Cholinergic System Drugs PDF

Pharmacology of the Autonomic Nervous System: Cholinergic System Drugs Dr. Eman Milad Maddy Introduction The autonomic nervous system (ANS) is a branch of the peripheral nervous system (PNS) that regulates the function of the viscera. It innervates smooth muscle as well as glands an...

Pharmacology of the Autonomic Nervous System: Cholinergic System Drugs Dr. Eman Milad Maddy Introduction The autonomic nervous system (ANS) is a branch of the peripheral nervous system (PNS) that regulates the function of the viscera. It innervates smooth muscle as well as glands and is further divided into; the parasympathetic and sympathetic systems. The ANS has an essential role in controlling internal organ function, regulating heart rate, blood pressure, micturition, sweating, sexual function and gastrointestinal transit (digestion and defecation). Broadly speaking the two branches of the ANS can be thought of as opposing or antagonistic systems, with the sympathetic arm acting as the exciter (eliciting the “fight or flight” response) and the parasympathetic as the suppressor (eliciting the “rest and digest” response). 1 2 Parasympathetic nervous system The parasympathetic nervous system consists of many pathways that connect its craniosacral components with the peripheral tissues. Each parasympathetic pathway consists of two neurons, the presynaptic (preganglionic) and postsynaptic (postganglionic) neurons, which are connected by the axons of the presynaptic neurons. The presynaptic neurons of the parasympathetic system are located within the medulla oblongata and sacral spinal cord. They give off long axons (presynaptic fibers) that leave the CNS and travel towards the postsynaptic neurons. Once they reach them, the presynaptic fibers synapse with the bodies of the postsynaptic neurons. This synapse uses the acetylcholine as a neurotransmitter, which is why the parasympathetic pathways are referred to as the cholinergic pathways. The presynaptic neurons of the parasympathetic pathways are located within the two major parts of the central nervous system: The postsynaptic neurons are found within the parasympathetic ganglia, which typically lie near or within the target organs. After receiving the impulse from the presynaptic neuron, the postsynaptic neuron conveys the neural impulse further down its axon (postsynaptic fiber). The postsynaptic fibers are significantly shorter than the presynaptic ones, given that the postsynaptic neuronal bodies lie in the close proximity of their target organs. 3 What is acetylcholine (ACh)? Acetylcholine (ACh) is a neurotransmitter, a chemical that carries messages from your brain to your body through nerve cells. It’s an excitatory neurotransmitter. This means it “excites” the nerve cell and causes it to “fire off the message.” Acetylcholine gets its name from the two substances that it’s made from — an acetyl group (acetyl coenzyme A, which comes from the sugar molecule glucose) and the nutrient choline. Acetylcholine is involved in many important functions in your body. It plays a major role in voluntary muscle movement all over your body. Nerve cells stimulate muscle nerve cells, causing muscles to contract. It also plays an important role in brain nerve cells, in such processes as memory, thinking and learning. Acetylcholine synthesis An enzyme called choline acetyltransferase causes a reaction between choline and the acetyl group to create acetylcholine. It’s made at the end of nerve cells. 4 How does acetylcholine (ACh) work? Acetylcholine is stored at the end of nerve cells until it’s triggered to be released. Once released from the end of the nerve cell, it moves into a space called the synaptic cleft. The synaptic cleft is between the nerve cell from which acetylcholine was released (the presynaptic nerve cell) and the next nerve cell acetylcholine is going to (the postsynaptic nerve cell). Once acetylcholine moves across the synapse, it can bind to two types of receptors: nicotinic receptors and muscarinic receptors. There are two subtypes of nicotinic receptors and five types of muscarinic receptors. After binding to the receptors, the chemical message moves along to the next nerve cell and then the process repeats until the message arrives at its destination. Acetylcholine in the synapse is broken down by an enzyme called acetylcholinesterase into choline and acetate. These products are reabsorbed and recycled so they can be used again in transmitting another chemical message. 