6-parasympathomimetic-and-parasympatholytic-drugs-2.pdf

# Introduction to parasympathomimetic and parasympatholytic drugs This section introduces drugs that either mimic or block the action of acetylcholine in the parasympathetic nervous system, exploring cholinergic neurotransmission and receptor types [2](#page=2). ### 1.1 The parasympathetic nervous system and acetylcholine The parasympathetic nervous system utilizes acetylcholine (ACh) as its primary neurotransmitter [2](#page=2). * **Parasympathomimetic drugs** enhance the effects of ACh, essentially mimicking its actions [2](#page=2). * **Parasympatholytic drugs** reduce or block the effects of ACh, preventing it from acting on its receptors [2](#page=2). ### 1.2 Neurotransmission in cholinergic neurons The process of neurotransmission in cholinergic neurons involves several key steps [3](#page=3): 1. **Synthesis of ACh:** Acetylcholine is synthesized [3](#page=3). 2. **Storage:** ACh is stored in vesicles [3](#page=3). 3. **Release:** ACh is released into the synaptic cleft [3](#page=3). 4. **Interaction with receptors:** ACh binds to its specific receptors on the postsynaptic membrane [3](#page=3). 5. **ACh breakdown:** ACh is broken down into choline and acetate, typically by the enzyme acetylcholinesterase [3](#page=3). 6. **Choline reuptake:** Choline is transported back into the presynaptic neuron for reuse in ACh synthesis [3](#page=3). ### 1.3 Cholinergic receptors Acetylcholine interacts with two main types of receptors: muscarinic and nicotinic receptors [4](#page=4). #### 1.3.1 Muscarinic receptors * Muscarinic receptors are G protein-coupled receptors (GPCRs) [4](#page=4). * There are five subtypes of muscarinic receptors, categorized by their G protein coupling: * **M1, M3, M5 receptors** are coupled to Gq proteins. Activation of Gq typically leads to activation of phospholipase C, increasing intracellular calcium levels [4](#page=4). * **M2, M4 receptors** are coupled to Gi proteins. Activation of Gi typically inhibits adenylyl cyclase, decreasing intracellular cyclic AMP levels, and can also activate potassium channels [4](#page=4). #### 1.3.2 Nicotinic receptors * Nicotinic receptors are ligand-gated ion channels [4](#page=4). * When ACh binds to nicotinic receptors, it causes a conformational change that opens an ion channel, allowing the passage of ions (primarily sodium and potassium) across the membrane, leading to depolarization. ### 1.4 Effects of acetylcholine Acetylcholine exerts a wide range of physiological effects throughout the body. These effects are mediated by its binding to muscarinic and nicotinic receptors at various target sites [5](#page=5). **General effects of ACh include:** [5](#page=5). * **Cardiovascular system:** Reduced heart rate and cardiac output, and a decrease in blood pressure (BP) [5](#page=5). * **Gastrointestinal system:** Increased salivary secretion and gastric acid secretion. Also, increased intestinal secretions and motility, promoting digestion [5](#page=5). * **Respiratory system:** Increased bronchial secretions and bronchoconstriction (narrowing of the airways) [5](#page=5). * **Urinary system:** Contraction of the bladder detrusor muscle and relaxation of the internal sphincter, facilitating urination [5](#page=5). * **Ocular effects:** Miosis (pupillary constriction) and focusing for near vision, achieved through the contraction of circular and ciliary muscles in the eye [5](#page=5). > **Tip:** At high doses, cholinergic agonists can cause accommodation spasm, which is a sustained contraction of the ciliary muscle leading to blurred vision for distant objects [5](#page=5). **Clinical applications:** * **Methacholine** is used in the diagnosis of asthma [5](#page=5). * In ophthalmic surgery, an **acetylcholine solution** can be applied locally to induce rapid and controlled miosis [5](#page=5). --- # Cholinomimetic drugs and their mechanisms Cholinomimetic drugs mimic the action of acetylcholine (ACh) by directly stimulating cholinergic receptors or indirectly by inhibiting acetylcholinesterase (AChE). These drugs are broadly classified into parasympathomimetic drugs (muscarinic agonists) and acetylcholinesterase inhibitors [6](#page=6) [7](#page=7). ### 1.1 Parasympathomimetic drugs (muscarinic agonists) Parasympathomimetic drugs directly bind to and stimulate cholinergic receptors, mimicking the effects