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Questions and Answers
What is the mechanism by which indirect agonists increase acetylcholine levels?
Which pharmacological action is NOT associated with direct agonists in the parasympathetic nervous system?
Which of the following is considered a natural alkaloid used as a direct agonist?
What is the physiological effect of cholinergic transmission on vascular endothelial cells?
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Which of the following is not a characteristic of the choline esters used as direct agonists?
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What effect does acetylcholine have on sweat glands?
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Which drug is primarily used to promote urination by stimulating the bladder sphincter?
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Which of the following actions is characteristic of the wandering nerve in cholinergic transmission?
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What is the primary role of acetylcholinesterase (AchE) in the cholinergic system?
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Which type of receptor is primarily associated with skeletal muscle contraction?
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Which of the following muscarinic receptors is responsible for causing inhibition in the heart?
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What is the mechanism by which muscarinic receptors M1, M3, and M5 primarily exert their effects?
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Which typically inhibits muscarinic receptors?
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What physiological effect does acetylcholine have on blood vessels, despite most lacking parasympathetic innervation?
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Which of the following is NOT a characteristic of nicotinic receptors?
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The reuptake of choline by the presynaptic neuron is crucial for which process?
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What is the primary therapeutic application of pilocarpine in ophthalmology?
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Which of the following is NOT a contraindication for using parasympathomimetic drugs?
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What is the mode of action for pilocarpine in treating xerostomia?
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Why are acetylcholine and methacholine not used clinically?
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What are common adverse drug reactions (ADRs) associated with using muscarinic agonists?
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Which of the following correctly describes the pharmacological action of pilocarpine in glaucoma treatment?
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In which condition is bethanechol primarily indicated?
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Which of the following describes a unique aspect of the side effects of choline esters?
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Which of the following drugs is an irreversible acetylcholinesterase inhibitor?
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What is the main result of acetylcholinesterase inhibition?
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In the context of pharmacokinetics, which route of administration is effective for poorly liposoluble drugs like Edrophonium?
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What condition is Neostigmine primarily used to treat?
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What is the function of the antidote Pralidoxime (2-PAM)?
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Which of the following statements regarding organophosphates is correct?
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Which of the following is NOT a likely adverse reaction of acetylcholinesterase inhibitors?
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Which feature distinguishes reversible acetylcholinesterase inhibitors from irreversible ones?
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What is the primary pharmacological application of edrophonium?
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Which drug is administered alongside neostigmine to limit parasympathomimetic effects?
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Which of the following conditions can neostigmine be used to treat?
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Which of the following is a characteristic of medium-duration anticholinesterases?
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How do muscarinic antagonists primarily function?
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What type of agents are atropine and scopolamine categorized as?
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What distinguishes 'myasthenic crisis' from 'cholinergic crisis'?
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Which of the following drugs is specifically used for treating Alzheimer’s disease?
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Study Notes
Acetylcholine Degradation and Receptors
- Acetylcholine (Ach) is a neurotransmitter that is broken down into acetyl coenzyme A and choline by the enzyme acetylcholinesterase (AchE).
- Choline is then re-uptaken by the pre-synaptic neuron for the synthesis of new Ach.
- Cholinergic receptors are classified into two groups: nicotinic and muscarinic.
- Nicotinic receptors are ion channel-coupled receptors that are activated by nicotine and Ach, and inhibited by tubocurarine and trimetafan.
- Muscarinic receptors are G-protein-coupled receptors that are activated by muscarine and Ach.
- Muscarinic receptors are further classified into five subtypes (M1-M5) that couple with various G proteins to activate different signaling pathways.
- M1, M3, and M5 couple with Gq to activate the inositol phosphate pathway.
- M2 and M4 couple with Gi to inhibit adenylyl cyclase and reduce intracellular cAMP, and open potassium (KATP) channels causing membrane hyperpolarisation.
Muscarinic Actions and Cholinergic Transmission
- Muscarinic actions correspond to those of Ach released at postganglionic parasympathetic nerve endings, with two exceptions:
- Ach causes vasodilation even though most blood vessels lack parasympathetic innervation. This effect is mediated by nitric oxide released from vascular endothelial cells by Ach.
- Ach evokes secretion from sweat glands, which are innervated by cholinergic fibers of the sympathetic nervous system.
- Cholinergic transmission includes the synthesis, release, and inactivation of Ach, as well as its action on nicotinic and muscarinic receptors.