5 What does acetylcholine (ACh) do? When it binds to muscarinic receptors, it: Regulates heart contractions and blood pressure and decreases heart rate. Moves food through your intestine by contracting intestinal muscles and increasing stomach and intestine secretions. Causes glands to secrete substances such as tears, saliva, milk, sweat and digestive juices. Controls the release of urine. Contracts muscles that control near vision. Causes an erection. Acetylcholine Receptors There are two types of Ach receptors: nicotinic and muscarinic. They are named this way because the muscarinic receptors can get activated by a substance called muscarine (mushroom poison) but not by nicotine, while the nicotinic receptors can get activated by nicotine. Acetylcholine can activate both of these receptors. Although both are ligand-gated (Ach-gated), the nicotinic and muscarinic receptors differ in structure, location and signal transduction mechanisms. 6 Nicotinic receptors Nicotinic receptors are found on the neurons of the central and peripheral nervous systems, as well as on the muscle cells within the neuromuscular junctions. There are two types of nicotinic receptors, namely N1 and N2. The NM receptors are those found within the neuromuscular junctions, while the NN are found on the postganglionic neurons of the ANS. the N1 receptors are often called the muscle nicotinic receptors, and their function is to elicit voluntary muscle movement in the skeletal muscle. The function of N2 receptors is to transmit signals from the preganglionic to postganglionic nerves in both sympathetic and parasympathetic systems. By the type of signal transduction, the nicotinic receptors are ion-channel receptors, or ionotropic receptors. As such, upon the binding of Ach, the nicotinic receptors specifically induce the formation of an ion channel on the cell membrane of the effector cell (called ligand-gated ion channel), through which positively charged ions (cations) can enter into the cell. The influx of ions leads to the 7  depolarization of the cell membrane and generation of an action potential, which is observed as e.g. muscle contraction When it binds to nicotinic receptors, it: Allows skeletal muscle to contract. Causes the release of adrenaline and norepinephrine from your adrenal glands. Activates your sympathetic system with the release of norepinephrine. Both types of receptors are involved in memory, including long-term and working memory, memory formation and consolidation and retrieval. Within your brain, acetylcholine is also involved in motivation, arousal, attention, learning and promoting rapid eye movement (REM) sleep. Muscarinic receptors Muscarinic receptors. There are five types of them, termed M1, M2, M3, M4 and M5. M1 receptors are mostly found in the cerebral cortex, gastric, and salivary glands M2 receptors are located on the cell membranes of the smooth and cardiac muscle M3 are also found on the smooth muscle cells, but also on the gastric and salivary glands 8  M4 and M5 are found predominantly in the substantia nigra and hippocampus The type of signal transduction, the muscarinic receptors are G-protein coupled receptors (GPCRs) As such, they produce effects through second messenger system The response may be either stimulatory or inhibitory in respect to the cell’s function. In particular, the M1, M3 and M5 receptors are excitatory, meaning that their activation increases the activity of the cell. On the other hand, the M2 and M4 receptors are inhibitory, as their activation results in the inhibition of the target cell. 9 Muscles of iris & pupil: A-sphincter pupillae (circular Muscle) B- dilator pupillae (radial muscle) The sphinctor pupillae →receive only parasympathetic innervations (M3) leading to miosis →iris stretched →filtration angle widens→↑drainage of aqueous humor →↓IOP The dilator papillae → receive only sympathetic innervations(α1)→ contraction of muscle → active mydriasis Accommodation The accommodation reflex is the visual response for focusing on near objects. 10  The ciliary ms receive only parasympathethtic innervations →contraction of ciliary ms therefore suspensory ligament become loose → convex lens fixing eye on near vision → accommodation cycloplegia Parasymptholytic →ciliary ms relaxed the ligament get taught & lens become less convex paralysis of accommodation (cycloplegia) 11 Effects of Drugs on Cholinergic Transmission 12 Muscarinic agonists (parasympathomimetics) muscarinic agonists divide into two groups: direct agonist and indirect agonist. Direct agonists resist acetylcholinesterase, thus preventing its breakdown. Indirect agonists work by inhibiting the acetylcholinesterase enzyme preventing the degradation of acetylcholine. Direct and indirect agonists both increase acetylcholine concentration in the synapse, prolonging acetylcholine effects on the receptor. Direct Agonists Bethanechol Choline esters indications include postoperative ileus, neurogenic ileus, and urinary retention. Bethanechol increases the smooth muscle tone of the gastrointestinal tract to promote motility and restores peristalsis in the absence of obstruction. Bethanechol also increases the tone of the detrusor muscle to increase bladder emptying. Carbachol Choline esters is indicated to treat open-angle glaucoma, acute angle-closure glaucoma, and increased intraocular pressure. Carbachol contracts the ciliary body muscle and opens the trabecular meshwork. Opening the meshwork increases aqueous humor outflow from the eye to reduce intraocular pressure. 