of ACh. They are further divided into synthetic esters of ACh and choline, and natural alkaloids. An ideal cholinergic agent would be resistant to AChE and selective for muscarinic receptors [7](#page=7). #### 1.1.1 Synthetic esters * **Bethanechol:** * Structurally similar to ACh but resistant to AChE, though it is degraded by other esterases [8](#page=8). * Exhibits strong muscarinic effects without nicotinic activity [8](#page=8). * Primarily acts on gastrointestinal (GI) and bladder smooth muscles [8](#page=8). * **Clinical uses:** Postoperative atonic bladder, neurogenic atony, and megacolon [8](#page=8). * **Side effects:** Sweating, salivation, flushing, hypotension (with reflex tachycardia), nausea, abdominal pain, diarrhea, and bronchospasm [8](#page=8). * **Carbachol (carbamylcholine):** * A carbamic acid ester of ACh with both muscarinic and nicotinic effects [9](#page=9). * Has marked effects on the cardiovascular system (CVS) and GI tract, including ganglion-stimulating effects and adrenaline release from the adrenal medulla [9](#page=9). * Topical application to the eyes causes accommodation spasm (spasticity) [9](#page=9). * **Clinical uses:** Rarely used due to long duration of action and low selectivity, but can be used to induce myosis in ocular surgery and lower intraocular pressure in glaucoma [9](#page=9). * **Side effects:** When used ophthalmically, systemic side effects are absent [9](#page=9). #### 1.1.2 Natural alkaloids * **Pilocarpine:** * A natural alkaloid resistant to AChE with only muscarinic effects, though less potent than other drugs [10](#page=10). * It can cross into the central nervous system (CNS) [10](#page=10). * A potent stimulant of secretions, including sweat, saliva, and tears [10](#page=10). * **Clinical uses:** Glaucoma emergencies (primary drug), atropine-induced mydriasis, dry mouth (xerostomia) due to radiotherapy, and dry eye caused by Sjögren's syndrome [10](#page=10). * **Side effects:** Blurred vision, night blindness, pain in the eyebrow area, hypersalivation, and increased sweating. Atropine is used to treat pilocarpine poisoning [10](#page=10). #### 1.1.3 Other synthetic and natural drugs * **Oxotremorine:** A synthetic drug that induces experimental Parkinson's disease (PD) models through its muscarinic effects [11](#page=11). * **Arecoline:** A natural alkaloid that increases attention and energy, and can produce euphoria and relaxation [11](#page=11). * **Aceclidine:** A synthetic drug similar to arecoline [11](#page=11). * **Muscarine:** An alkaloid found in some fungi, possessing no pharmaceutical value [11](#page=11). ### 1.2 Acetylcholinesterase inhibitors Acetylcholinesterase (AChE) inhibitors indirectly increase cholinergic activity by preventing the breakdown of ACh. This leads to increased levels of ACh at the synapse, stimulating both muscarinic and nicotinic receptors in the brain, neuromuscular junction (NMJ), adrenal medulla, and ganglia. They are classified as reversible and irreversible inhibitors. Reversible inhibitors are used therapeutically, while many irreversible inhibitors are highly toxic agents like war gases and pesticides (with the exception of ecothiophate) [12](#page=12). #### 1.2.1 Reversible acetylcholinesterase inhibitors * **Edrophonium:** * A short-acting AChE inhibitor rapidly excreted by the kidneys, with a duration of action of 10-20 minutes [13](#page=13). * Primarily exerts peripheral effects [13](#page=13). * **Clinical uses:** Diagnosis of myasthenia gravis, distinguishing between a cholinergic crisis and a myasthenic crisis, and terminating the effects of non-depolarizing neuromuscular blocking drugs (NMBs) [13](#page=13). * **Physostigmine:** * A natural alkaloid with a moderate duration of action (0.5-2 hours) [14](#page=14). * It can pass into the CNS [14](#page=14). * Serves as an antidote for atropine poisoning and can reverse the effects of NMB drugs [14](#page=14). * **Side effects:** Convulsions, bradycardia, and spastic paralysis at the NMJ in high doses [14](#page=14). * **Neostigmine:** * A synthetic drug poorly absorbed from the GI tract and unable to cross the blood-brain barrier due to its polar structure [15](#page=15). * Has a moderate duration of action (30 minutes to 2 hours) [15](#page=15). * Reverses the effects of NMB drugs and is more potent than physostigmine in this regard. It is not used for