Parasympathomimetic Drugs
- Parasympathomimetic drugs, also known as cholinergic agonists or muscarinic agonists, mimic the effects of the parasympathetic nervous system.
- Parasympathomimetic drugs are classified into direct and indirect agonists:
- Direct agonists act directly on cholinergic receptors.
- Indirect agonists increase Ach levels indirectly by increasing Ach release or inhibiting AchE.
- Direct-acting parasympathomimetic drugs include:
- Choline esters such as carbachol, bethanechol, acetylcholine, and methacholine.
- Natural alkaloids such as muscarine and pilocarpine.
- Synthetic drugs such as cevimeline.
- Betanechol, pilocarpine, and cevimeline are the only direct-acting parasympathomimetic drugs used clinically.
- Choline esters are hydrophilic and are primarily administered parenterally.
- Natural alkaloids are administered orally.
- Direct-acting parasympathomimetic drugs have various pharmacological actions:
- Cardiovascular: They decrease heart rate and output, and cause generalized vasodilation, leading to decreased blood pressure.
- Gastrointestinal: They increase secretions and peristaltic activity, leading to increased intestinal transit, cramping pain, and diarrhea (bethanechol and pilocarpine).
- Urinary tract: They stimulate the bladder sphincter, increase urination pressure, and promote urination (bethanechol).
- Airways: They increase bronchoconstriction.
- Secretions: They increase exocrine secretions.
- Eyes: They cause accommodation of near vision (miosis) and contraction of the ciliary muscle, leading to decreased intraocular pressure (treatment of glaucoma).
- CNS: Intravenous pilocarpine can cause toxicity including tremor and ataxia.
- Choline esters do not cross the blood-brain barrier.
- Muscarine is not used clinically due to its toxicity.
- Acetylcholine and methacholine are not used clinically due to rapid inactivation by AchE.
- Therapeutic applications of direct-acting parasympathomimetic drugs include:
- Glaucoma treatment: Pilocarpine eye drops.
- Intestinal or gastrointestinal atony and urinary bladder dysfunction: Bethanechol.
- Abdominal distension after surgery: Bethanechol.
- Xerostomia (dry mouth): Pilocarpine and cevimeline.
Pilocarpine and Cevimeline
- Pilocarpine is used for the treatment of glaucoma.
- It activates the constrictor pupillae muscle, lowering intraocular pressure and improving drainage by realigning the connective tissue trabeculae through which the canal of Schlemm passes.
- Pilocarpine and cevimeline are used for xerostomia and Sjögren’s syndrome.
- They increase salivation and lacrimal secretion in patients with dry mouth or dry eyes due to radiation therapy or autoimmune damage to salivary or lacrimal glands, such as in Sjögren’s syndrome.
Indirect-Acting Parasympathomimetic Drugs
- Indirect-acting parasympathomimetic drugs are acetylcholinesterase inhibitors.
- They inhibit AchE, thereby increasing Ach levels in the synaptic cleft and prolonging its action on cholinergic receptors.
- Acetylcholinesterase inhibitors are classified as reversible or irreversible:
- Reversible inhibitors form weak bonds (hydrogen bonds) with AchE.
- Irreversible inhibitors form strong bonds (covalent bonds) with AchE.
- Reversible acetylcholinesterase inhibitors include neostigmine, physostigmine, edrophonium, and ambenonium.
- Irreversible acetylcholinesterase inhibitors are commonly called organophosphates and include ecothiophate and parathion.
- Organophosphates have acute toxicity and can cause death by respiratory paralysis as a consequence of Ach action at the neuromuscular plaque.
- The antidote for organophosphate poisoning is pralidoxime (2-PAM), which can remove the organophosphate from the active site of AchE but only in the early stages of exposure.
- Pharmacokinetics of acetylcholinesterase inhibitors:
- Edrophonium and neostigmine are poorly absorbed orally and are primarily administered subcutaneously or intravenously.
- Physostigmine and ecothiophate are highly lipophilic and can be administered topically for glaucoma.
Pharmacological Effects and Adverse Reactions of Acetylcholinesterase Inhibitors
- The pharmacological effects and adverse effects of acetylcholinesterase inhibitors are similar to those of direct-acting parasympathomimetic drugs and include:
- Cardiovascular: Decreased heart rate and output, generalized vasodilation, decreased blood pressure.
- Gastrointestinal: Increased secretions and peristaltic activity, diarrhea, cramping pain.
- Urinary tract: Stimulation of the bladder sphincter, increased urination pressure.
