CHOLINERGIC AGONISTS.ppt

CHOLINERGIC AGONISTS Prof. Dr. Aşkın TAŞ Somatomotor sinir sistemi Nöral Sistem Sinir Sistemi Periferik Otonomik (controls Santral (beyin ve spinal kord) İskelet / somotomotor self-regulated action of internal organs and glands) (controls voluntary movements of skeletal muscles) Sempatik...

CHOLINERGIC AGONISTS Prof. Dr. Aşkın TAŞ Somatomotor sinir sistemi Nöral Sistem Sinir Sistemi Periferik Otonomik (controls Santral (beyin ve spinal kord) İskelet / somotomotor self-regulated action of internal organs and glands) (controls voluntary movements of skeletal muscles) Sempatik (arousing/canlı) Parasempatik (calming/durgun, sakin) AUTONOMOUS NERVOUS SYSTEM The autonomic nervous system is very important in two cases. "rest" and "digest" in non-emergency situations And In a stressful emergency, "fight" or take "flight" (run away) AUTONOMOUS NERVOUS SYSTEM • General: regulates glands, smooth muscles, heart • • Spinal Nerves T1-L2 (thoracolumbal) • Parasympathetic: retains energy (anabolic), or stagnates it • CS 3,7,9,10 and S2-4 (Craniosacral) • Sympathetic: increases energy (catabolic), or stimulates "rest" and "digest" CNS A N S Cholinergic nerve Adrenergic nerve Motor nerve (cholinergic but not like sympathetic or parasympathetic, it doesn't have ganglia, it terminates in the neuromuscular junction, it has a nicotinic receptor and is broken down by AChE.) • The neurotransmitter responsible for impulse transmission at the following synapses or junctions is acetylcholine (cholinergic synapses or junctions): • • • • • Activated by muscarin extracted from the Amanita muscaria mushroom • Junctions between parasympathetic postganglionic nerve fibers and effector cells (MUSCARINIC) • Synapses between preganglionic (splanchnic) sympathetic nerve fibers and chromaffin cells in the adrenal medulla (NICOTINIC) • Synapses in the sympathetic and parasympathetic ganglia (NICOTINIC) • The following neurons of the autonomous nervous system are cholinergic: • First-line neurons of the sympathetic and parasympathetic system • There are two exceptions to this: • The sympathetic neurons that innervate the eccrine sweat glands are all cholinergic. • Some of the sympathetic neurons that innervate the vessels of skeletal muscles are cholinergic, and the other part is adrenergic. • Second-line neurons of the parasympathetic system. The second-line neurons of the sympathetic system, on the other hand, are usually adrenergic. Cholinergic receptors: Nicotinic receptors: Superfamily of ion channel receptors (directly urbanized by the Na+ ion channel) Cation channel •Muscarinic receptors: (Superfamily of G protein-coupled receptors) Receptors with seven transmembranal segments Alpha-adrenergic, N type by omega-conotoxin Selectively Calcium channel (Blocked dopaminergic, opioid mu serotonergic presynaptic Heteroreceptor In general M2 presynaptic autoreceptors Kolinerjik sinaps 1. Synthesis of acetylcholine (ACh) from acetyl CoA and choline 2. Storage of ACh in synaptic vesicles 3. Release of ACh ( fusion of synaptic vesicle with presysnaptic membrane and release of ACh into the synapse) 4. Action of ACh by binding to and activating receptors (nicotinic in autonmic ganglia and NMJ and muscarinic in many sites) 5. Inactivation by enzymatic breakdown of ACh by acetylcholinesterase (AChE) located in the synapse 2. Enzymatic Destruction (Deactivation): • A specific enzyme changes the structure of the neurotransmitter, resulting in a structure that cannot recognize the receptor. • A second type of cholinesterase, called pseudocholinesterase, breaks down acetylcholine more slowly, break down butyrylcholine the fastest. • This is also called butyrylcholinesterase. • Pseudocholinesterase is not found in synapses and does not contribute to acetylcholine hydrolysis at these sites. • It is also present in plasma, liver and other organs, where it functions as a non-selective esterase. It also breaks down succinylcholine. Nicotinic Receptors: • The nicotinic receptors at the neuromuscular junctions of the skeletal muscles, the nicotinic receptors of the autonomic ganglia and the nicotinic receptors of the chromophin cells in the adrenal medulla are of two distinct types: • Skeletal muscle type NM receptors: • D-Tubocurarin, Pancuronium, etc., are selectively blocked by skeletal muscle paralyzing drugs. • Alpha-bungarotoxin selectively blocks the receptors. • Ganglion type NN receptors: • Hexamethonium is selectively blocked by mecamylamine and other ganglion blocking drugs. • Dimethylphenylpiperazinium is a selective agonist. • Kappa-bungarotoxin selectively blocks receptors. • Acetylcholine and nicotine are non-selective agonists of skeletal muscle