Direct Cholinergic Drugs PDF

Dr. Asmaa F. Sharif Ph D., JMHPE, MSc, MBBCh. College of Medicine – ‫كلية الطب‬ – Course Name and ‫اسم ورقم المقرر‬ 11/30/2024 1 No. ...

Dr. Asmaa F. Sharif Ph D., JMHPE, MSc, MBBCh. College of Medicine – ‫كلية الطب‬ – Course Name and ‫اسم ورقم المقرر‬ 11/30/2024 1 No.  At the end of this lecture the student should: College of Medicine – ‫كلية الطب‬  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 cholinomimetic drugs.  Know the major side effects for the different classes of direct cholinomimetics. – Course Name and ‫اسم ورقم المقرر‬ 11/30/2024 2 No.  Nervous system Peripheral nervous Central nervous system system College of Medicine – ‫كلية الطب‬ Efferent Division Afferent Division (Motor) (Sensory) Autonomic nervous Somatic system system (skeletal muscles) Parasympathetic nervous system Sympathetic nervous system  College of Medicine – ‫كلية الطب‬ 4  Sympathetic NS Parasympathetic NS Origin Thoracolumbar Craniosacral Pre-ganglionic NTs Ach Ach College of Medicine – ‫كلية الطب‬ Pre-ganglionic Neuron Cholinergic neuron Cholinergic neuron Ganglionic Receptor Cholinergic receptor Cholinergic receptor (Nn) (Nn) Postgangilonic NTs NE Ach Postgangilonic neuron Adrenergic neuron Cholinergic neuron Target-tissue receptor Adrenergic receptor Cholinergic receptor (α, β) (M) 5  Sympathetic Parasympathetic In stress (fight , flight) In psychic relaxation (Rest, digest) College of Medicine – ‫كلية الطب‬ heart Increase all cardiac Decrease most of cardiac properties properties Blood - VC of skin & m.m. Non innervated (indirect effect) vs - VD of skeletal & coronary BV Bl.pr Increased “Hypertension” Decreased “Hypotension” eye Activates dilator pupillae Activates constrictor pupillae (miosis) (active mydriasis) Activates ciliary muscles (accommodation to near vision) 6  Sympathetic Parasympathetic Bronchi Bronchodilatation Bronchospasm College of Medicine – ‫كلية الطب‬ GIT - Inhibits tone & motility of wall. - Contract wall - Contract sphincter - Relax sphincter Urinary tract Relax wall & Contract sphincter Contract wall & Relax sphincter Sex organs Ejaculation in male Erection in male - Relax uterine wall in females Exocrine Decrease Increase glands Sweat glands Decrease Increase 7 College of Medicine – ‫كلية الطب‬ “Uses cholinergic neurons to release Acetylcholine that binds to cholinergic receptors (Muscarinic receptors) at target tissues to provide their effects” 8   Neurotransmission in cholinergic neurons involves six sequential steps: 1. Synthesis College of Medicine – ‫كلية الطب‬ 2. Storage 3. Release 4. Binding of Ach to a receptor. 5. Response effect a. Stimulation = depolarization : Na+ influx → Excitatory postsynaptic potential b. Inhibition = hyperpolarization : Cl- influx & K+ efflux → Inhibitory postsynaptic potential. 6. Degradation of the neurotransmitter in the synaptic cleft by acetylcholinesterase. 7. Recycling of choline and acetate Course Name and – ‫اسم ورقم المقرر‬ 11/30/2024 9 No. College of Medicine – ‫كلية الطب‬ – Course Name and ‫اسم ورقم المقرر‬ 11/30/2024 10 No.   A neuron that secretes Acetylcholine to exert its action. Can be: College of Medicine – ‫كلية الطب‬ 1. Preganglionic fibers terminating in the adrenal medulla and the autonomic ganglia (both parasympathetic and sympathetic), 2. Postganglionic fibers in parasympathetic division 3. The postganglionic sympathetic division of sweat glands 4. Neurons that innervate the skeletal muscles of the somatic system Course Name and – ‫اسم ورقم المقرر‬ 11/30/2024 11 No. College of Medicine – ‫كلية الطب‬ Central nicotinic receptor Peripheral muscarinic receptor Course Name and – ‫اسم ورقم المقرر‬ 11/30/2024 12 No.   