atropine poisoning [15](#page=15). * **Clinical uses:** Myasthenia gravis, increasing GI and bladder motility, and reversing the effects of NMBs [15](#page=15). * **Side effects:** Salivation, flushing, hypotension, nausea, abdominal pain, diarrhea, and bronchospasm [15](#page=15). * **Other agents for myasthenia gravis:** Distigmine, pyridostigmine, and ambenonium are used for treating myasthenia gravis and share similar side effects to neostigmine. Demecarium is used for glaucoma treatment [16](#page=16). * **Agents for Alzheimer's disease:** Cholinesterase inhibitors that act centrally are used to treat Alzheimer's disease (AD), where cholinergic activity is reduced. These include tacrine, donepezil, rivastigmine, and galantamine. Their general side effects result from increased cholinergic activity [17](#page=17). #### 1.2.2 Irreversible acetylcholinesterase inhibitors * **Synthetic organophosphate compounds:** * These compounds bind covalently to AChE enzymes, necessitating the synthesis of new enzymes for restoration of function [18](#page=18). * They are highly toxic [18](#page=18). * Examples include parathion and malathion (insecticides), and tabun, sarin, and soman (war gases) [18](#page=18). * **Antidotes:** Atropine is administered for poisoning. Pralidoxime and obidoxime can reactivate the enzyme if given within the first few hours of exposure. Diazepam is used to prevent convulsions [18](#page=18). * **Ecothiophate:** * An irreversible cholinesterase inhibitor available only in topical ophthalmic preparations for treating open-angle glaucoma by facilitating aqueous outflow [19](#page=19). * It is rarely used due to the risk of cataracts and severe side effects [19](#page=19). --- # Parasympatholytic drugs and related agents This section details drugs that antagonize acetylcholine's effects, focusing on parasympatholytics, ganglion blockers, and neuromuscular blockers. ### 3.1 Parasympatholytic drugs Parasympatholytic drugs, also known as antimuscarinic agents, antagonize the effects of acetylcholine (ACh) and other agonist drugs by binding to muscarinic receptors. They do not inhibit the parasympathetic system but rather suppress its effects, allowing the sympathetic system to dominate. These drugs have no effect on nicotinic receptors. Certain antihistamines, antidepressants, and neuroleptics also possess anticholinergic effects [21](#page=21) [22](#page=22). #### 3.1.1 Atropine Atropine is a natural alkaloid, with l-hyoscyamine being its active isomer. It is a non-selective muscarinic receptor antagonist with both central and peripheral effects. Its duration of action (DOA) is up to 4 hours, but topical application to the eye can last for days. Atropine is readily absorbed, metabolized in the liver, and excreted by the kidneys. Bronchial tissue, the heart, sweat glands, and salivary glands are most sensitive to its effects, while stomach parietal tissue is less sensitive [23](#page=23). > **Mnemonic for Atropine Effects:** Red as a beet, dry as a bone, blind as a bat, mad as a hatter, and hot as a hare [24](#page=24). ##### 3.1.1.1 Effects of atropine * **Eye:** Causes mydriasis (pupil dilation), unresponsiveness to light, and cycloplegia (paralysis of accommodation). It increases intraocular pressure in patients with closed-angle glaucoma [25](#page=25). * **Gastrointestinal System (GIS):** Exhibits a spasmolytic effect, making it one of the most potent agents for this purpose (along with scopolamine). It reduces gastric motility but does not affect acid secretion [25](#page=25). * **Cardiovascular System (CVS):** Causes tachycardia due to blockade of M2 receptors [25](#page=25). * **Secretions:** Decreases saliva and tear secretion, and reduces sweating, which can lead to an increase in body temperature [25](#page=25). ##### 3.1.1.2 Clinical uses of atropine * As a mydriatic agent, although cyclopentolate and tropicamide are now preferred [26](#page=26). * As an antispasmodic in the gastrointestinal tract [26](#page=26). * For the treatment of bradycardia [26](#page=26). * As preanesthetic medication, though glycopyrrolate is now commonly used [26](#page=26). * As an antidote for cholinergic agonists, such as organophosphates and physostigmine [26](#page=26). ##### 3.1.1.3 Side effects of atropine Common side effects include dry mouth, blurred vision, a feeling of sand in the eye, tachycardia, urinary