and ganglion type cholinergic receptors. Muscarinic receptors: • There are 3 types that have been studied in detail (M1, M2, M3). • In addition, there are still M4 and M5 receptors that have been shown to exist only in the brain and neuroblastoma cells. • M1 receptors: • It is found in pathways related to learning and memory in the brain, in sympathetic, parasympathetic ganglion cells. G protein coupled. • Pirenzepine, telenzepine are selective antagonists. • Arecholine, isoarecholine, oxotremorin are partial agonists. M2 receptors: •It is common in the heart. •It is a presynaptic autoreceptor is in many places (reduces its self-release). •Presynaptic M1 in the heart. •Adenylate cyclase inhibition, Inward K channel activation, Voltage-dependent calcium channel inhibition M3 receptors: •It is found in exocrine gland cells and in the gastrointestinal tract, tracheobronchial channel and bladder smooth muscle, autonomic ganglia and some areas of the brain. •If activated, it increases the secretion of the gland and promotes the contraction of smooth muscular structures. Darifenacin is a selective antagonist. •It increases the release of NO (endothelium-derived relaxing factor) by stimulating nitric oxide (NO) synthase in vascular endothelial cells. Phospholipase C activation (Cellular action excitation) CHOLINOMIMETIC DRUGS They are the drugs that directly or indirectly activate muscarinic and/or nicotinic cholinergic receptors and mimic the action of acetylcholine in target cells which are carrying these receptors. • They are divided into three groups according to the type of cholinergic receptor they affect and its mode of action: • Parasympathomimetic drugs (muscarinic agonists) • Drugs that directly stimulate the ganglia nicotinic stimulants or nicotinic agonists • Anticolinesterazes Cholinesterase inhibitors • CHOLINOMIMETIC DRUGS •Parasympathomimetic drugs (muscarinic drugs); • By directly activating the muscarinic type cholinergic receptors of effector cells, they excite or inhibit these cells, thus producing effects similar to those of parasympathetic nerve stimulation. • Anticholinesterases (cholinesterase inhibitors); • By inhibiting the acetylcholinesterase enzyme, they cause acetylcholine to accumulate in all cholinergic junctions, including synapses in the neuromuscular junction and autonomic ganglia in the periphery, and indirectly activate cholinergic receptors in the postsynaptic membrane, whether muscarinic or nicotinic, through acetylcholine. • In addition to parasympathomimetic effects, they also produce significant nicotinic effects in the periphery. CHOLINOMIMETIC DRUGS • • • • They replicate the effects of parasympathetic stimulation by activating muscarinic receptors in the effector cells. Their affinity for M1,2,3,4 is usually equal (Non-selective muscarinic agonist). Arecolin, pilocarpine, oxotremorine show relative selectivity towards M1. They are divided into two groups: 1. Acetylcholine and other choline esters 2. Parasympathomimetic alkaloids and their synthetic analogues CHOLINOMIMETIC DRUGS • In general, they contract the smooth muscles of other structures, although they relax the vascular smooth muscles and sphincter muscles. • Cardiovascular system: • Lowers arterial blood pressure (M3 receptor-mediated, Vasodilation due to NO release from the vascular endotheliumVasoconstriction due to stimulation of receptors in vascular smooth muscle). • Heart rate decreases, bradycardia (negative chronotropic effect), • Decreased contraction strength in the atrium (negative inotropic effect), • A decrease in conduction velocity in the A-V node (negative dromotropic effect) may cause partial or complete heart block. • Effects on the heart M2 receptor-mediated (direct, indirectreduction of NA release). • Skin flushing due to vasodilation. CHOLINOMIMETIC DRUGS Pharmacological Effects of Acetylcholine: • In general, they contract the smooth muscles of other structures, although they relax the vascular smooth muscles and sphincter muscles. • Gastrointestinal System: • It contracts the smooth muscles in the stomach and intestinal wall. • Gastric emptying time, intestinal transit time is shortened. • Cramping causes defecation. • Although M2s are common, but the control of motility is more M3 receptor-mediated CHOLINOMIMETIC DRUGS CHOLINOMIMETIC DRUGS Pharmacological Effects of Acetylcholine: • Other smooth muscular organs: • It contracts the bladder wall (detrusor) muscle, relaxes the trigon and sphincter muscle. • At high doses, involuntary micturition occurs. • Increases ureteral tone and peristaltic contractility. • Although M2s are common, but the contraction of detrusor is M3 mediated. • Contracts bronchial