13 Pilocarpine Cholinomimic Alkaloids is indicated for open-angle glaucoma, acute angle-closure glaucoma, and ocular hypertension. When given topically, pilocarpine contracts the ciliary body muscle and opens the trabecular meshwork to increase the outflow of aqueous humor. Oral pilocarpine can be used to increase secretion of the salivary glands to treat dry mouth in patients with Sjogren's syndrome or salivary gland dysfunction. Methacholine Choline esters is most commonly used to diagnose asthma or bronchial hyperactivity. Methacholine stimulates the muscarinic receptor in the airway when inhaled and induces bronchoconstriction, and increases tracheobronchial secretions. The lower the dose it takes for methacholine to induce bronchoconstriction, the more reactive the bronchial airway is. 14 Indirect Agonists Anticholinesterases drugs Cholinesterase inhibitors (also called acetylcholinesterase inhibitors) are a group of medicines that block the normal breakdown of acetylcholine. Cholinesterase inhibitors block the action of the enzyme cholinesterase, which is responsible for breaking down acetylcholine. This increases levels of acetylcholine in the synaptic cleft (the space between two nerve endings). Anticholinesterases drugs Classification: 1. Reversible anticholinesterases 2. Irreversible anticholinesterases Reversible Acetylcholinesterase Inhibitors Reversible AChE inhibitors play an important role in pharmacological manipulation of the enzyme activity. These inhibitors include compounds with different functional groups (carbamate, quaternary or tertiary ammonium group), and have been applied in the diagnostic and/or treatment of various diseases such as: myasthenia gravis, AD, post-operative ileus, bladder distention, glaucoma, as well as antidote to anticholinergic overdose. Edrophonium used in diagnosis of myasthenia gravis because of it has short duration of action (5- 15min.) Neostigmine used in treatment of myasthenia gravis, paralytic ileus Reverse neuromuscular block (1- 2hr.) Pyridostigmine used in treatment of myasthenia gravis, better absorbed than neostigmine and longer duration of action (3- 6hr.) Ambenonium used in treatment of myasthenia gravis Physostigmine used in treatment of glucoma myasthenia gravis a chronic autoimmune disorder in which antibodies destroy the communication between nerves and muscle, resulting in weakness of the skeletal muscles. Myasthenia gravis affects the voluntary muscles of the body, especially those that control the eyes, mouth, throat and limbs. 15  Myasthenia gravis is a chronic (long-lasting) neuromuscular condition (it affects the junction between your nerves and muscles). There isn’t a cure, but effective treatment can help you manage your symptoms and function well. Tacrine Galantamine, donepezil, and rivastigmine are indicated for Alzheimer disease. The medications help with memory loss as well as decrease plaque build-up. Galantamine, donepezil, and rivastigmine do not cure Alzheimer disease and can only delay the progression of the disease. 16  Irreversible anticholinesterases(Organophosphates Parathion Malathion Both used as insecticides Echothiophat Used in treatment of glucoma All has long duration of action Effects of Muscarinic Agonists Muscarinic agonists are agents that activate the muscarinic acetylcholine receptor. There are five different muscarinic receptors labeled M1-M5. Muscarinic agonists are parasympathomimetics, and their mechanism of action is different depending on which receptor is activated. The M1, M3, and M5 are transmembrane receptors that couple to a Gq protein. The Gq protein upregulates phospholipase C (PLC). PLC cleaves phosphatidylinositol 4,5- bisphosphate (PIP2) into 1,2- diacylglycerol (DAG) and inositol 1,4,5-triphosphate (IP3). DAG activates protein kinase C, which activates downstream protein and causes calcium influx. IP3 causes the sarcoplasmic reticulum to release stored calcium. Increased intracellular calcium causes smooth muscle contraction and exocrine glandular secretions. The M2 and M4 receptors are Gi receptor, which inhibits adenylyl cyclase. Inhibition of adenylyl cyclase decreases cyclic adenosine 3’,5’-monophosphate (cAMP) production from ATP. The decrease in cAMP concentration subsequently decreases the activation of protein kinase A. The clinically significant muscarinic receptors are the M1, M2, and M3 receptors. The M1 muscarinic receptor is clinically significant in the central nervous system, and it influences neurologic functions. Muscarinic agonists play an important role in the treatment of Alzheimer disease(AD). The M2 muscarinic receptor is the predominant receptor found in the sinoatrial and atrioventricular nodal cells of the heart. The downstream