retention, constipation, delirium, and in severe cases, respiratory-circulatory collapse and death [26](#page=26). ##### 3.1.1.4 Atropine poisoning The initial symptoms of atropine poisoning are dry mouth and skin, followed by tachycardia and mydriasis. Other symptoms include photophobia, sudden onset of near vision loss (due to cycloplegia), difficulty urinating and defecating, redness of the skin, hyperthermia, convulsions, delirium, and potentially respiratory paralysis. Poisoning can be diagnosed by a subcutaneous injection of methacholine, which is also used in asthma and COPD methacholine challenges. The antidote for atropine poisoning is physostigmine [27](#page=27). #### 3.1.2 Scopolamine Scopolamine, also known as hyoscine or "devil's breath," is another natural alkaloid. It shares peripheral effects similar to atropine but exhibits more pronounced central nervous system (CNS) effects. Its duration of action is longer than atropine. Scopolamine can cause sedation and euphoria, leading to abuse. It also impairs memory functions and is used to create experimental dementia models. Its side effects are comparable to those of atropine [28](#page=28). ##### 3.1.2.1 Clinical uses of scopolamine * Primary treatment of motion sickness [28](#page=28). * Management of postoperative nausea and vomiting (NV) [28](#page=28). * Hyoscine-N-butyl bromide, a derivative of scopolamine, is used to treat gastrointestinal spasms [28](#page=28). #### 3.1.3 Other parasympatholytic agents A variety of other muscarinic antagonists exist, categorized by their pharmacokinetic properties and routes of administration. ##### 3.1.3.1 Inhaled muscarinic antagonists These include aclidinium, umeclidinium, glycopyrrolate, ipratropium, and tiotropium. Ipratropium is a short-acting muscarinic antagonist (SAMA), while the others are long-acting muscarinic antagonists (LAMA). All are administered via inhalation, do not enter the systemic circulation, and have no CNS effects [29](#page=29). * **Clinical uses:** Primarily for Chronic Obstructive Pulmonary Disease (COPD) and asthma [29](#page=29). ##### 3.1.3.2 Ophthalmic muscarinic antagonists Tropicamide and cyclopentolate are used in ophthalmology. They induce mydriasis and cycloplegia when administered as ophthalmic solutions. Their duration of action is shorter than atropine: tropicamide produces mydriasis for approximately 6 hours, while cyclopentolate lasts for about 24 hours [30](#page=30). ##### 3.1.3.3 Central acting antimuscarinics Benztropine and trihexyphenidyl primarily exert their effects centrally [31](#page=31). * **Clinical uses:** Symptomatic treatment of Parkinson's disease (PD), particularly for symptoms arising from increased cholinergic activity. They are also used to treat extrapyramidal side effects (EPS) caused by antipsychotic drugs [31](#page=31). ##### 3.1.3.4 Agents for overactive bladder This group includes oxybutynin, darifenacin, solifenacin, trospium, fesoterodine, and tolterodine. These drugs act similarly to atropine and are taken orally [32](#page=32). * **Clinical uses:** Treatment of overactive bladder and urinary incontinence. Oxybutynin is also employed in the management of neurogenic bladder [32](#page=32). * **Side effects:** Common side effects include dry mouth, constipation, and blurred vision [32](#page=32). ### 3.2 Ganglion blockers Ganglion blockers are a class of drugs that suppress activity in both the sympathetic and parasympathetic nervous systems by blocking nicotinic receptors in the autonomic ganglia. They were historically used for hypertensive crises but have no significant clinical importance today. Examples include hexamethonium, mecamylamine, and trimethaphan [31](#page=31) [33](#page=33). #### 3.2.1 Effects of ganglion blockers * Hypotension [33](#page=33). * Tachycardia [33](#page=33). * Difficulty urinating and decreased gastrointestinal motility [33](#page=33). * Decreased secretions [33](#page=33). * Mydriasis and cycloplegia [33](#page=33). * Difficulties with erection and ejaculation [33](#page=33). #### 3.2.2 Nicotine Nicotine initially stimulates autonomic ganglia and, at higher doses, can block them. Its therapeutic use is confined to smoking cessation treatments. Nicotine increases norepinephrine (NE) release, leading to central excitation, peripheral vasoconstriction, and tachycardia. It also increases gastrointestinal movements [34](#page=34). ### 3.3 Neuromuscular blockers (NMBs) Neuromuscular blockers are unrelated to the autonomic nervous system. They act by blocking nicotinic receptors located at the neuromuscular junction (NMJ), which are responsible for mediating striated muscle contraction. By blocking these receptors, NMBs facilitate surgical operations and endotracheal intubation by providing muscle relaxation. The effects of NMBs can be reversed with agents like neostigmine. High doses of cholinesterase inhibitors can potentially induce a depolarizing block due to excessive acetylcholine accumulation [35](#page=35). --- # Clinical applications and contraindications This topic outlines contraindications for parasympathomimetic drugs and reviews their clinical applications, including treatments for postoperative bladder atony and asthma, as well as atropine poisoning, while also detailing acetylcholine effects that atropine cannot antagonize. ### 4.1 Contraindications for parasympathomimetic drugs Parasympathomimetic drugs, which mimic the effects of acetylcholine, have several critical contraindications that must be considered to avoid exacerbating existing conditions or causing harm. These contraindications include [20](#page=20): * **Asthma:** Stimulating the parasympathetic nervous system can lead to bronchoconstriction, which is dangerous for individuals with asthma [20](#page=20). * **Coronary insufficiency:** Parasympathomimetics can cause bradycardia and vasodilation, potentially reducing coronary blood flow and worsening coronary insufficiency [20](#page=20). * **Mechanical obstruction in the GI tract and bladder:** These drugs increase smooth muscle motility. In cases of mechanical obstruction in the gastrointestinal (GI) tract or bladder, this increased motility can worsen the obstruction and lead to severe complications [20](#page=20). * **Peptic ulcer:** Increased GI motility and secretions stimulated by parasympathomimetics can exacerbate peptic ulcers [20](#page=20). * **Parkinson's disease:** Some parasympathomimetics can increase cholinergic activity, potentially worsening symptoms in patients with Parkinson's disease [20](#page=20). * **Pregnancy:** The use of parasympathomimetics during pregnancy is generally contraindicated due to potential risks to the fetus [20](#page=20). > **Tip:** Always remember to review the patient's medical history for any of these conditions before administering parasympathomimetic drugs. ### 4.2 Clinical applications of parasympathomimetics Parasympathomimetic drugs have specific therapeutic uses in medicine. #### 4.2.1 Treatment for postoperative bladder atony Postoperative bladder atony, a condition where the bladder fails to contract effectively after surgery, can be treated with certain parasympathomimetics. Betanechol is a common choice for this indication because it stimulates muscarinic receptors, promoting bladder contraction and aiding in urine voiding [37](#page=37). > **Example:** A patient recovering from abdominal surgery experiences difficulty urinating due to a hypotonic bladder. Betanechol may be prescribed to help the bladder muscles contract and facilitate urination. #### 4.2.2 Asthma treatment While many parasympathomimetics are contraindicated in asthma, certain related compounds or drugs used in specific contexts can be relevant. However, direct stimulation of parasympathetic activity leading to bronchoconstriction is a concern. Vilanterol, while not a direct parasympathomimetic, is a long-acting beta-agonist used in asthma treatment. The question implies a scenario where a drug is used *in asthma treatment*, and among the options, vilanterol fits this clinical application [39](#page=39). #### 4.2.3 Atropine poisoning treatment Physostigmine, an acetylcholinesterase inhibitor, is a key drug used in the treatment of atropine poisoning. Atropine is an anticholinergic drug that blocks muscarinic receptors. Physostigmine increases acetylcholine levels in the synaptic cleft, which can overcome the effects of atropine, particularly central nervous system (CNS) effects like delirium and coma, by restoring cholinergic activity [39](#page=39). ### 4.3 Effects of acetylcholine that atropine cannot antagonize Atropine is a competitive antagonist of acetylcholine at muscarinic receptors. However, it cannot antagonize all effects of acetylcholine. Specifically, atropine cannot antagonize