Ion channel linked receptors  Locations: ❖ At neuromuscular junctions of skeletal muscle (Nm) College of Medicine – ‫كلية الطب‬ ❖ Adrenal medulla (Nn) ❖ CNS (Nn) ❖ Autonomic ganglia (Nn) 13  Nicotinic Actions Skeletal muscles:  Low conc. of nicotine → muscle contraction  High conc. of nicotine→ persistent depolarization & College of Medicine – ‫كلية الطب‬ relaxation. Ganglia: Stimulation of sympathetic& parasympathetic ganglia. Adrenal medulla Release of catecholamines (A & NA).   Muscarinic receptors belong to the class of G protein– coupled receptors College of Medicine – ‫كلية الطب‬  Located at all target organs that are innervated by parasympathetic fibers (e.g, heart, CVS, eye, bladder, etc).  Five subclasses exist (M1 - M5)  M1, M3, M5 are excitatory in function (stimulation).  M2, M4 are inhibitory in function (inhibition). 15  College of Medicine – ‫كلية الطب‬ Phospholipase C 16  Receptor Location Pharmacological action M1 Excitatory CNS Increases gastric acid +++++ Gastric parietal cells secretion College of Medicine – ‫كلية الطب‬ M2 Inhibitory Heart Cardiac inhibition ------- (Bradycardia) M3 Excitatory Exocrine glands Increase secretion of glands +++++ Smooth muscles Smooth muscle contraction Vascular endothelium Vasodilatation (via releasing nitric oxide) M4 & M5 CNS Memory, arousal, attention 17  Organs Cholinergic actions Eye Contraction of constrictor puipllae muscle (miosis)(M3) Contraction of ciliary muscles for near vision (M3) Decrease in intraocular pressure College of Medicine – ‫كلية الطب‬ Heart Bradycardia ( heart rate ) (M2) Endothelium Release of NO (Vasodilatation) Lung Constriction of bronchial smooth muscles Increase bronchial secretion M3 GIT Increase motility (peristalsis) Increase secretion Relaxation of sphincter M3 Urinary Contraction of muscles bladder Relaxation of sphincter M3 - Urination Exocrine Increase of all secretions glands sweat, saliva, lacrimal, bronchial, intestinal secretions M3   Drugs that produce actions similar to stimulation of College of Medicine – ‫كلية الطب‬ parasympathetic system (or similar to natural neurotransmitter, Ach). Direct:  Bind directly to cholinergic receptor (M receptor) Indirect-acting  Inhibit the degradation of Ach by acetylcholinesterase enzyme – Course Name and ‫اسم ورقم المقرر‬ 11/30/2024 19 No. College of Medicine – ‫كلية الطب‬ – Course Name and ‫اسم ورقم المقرر‬ 11/30/2024 20 No.  Direct cholinomimetics:  These are drugs that mimic the effects of ACh by binding directly to cholinoreceptors (muscarinic or nicotinic)  These are classified into two groups: i) Direct acting muscarinic  Acetylcholine (M,N) College of Medicine – ‫كلية الطب‬  Carbachol (M,N) Quaternary amines (choline  Bethanechol (M) esters): bad distribution Pilocarpine (M): Tertiary amine (well distributed) ii) Direct acting nicotinic:  Acetylcholine  Nicotine  Carbachol Note: All of the direct-acting cholinergic drugs have a longer duration of action than Ach. 21 College of Medicine – ‫كلية الطب‬ – Course Name and ‫اسم ورقم المقرر‬ 11/30/2024 22 No.   It has both muscarinic and nicotinic agonistic actions.  Not used clinically due to: ❖Rapid inactivation by the cholinesterase. ❖Non-selective (N, M) College of Medicine – ‫كلية الطب‬ Actions:  HR & Cardiac output  Salivary secretion & stimulate intestinal secretions and motility  Enhance bronchial secretion  Tone of detrusor muscle causing urination  Ciliary & iris circular muscle constriction causing miosis 11/30/2024 23  ❑Include drugs as Carbachol & Bethanechol. ❑Quaternary ammonium compounds (polar) College of Medicine – ‫كلية الطب‬ ❑ Poor oral absorption and 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. – Course Name and ‫اسم ورقم المقرر‬ 11/30/2024 24 No.  