- Airways: Bronchoconstriction.
- Secretions: Increased exocrine secretions.
- Eyes: Miosis (constriction of the pupil), accommodation of near vision, decreased intraocular pressure.
- CNS: Tremor, ataxia.
Therapeutic Applications of Acetylcholinesterase Inhibitors
- Myasthenia gravis: Neostigmine is used to treat myasthenia gravis, an autoimmune disease characterized by muscle weakness due to impaired neuromuscular transmission.
- Neutralization of non-depolarizing neuromuscular blockers: Neostigmine is used to reverse the action of non-depolarizing neuromuscular blockers, which are used to induce muscle paralysis during surgery.
- Glaucoma treatment: Physostigmine is used as eye drops for the treatment of glaucoma.
- Atony of the digestive and urinary system: Neostigmine is used to treat atony, or lack of muscle tone, in the digestive and urinary systems.
- Diagnostic testing for myasthenia gravis: Edrophonium is used to distinguish weakness caused by myasthenia gravis from weakness due to other causes.
- Alzheimer's disease: Drugs such as donepezil, an acetylcholinesterase inhibitor, are used to treat Alzheimer's disease, a neurodegenerative disorder characterized by memory loss and cognitive impairment.
Edrophonium
- Edrophonium is a short-acting acetylcholinesterase inhibitor that is used for diagnostic testing of myasthenia gravis.
- It is administered intravenously, and improvement in muscle strength following administration is characteristic of myasthenia gravis but not of other causes of muscle weakness.
- Edrophonium can also be used to distinguish myasthenic crisis from cholinergic crisis.
- Cholinergic crisis is an overdosage of cholinesterase inhibitors that exacerbates the symptoms of myasthenia gravis.
- Myasthenic crisis refers to an exacerbation of myasthenia gravis symptoms due to a lack of acetylcholinesterase inhibitors.
- Edrophonium is not used to treat myasthenia gravis, as its short duration of action prevents the maintenance of therapeutic effects.
Neostigmine, Physostigmine, and Pyridostigmine
- Neostigmine, physostigmine, and pyridostigmine are medium-duration acetylcholinesterase inhibitors.
- Neostigmine is used to treat myasthenia gravis and to reverse the action of non-depolarizing neuromuscular blockers.
- Physostigmine is used for the treatment of glaucoma.
- Pyridostigmine is also used for the treatment of myasthenia gravis.
- These long-acting drugs are preferred to edrophonium for the treatment of myasthenia gravis because of their longer duration of action and potential for daily dosing.
Parasympatholytic Drugs
- Parasympatholytic drugs, also known as muscarinic antagonists, block or inhibit the actions of the parasympathetic nervous system by competitively inhibiting muscarinic receptors.
- At high doses, parasympatholytic drugs can also inhibit nicotinic receptors.
- Parasympatholytic drugs are divided into two categories:
- Natural alkaloids: Atropine, scopolamine, derived from plants such as Atropa belladonna (deadly nightshade), Hyoscyamus niger (black henbane).
- Synthetic: Various synthetic drugs are available, often with different specificities and durations of action.
- Therapeutic applications of parasympatholytic drugs include:
- Treatment of bradycardia: Atropine is used to treat bradycardia, or a slow heart rate.
- Reduction of GI motility: Atropine is used to reduce gastrointestinal motility in conditions such as diarrhea and irritable bowel syndrome.
- Premedication for surgery: Atropine is often used as premedication for surgery to reduce secretions and prevent bradycardia.
- Treatment of organophosphate poisoning: Atropine is used to treat organophosphate poisoning by competitively blocking Ach at muscarinic receptors.
- Treatment of Parkinson's disease: Some parasympatholytic drugs can be used to treat Parkinson's disease by blocking muscarinic receptors in the brain.
- As an antispasmodic agent: Atropine can relax smooth muscles, making it useful to relieve spasms in the urinary tract, digestive tract, and respiratory tract.
- To treat overactive bladder: Atropine can decrease bladder spasms and urine frequency.
- To improve vision in certain conditions: Atropine can dilate the pupils, useful in some eye examinations.
Important Considerations
- The text provides a foundational overview of cholinergic transmission and the use of parasympathomimetic and parasympatholytic drugs.
- Clinical application of these drugs requires a thorough understanding of their pharmacological actions, potential adverse effects, and appropriate dosages.
- Please consult with a medical professional for specific medical advice and treatment.
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