smooth muscles, bronchospasm is mediated by M3 receptor CHOLINOMIMETIC DRUGS Pharmacological Effects of Acetylcholine: • Eye: • Contracts the circular muscle, of iris miosis. • The iridocorneal angle expands, the flow of aqueous humor is facilitated, intraocular pressure decreases in glaucoma. • M3 receptor-mediated • Contracting the ciliary muscle, contracting in the form of a ring • The lens curves, the optical refraction increases. • Temporary myopia occurs due to the formation of near vision. Distance vision is impaired. • It is called accommodation spasm. • M3 receptor-mediated CHOLINOMIMETIC DRUGS Pharmacological Effects of Acetylcholine: • Glands of external secretion: • Salivary gland: Abundant and watery saliva (hypersalivation) • In the gastric mucosa, the secretion of acid, pepsin, mucin increases. • Exocrine secretion of the intestinal mucous glands and pancreas increases. • The secretion of the mucous glands of the respiratory tract increases. • Airway resistance increases. • It causes rhinorrhea, sweating and lacrimation. • M3 receptor-mediated, M1 receptor-mediated contribution to salivary secretion. • CNS: • Acetylcholine and choline esters and other drugs cannot cross the blood-brain barrier because they contain a quaternary ammonium group. • Alkaloids and some anticholinesterases pass into the CNS. • All of the muscarinic receptors are present. • It plays a role in cognitive functions, motor control, appetite regulation and nociception. CHOLINOMIMETIC DRUGS 1. CHOLINE ESTERS • Acethylcholine • It is hardly used as a medicine. • It breaks down quickly in plasma. • The effect is not selective. • It is ineffective when used orally. • It is used in eye surgery to cause miosis. • Betanecol • No nicotinic effect • Carbamylcholine • There is a preparation used in ophthalmology • Metacholine • It is used for bronchial provocation testing. • No nicotinic effect. • Oxotremorine • It selectively stimulates muscarinic receptors in the striatum of the brain, producing parkinsonian-like symptoms. CHOLINOMIMETIC DRUGS 2. PARASYMPATHOMIMETIC ALKALOIDS AND THEIR SYNTHETIC COUNTERPARTS • Pilokarpin: • The M1 effect is greater. • Its most obvious effect is on the sweat glands. • It causes miosis and accommodation spasm in local application to the eye. • It causes the iridocorneal angle to open. • Increases drainage from the Schlemm channel. • Open-angle glaucoma, acute-narrow-angle glaucoma. • Alleviation of symptoms of salivary gland hypofunction in patients with severe xerostomia following radiation to the head and neck area, • Treatment of symptoms of dry mouth and eyes in patients with Sjogren's syndrome, CHOLINOMIMETIC DRUGS 2. PARASYMPATHOMIMETIC ALKALOIDS AND THEIR SYNTHETIC COUNTERPARTS • Sevmelin • It has a high affinity for M3 receptors in the lacrimal and salivary gland epithelium. • It has a sialogog effect. • Side effects are less than pilocarpine. • Arekolin: • It has an M1-mediated effect on learning and memory at CNS. • But the effect is short-lived. • Muscarin: • It is not used as a medicine. • It is derived from the fungus called Amanita muscaria. • Later, it was observed that it was found in higher proportions in different types of fungi (Inocybe and Clitocybe). CHOLINOMIMETIC DRUGS 2. ANTICHOLINESTERASE DRUGS • By inhibiting acetylcholinesterase at synapses and junctions, they cause acetylcholine to accumulate. Therefore: • In addition to muscarinic effects, they also produce nicotinic effects. • They stimulate the sympathetic and parasympathetic ganglia and skeletal muscles. CHOLINOMIMETIC DRUGS • Anticholinesterase Drug These drugs differTypes according to their mechanism of interaction with the active center of the enzyme and whether it is inhibited, reversible or irreversible. • Reversible inhibitors: • Carbamates are important. • Physiostigmine, neostigmine, pridostigmine. • They contain a quaternary amine group, except for the first one. • Physostigmine is an alkaloid in the tertiary amine structure. • They compete with acetylcholine against the active center of the enzyme. • Edrophonium is a drug whose effect lasts for a very short time (5-10 minutes) • It is used for the diagnosis of myasthenia gravis, differentiation of myasthenic and cholinergic crises). • There are also those that are used against head lice in the form of CHOLINOMIMETIC DRUGS Anticholinesterase Drug Types Irreversible inhibitors: • Organophosphates are important. • It is bound by a covalent bond and therefore the resumption of enzyme activity occurs through new enzyme synthesis, it takes weeks or months (Pralidoxime and similar drugs release the enzyme). • Some of the organophosphates are volatile and unstable compounds. • Stable