It has both muscarinic (Eye, GIT, UT) and nicotinic actions.  Orally (poor absorption) or SC. College of Medicine – ‫كلية الطب‬ Carbachol is rarely used therapeutically except: 1) Eye: drops as a miotic agent to treat glaucoma by causing pupillary muscle contraction and a decrease in intraocular pressure. 2) Urinary retention & paralytic ileus (rarely used due to its nicotinic actions) Adverse effects:  Stimulate NE release form adrenal medulla by its nicotinic action 25  Orally (poor absorption) -SC Prominent muscarinic actions on GIT, UT & No nicotinic action  Directly stimulates muscarinic receptors, causing increased College of Medicine – ‫كلية الطب‬ intestinal motility and tone.  It also stimulates the detrusor muscle of the bladder, whereas sphincter muscles are relaxed urination. Uses: 1. Stimulate the atonic bladder, in postpartum or postoperative urinary retention. 1. Treat paralytic ileus 26  Adverse effects:  Generalized cholinergic stimulation College of Medicine – ‫كلية الطب‬  Sweating, salivation, flushing, diaphoresis  Nausea, abdominal pain, diarrhea  Urinary urgency  Decreased blood pressure  Bronchospasm  NB: Choline esters are Never given IV or IM → severe bradycardia & hypotension. – Course Name and ‫اسم ورقم المقرر‬ 11/30/2024 27 No.   Natural Alkaloid  Tertiary amine lipophilic ( well absorbed, Good distribution & Cross BBB (has central effects). College of Medicine – ‫كلية الطب‬  Oral, eye drops  It exhibits muscarinic activity and is used primarily in ophthalmology. Actions & uses : 1. It is drug of choice for emergency lowering of intraocular pressure of glaucoma. 2. Given orally to treat Xerostomia (dry mouth) Adverse effects: when given orally  Sweating (diaphoresis)  Salivation.  Blurred vision and night blindness  Diarrhea  Bronchospasm Course Name and – ‫اسم ورقم المقرر‬ 11/30/2024 28 No.  ACh Carbachol Bethanechol Pilocarpine Chemistry Quaternary Quaternary Quaternary Tertiary Polar Polar Polar nonpolar Oral NOT Poor but Poor but Complete Absorption better better College of Medicine – ‫كلية الطب‬ absorbed absorbed than than Ach Ach Metabolism Metabolized NOT NOT NOT by by cholinesterase cholinesterase Duration Very short Longer (++) Longer (++) Longer (++) Administrati No available Oral, Oral oral, on preparation eye drops S.C. eye drops S.C.  ACh Carbachol Bethanechol Pilocarpine Receptors Muscarinic Muscarinic Muscarinic Muscarinic Nicotinic Nicotinic only only Selectivity NOT Eye, GIT GIT, More on eye, College of Medicine – ‫كلية الطب‬ Urinary Urinary salivary bladder bladder secretion Nicotinic +++ +++ NO NO actions Uses NO Glaucoma Glaucoma Paralytic Paralytic ileus ileus Xerostomia Urinary Urinary retention retention  Cevimeline ◦Direct acting muscarinic agonist ◦Used for treatment of dry mouth symptom associated with Sjogren's syndrome. College of Medicine – ‫كلية الطب‬ Contraindications of cholinomimetics 1. Bronchial asthma. 2. Peptic ulcer. 3. Angina pectoris 4. Urinary incontinence 5. Intestinal obstruction  Nicotine  Available as oral gum, lozenges, inhaler or patches College of Medicine – ‫كلية الطب‬ M.O.A & Actions:  Agonist at both Nn (CNS) and Nm (skeletal muscle neuromuscular end plates) receptors Clinical uses:  Smoking cessation Adverse effects:  Common: GI adverse effects  nausea, vomiting, diarrhea – Course Name and ‫اسم ورقم المقرر‬ 11/30/2024 32 No. College of Medicine – ‫كلية الطب‬ – Course Name and ‫اسم ورقم المقرر‬ 11/30/2024 33 No.