effect, once the M2 receptor is activated, allows potassium efflux. Potassium efflux results in hyperpolarization and reduction of the action potential 17  duration in the nodal cells. Therefore, the activation of the M2 receptor in the heart causes decreased heart rate and atrial contractility. The M3 muscarinic receptor is clinically significant in the intestine's smooth muscle, bladder, airway, eye, exocrine glands, and blood vessels. Smooth muscle of the intestine, bladder, airway, and the eye. contracts when calcium concentration increase within the cell. Calcium binds with calmodulin to form a complex that can now activate the enzyme myosin light chain kinase. Myosin light chain kinase phosphorylates myosin resulting in contraction. Muscarinic agonists' action on blood vessels results in vasodilatation rather than vasoconstriction. Calcium in the endothelial cells activates nitric oxide synthase, converting L-arginine into nitric oxide. Nitric oxide diffuses into the underlying smooth muscle causing an increase in cGMP. cGMP activates myosin light chain phosphatase resulting in smooth muscle relaxation. When the endothelium is damaged, it does not produce nitric oxide and acetylcholine results in smooth muscle contraction Administration Bethanechol is administered orally on an empty stomach two to four times a day to prevent stomach upset and nausea. Carbachol is commonly administered topically ocularly. Pilocarpine is administered topically, ocularly, or orally. Methacholine is administered through inhalation. Neostigmine is administered through intramuscular, intravenous, and subcutaneous injection. Physostigmine is administered intravenously. Galantamine, donepezil, and rivastigmine are administered orally. Edrophonium is administered through intramuscular injection. Pyridostigmine is administered orally. Adverse Effects Adverse effects of muscarinic agonists can be memorized using the mnemonic "DUMBBELSS." Diarrhea Urination Miosis 18  Bronchospasm Bradycardia Excitation of skeletal muscle and CNS Lacrimation Sweating Salivation Contraindications Asthma or Chronic Obstructive Pulmonary Disease (COPD) Peptic Ulcer Coronary Vascular Disease Hyperthyroidism Toxicity Organophosphate agents are used for insecticides and work by irreversibly inhibiting acetylcholine esterase. Excess acetylcholine act on muscarinic and nicotinic receptors and present with signs of acetylcholine toxicity. Toxicity characteristically demonstrates overactive parasympathetic stimulation and presents with symptoms of diarrhea, urination, miosis, bronchospasm, bradycardia, excitation of skeletal muscle and CNS, lacrimation, sweating, and salivation. Cholinergic crisis, sometimes known by the mnemonic "SLUDGE syndrome" (Salivation, Lacrimation, Urination, Defecation, Gastrointestinal distress and Emesis) Organophosphate poisoning antidotes are atropine and pralidoxime. Atropine is a muscarinic antagonist, and pralidoxime can regenerate acetylcholinesterase What medical conditions are associated with low levels of acetylcholine (ACh)? Low levels (deficiency) of acetylcholine play an important role in several diseases, the most common being: Alzheimer’s disease. People who have Alzheimer’s disease don’t have enough acetylcholine in their brains. Lambert-Eaton myasthenic syndrome. This disorder is caused by a reduction in the release of acetylcholine from nerve cells. 19  Myasthenia gravis. This is an autoimmune disorder in which there’s a rapid weakening of skeletal muscles after repeated use. Some of the body’s antibodies interfere with acetylcholine receptors at the neuromuscular junction. 20 Cholinergic Antagonists (Parasympatholytic) 21 Musscarinic Antagonists(Parasympatholytics) atropine belladonna alkaloids Hyoscine glycopyrrolate Propantheline selective action on GIT Antispamodic Atropine Homatropine passive mydrsis, cycloplegia cyclopentolate used in ophthalmology examination benztropine Orphenadrine used in parkinsonism benzhexol ipratropium tiotropium used in bronchial asthma and COPD oxybutynin Tolterodine used in urinary incontinence Hyoscine used in motion sickness, preanethetic medication , it produce amnesia and drowsiness Pirenzepine and Telenzepine used in treatment of peptic ulcer Antagonists at M1 receptors Atropine used in treatment of sinus bradycardia Mechanism of Action Muscarinic receptors are predominately present on glandular cells, smooth muscle cells, and cardiac muscle cells. The parasympathetic nervous system releases ACh, which binds to and activates muscarinic receptors. Muscarinic receptor antagonists function by competitively blocking the binding of ACh to muscarinic receptors resulting in an anticholinergic response. 