derivatives that are not very volatile and do not break down quickly over time are agricultural warfare vehicles, malation, paration, etc. CHOLINOMIMETIC DRUGS Anticholinesterase Drug Types • The most toxic of the organophosphates are those used as chemical warfare poisons: • The so-called nerve gas agents are tabun, sarin and soman. CHOLINOMIMETIC DRUGS Pharmacological effects of anticholinesterases • Parasympathomimetic effects: • It is the same as parasympathomimetics, except for the cardiovascular system. • Blood pressure rises as the sympathetic ganglia is stimulated. • Stimulates skeletal muscles. When given in therapeutic doses, symptoms of muscle weakness, fatigue and paralysis disappear in patients with myasthenia. • CNS • Organophosphates and physostigmine pass the blood-brain barrier. They stimulate respiration and vasomotor center. Blood pressure rises. Most of the effects are blocked by atropine, as they are dominantly muscarinic . • Rivastigmine, donepezil, galantamine are reversible inhibitors. It is used in mild and moderate Alzheimer's disease. CHOLINOMIMETIC DRUGS Pharmacological effects of anticholinesterases • Neostigmine and other drugs containing the quaternary ammonium group do not affect the CNS because they cannot enter the brain. • Neostigmine is used in paralytic ileus and bladder atony. • Neostigmine, pyridostigmine, ambenonium, distigmine are used in patients with myasthenia gravis. CHOLINOMIMETIC DRUGS Side effects of parasympathomimetic drugs • They have common muscarinic side effects. • They can cause nausea, vomiting, abdominal pain, diarrhea, excessive sweating, hypersalivation, the need to urinate, blurred vision, sometimes bronchospasm. • All anticholinesterases cause fasciculations in skeletal muscles, and paralysis in excessive doses. CHOLINOMIMETIC DRUGS Clinical Pharmacology of Parasympathomimetic and Anticholinesterase Drugs Postoperative paralytic ileus and bladder atony Neurogenic bladder disorders Glaucoma (Pilocarpine is frequently used) To finish the action of neuromuscular blocking drugs of the competitive type • Myasthenia gravis • Alzheimer's disease treatment • • • • CHOLINOMIMETIC DRUGS Contraindications of Parasympathomimetic and Anticholinesterase Drugs • • • • • • • • Congestion in the gastrointestinal tract or urethra, Hyperthyroidism (atrial fibrillation), Asthma (crisis), Coronary heart disease, peptic ulcer, Severe postoperative shock, Circulatory disorder, Pregnancy Poisoning with organophosphate insecticides: They are widely used as pesticides Occupational, accident and suicide Absorptions through the skin, GIS, conjunctiva and lungs Maximum toxic effect inhalation>GIS>dermal In the liver, they are hydrolyzed by paraoxonases, and the resulting products are excreted in the urine • Sulfur-containing organophosphates such as paration and malation are inactive and become active after metabolism in the liver • • • • • Poisoning with organophosphate insecticides: • They block acetylcholinesterase and butyrylcholinesterase. • They cause phosphorylation of the hydroxyl group of the serine at the active site of acetylcholinesterase. • A new enzyme synthesis or enzyme reactivator is needed to end the effect. • Acetylcholinesterase is found at the neuromuscular junction and in erythrocytes. • ACh can not be degraded and there is an increase in the activity of cholinergic, muscarinic and nicotinic receptors. Poisoning with organophosphate insecticides: • Cholinergic crisis: • Symptoms of skeletal muscles: Fasciculation and involuntary movements and weakness in the eyelids, face, tongue, extremities (proximal) muscles, and skeletal muscle paralysis in the advanced period are seen 24-96 hours after the acute cholinergic crisis • CNS symptoms: Confusion, ataxia, speech dysphagi, convulsions, coma • Late-onset neuropathy: Fat-soluble phosphates (trichlorfan, trichloronate, mipofox, lepophos, metamidophos, triorthocrezil phosphates) • Begins within 2-5 weeks after symptoms of acute cholinergic crisis Poisoning with organophosphate insecticides: • Muscarinic Effects Miyozis Bradicardium Hypotension Bronkospazm Increased bronchial secretion, salivation, lacrimation, nasal secretion • Perspiration • Vomiting, diarrhoea • Urinary incontinence • • • • • • Nicotinic Effects • • • • • • • • Midriyazis Tachycardia Hypertension Twitches (Fasciculations) Muscle cramps Muscle weakness Respiratory paralyses Cause of death: respiratory paralysis • Poisoning with organophosphate insecticides: • Therapy: • Atropine enters the central nervous system, preventing muscarinic effects. • Enzyme reactators: pralidoxime, obidioxime (can not enter the CNS). • Carbamate insecticide poisoning: • Therapy: • Atropin