydrolysis by AChE enzyme. 2) Non selective. DR. M. M. Page| 4  2- Other Direct acting Parasympathomimetic drugs  They produce effects similar to ACh but with more selectivity and fewer side effects than ACh DR. M. M. Page| 5  2- Carbachol 3- Bethanechol 4- Pilocarpine 5- Cevimeline It is choline ester but It is a choline ester but resistant to hydrolysis resistant to hydrolysis is a natural plant Nature Is synthetic drug by AChE → long by AChE → long alkaloid. duration duration (2 - 3 h). It stimulates muscarinic It stimulates It stimulates both It stimulates muscarinic receptors receptors with no muscarinic receptors Action muscarinic and with no activity on nicotinic activity on nicotinic with no activity on nicotinic receptors. receptors. receptors. MCQ nicotinic receptors. Given orally to increase salivary and lacrimal secretion. It is used to reverse It is used as local eye post-operative urine Used as local eye and decrease symptoms of dry drops to decrease retention and paralytic drops to decrease IOP mouth (xerostomia) and dry eyes Uses e.g. following irradiation or in IOP in chronic open ileus (in absence of in chronic open angle angle glaucoma. organic obstruction). glaucoma. MCQ patients with Sjögren’s syndrome MCQ (an autoimmune disorder characterized by dryness of mouth and eyes). MCQ DR. M. M. Page| 6  Adverse effects of muscarinic agonists:  CVS: hypotension  Respiratory: bronchoconstriction  GIT: nausea, vomiting and diarrhea  Sweating, salivation.  Contraindications of muscarinic agonists:  Bronchial asthma  Heart block.  Peptic ulcer DR. M. M. Page| 7