22  Muscarinic receptor antagonists function by acting as competitive inhibitors on the numerous muscarinic receptors. There are five different muscarinic receptors: M1, M2, M3, M4, and M5. The M1, M4, and M5 receptors are in the central nervous system (CNS), and the action of these agents on these receptors can manifest as cognitive impairment. The M2 receptors are found in cardiac tissue and are predominately in the atrioventricular (AV) and sinoatrial (SA) nodal cells, resulting in decreased heart rate and reduced atrial contractility. Therefore, muscarinic receptor antagonist binding to M2 receptors leads to an increase in heart rate. M3 receptors are on the smooth muscle of the gastrointestinal tract, urinary tract, airway, and blood vessels. Muscarinic receptor antagonist binding to M3 receptors reduces intestinal peristalsis and bladder contraction, reduces salivary and gastric secretions, reduces bronchial secretions, and increases bronchodilation Adverse Effects adverse effects of confusion and disorientation. The action of muscarinic receptor antagonists on M2 receptors in cardiac tissue leads to tachycardia. Muscarinic receptor antagonists acting on M3 receptors in exocrine glands can lead to dry mouth, dry skin, and sore throat. Moreover, muscarinic receptor antagonists act on receptors in the eyes resulting in mydriasis and photophobia. Muscarinic receptor antagonists also cause decreased smooth muscle tone, resulting in constipation, ileus, urinary retention, and gastroesophageal reflux Contraindications myocardial infarction hyperthyroidism paralytic ileus benign prostatic hyperplasia urinary retention narrow-angle glaucoma myasthenia gravis. 23  Toxicity Clinical features of muscarinic receptor antagonist toxicity include dry mouth, blurry vision, hyperthermia, tachycardia, mydriasis, delirium, and hallucinations. Physostigmine, an acetylcholinesterase inhibitor, is used as the antidote for muscarinic antagonist toxicity. Ganglion Stimulating Drugs Nicotine, Lobeline. These drugs act only on nicotinic receptors, and cause generalized stimulation of autonomic ganglia. They have no clinical use, used only experimentally. Ganglion Blocking Drugs Trimetaphan Mecamylamine, Hexomethonium Act by competitive inhibition of Ach receptors, at postsynaptic membrane. These drugs were used as antihypertensive but now only Trimetaphan is used During general anesthesia to produce controlled hypotension to decrease bleeding during surgery, Also used in emergency in case of malignant hypertension Side Effects of ganglion Blocking Drugs Hypotension results mainly from block of sympathetic ganglia causes arterial vasodilatation. Moderate Tachycardia due to parasympathetic inhibition at S A node Constipation due to inhibition of parasympathetic effects Urinary retention Sexual function impaired. Neuromuscular Blocking Drugs (Muscle Relaxants) They are classifed in to two groups: 1. Non depolarizing blocking drugs. 2. Depolarizing blocking drugs. Non depolarizing blocking drugs. Curare Metocurare Gallamine Pancuronium Rocuronium 24  Vecuonium Atracurium Hivacurium Cisatracurium (most common used clinically) They act by competitive block of Ach receptors at post junctional membrane They do not cross BBB, and also do not cross placenta All are quarterly ammonium compounds. Their effects are mainly due to motor paralysis The first muscle affected are small muscles of eyes, then larger muscle of the body. The last muscles affected and first to recover are respiratory muscles. Side Effects: Hypotension and broncospasm due to ganglion block and histamine release specify with Tubacurarine. Less common with other drugs. Depolarizing blocking drugs. Succinylcholine (Suxamethonium) (used clinically) Decamethoium (agonists at Ach receptors) Mechanism of action Phase I Block (Depolarizing) First these drugs depolarize membranes by opening Na-K channels leading to repetitive excitation which might lead to muscle fasciculation. This phase followed by block of neuromuscular transmission and flaccid paralysis. Phase II Block (Desensitization) This phase not well understood Continues exposure to Succinylcholine will lead to repolarization of membrane and this is thought may lead to receptors desensitization. Side Effects of Depolarizing Drugs: 1. Bradycarbia 2. Hyperkalemia 3. Malignant Hyperthermia 4. Muscle pain 5. Prolonged paralysis 6. Increased intraocular pressure Malignant Hyperthermia 25  This is congenital (autosomal dominant) condition leads to muscle spasm and increase in body temperature ,this case occur with exposure to cretin drugs such as Succinylcholine and Halothane. This condition causes excessive release of Ca from sarcoplasmic reticulum. Treatment with Dantrolene (dirct acting muscle relaxant) this drug inhibit ca release from sarcoplsmic reticulum. Clinical use of Muscle Relaxants: The main use of neuromuscular blocking drugs is in surgical anesthesia to obtain muscular relaxation such as; Abdominal wall relaxation to facilitate surgical operation Muscle relaxation during orthopedic surgery. To prevent trauma during electroshock therapy in psychiatric diseases Best of luck 26