the effects of acetylcholine at nicotinic receptors. * **Muscle spasms:** Acetylcholine acts on nicotinic receptors at the neuromuscular junction to cause muscle contraction. Atropine does not block these nicotinic receptors, and therefore cannot antagonize acetylcholine-induced muscle spasms [38](#page=38). Atropine *can* antagonize: * Bronchoconstriction induced by parasympathetic stimulation [38](#page=38). * GI and bladder spasm caused by parasympathetic stimulation [38](#page=38). * Hypersalivation resulting from increased parasympathetic activity [38](#page=38). * Bradycardia mediated by the vagus nerve [38](#page=38). > **Tip:** Understanding the difference between muscarinic and nicotinic receptor effects is crucial for predicting drug actions and inactions, especially with antagonists like atropine. --- ## Common mistakes to avoid - Review all topics thoroughly before exams - Pay attention to formulas and key definitions - Practice with examples provided in each section - Don't memorize without understanding the underlying concepts

| Term | Definition | |------|------------| | Acetylcholine (Ach) | A neurotransmitter that plays a crucial role in the parasympathetic nervous system, mediating nerve impulses to target organs and muscles. | | Parasympathomimetic drugs | Drugs that mimic the effects of acetylcholine by directly stimulating cholinergic receptors, thus enhancing parasympathetic activity. | | Parasympatholytic drugs | Drugs that reduce the effects of acetylcholine by blocking its action at cholinergic receptors, leading to a suppression of parasympathetic activity. | | Cholinergic neurons | Neurons that utilize acetylcholine as their primary neurotransmitter in the process of synaptic transmission. | | Muscarinic receptors | A type of acetylcholine receptor that is G protein-coupled, with subtypes M1, M3, M5 (Gq) and M2, M4 (Gi), mediating various physiological responses. | | Nicotinic receptors | A type of acetylcholine receptor that is coupled with ion channels, found at neuromuscular junctions and autonomic ganglia, mediating rapid excitatory responses. | | Acetylcholinesterase (AChE) | An enzyme responsible for the breakdown of acetylcholine into choline and acetate, thereby terminating its action at the synapse. | | Acetylcholinesterase inhibitors | Drugs that block the action of acetylcholinesterase, leading to increased levels of acetylcholine and thus potentiating cholinergic effects. | | Ganglion stimulants | Drugs that stimulate nicotinic receptors in autonomic ganglia, leading to widespread activation of both sympathetic and parasympathetic systems. | | Myasthenia gravis | A chronic autoimmune neuromuscular disease characterized by weakness in the voluntary muscles, often treated with acetylcholinesterase inhibitors to increase acetylcholine availability. | | Mydriasis | Dilation of the pupil, typically caused by drugs that block muscarinic receptors in the iris sphincter muscle. | | Cycloplegia | Paralysis of the ciliary muscle of the eye, preventing accommodation for near vision, often caused by antimuscarinic drugs. | | Glaucoma | A group of eye conditions that damage the optic nerve, often associated with elevated intraocular pressure, which can be managed with drugs that affect aqueous humor production or outflow. | | COPD (Chronic Obstructive Pulmonary Disease) | A progressive lung disease that makes breathing difficult, often treated with bronchodilators like ipratropium and tiotropium. | | Neurogenic bladder | A bladder dysfunction resulting from damage to the nervous system, which can lead to urinary incontinence and is sometimes treated with anticholinergic medications. | | Extrapyramidal side effects (EPS) | Movement disorders that can occur as a side effect of antipsychotic medications, often related to dopamine blockade, and can sometimes be managed with anticholinergic drugs. | | Atropine poisoning | A condition resulting from excessive exposure to atropine or other anticholinergic substances, characterized by a set of characteristic symptoms including dry mouth, tachycardia, and delirium. | | Pralidoxime | An oxime cholinesterase reactivator used as an antidote for organophosphate poisoning, helping to restore acetylcholinesterase function. | | Hyoscyamine | The active isomer of atropine, a potent antimuscarinic agent with significant effects on the peripheral nervous system. |