Cholinergic Agonists Overview
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What are cholinergic agonists primarily classified as?

  • Monoamine oxidase inhibitors
  • Beta-adrenergic antagonists
  • ACh receptor blockers
  • Ach-R stimulants and cholinesterase inhibitors (correct)

    • What is a common treatment for Alzheimer's disease based on loss of cholinergic neurons?

  • Cholinergic receptor antagonists
  • Beta-blockers
  • Antidepressants
  • Acetylcholinesterase inhibitors (correct)

    • Which of the following is NOT a step in neurotransmission at cholinergic neurons?

  • Binding of Ach to a receptor
  • Formation of myelin sheath (correct)
  • Synthesis
  • Degradation of the NT in the synaptic gap

    • How are Ach-R stimulants categorized?

    <p>According to the type of receptors they selectively stimulate</p> Signup and view all the answers

    What is the role of the high-affinity choline transporter?

    <p>It transports choline into the neuron</p> Signup and view all the answers

    Which statement about cholinergic neurons is true?

    <p>They innervate both the autonomic and somatic systems.</p> Signup and view all the answers

    What type of cholinergic agonists directly bind to ACh receptors?

    <p>Direct acting cholinergic agonists</p> Signup and view all the answers

    What characterizes choline in relation to its transport into neurons?

    <p>It is a quaternary ammonium compound and polar.</p> Signup and view all the answers

    What is the primary consequence of aging in the context of enzyme-inhibitor interactions?

    <p>It makes chemical reactivators ineffective in breaking bonds.</p> Signup and view all the answers

    Which of the following statements best describes the action of atropine on isoflurophate effects?

    <p>Atropine reverses many muscarinic effects if given in high doses.</p> Signup and view all the answers

    What distinguishes newer nerve agents from DFP in terms of aging?

    <p>Newer nerve agents age in minutes or seconds instead of hours.</p> Signup and view all the answers

    How do oximes like pralidoxime and obidoxime function in reactivating inhibited AChE?

    <p>They contain charged groups that assist in displacing the organophosphate.</p> Signup and view all the answers

    What therapeutic role does echothiophate play in comparison to isoflurophate?

    <p>Echothiophate has largely replaced isoflurophate for treating open-angle glaucoma.</p> Signup and view all the answers

    What is one of the primary clinical uses of methacholine?

    <p>To diagnose bronchial hyper-reactivity in asthma</p> Signup and view all the answers

    Which of the following is a known side effect of carbachol?

    <p>Diarrhea</p> Signup and view all the answers

    What action does methacholine primarily affect compared to carbachol?

    <p>It has little to no effect on N cholinergic receptors.</p> Signup and view all the answers

    What is a common adverse effect of bethanechol?

    <p>Hypotension</p> Signup and view all the answers

    What unique property does methacholine possess regarding acetylcholinesterase?

    <p>It is resistant to AChE.</p> Signup and view all the answers

    In its therapeutic application, how does carbachol primarily function when used in the eye?

    <p>To induce miosis</p> Signup and view all the answers

    What is a primary reason for the limited therapeutic use of carbachol?

    <p>High potency and lack of selectivity</p> Signup and view all the answers

    Which type of receptors does carbachol affect?

    <p>Both M and N cholinergic receptors</p> Signup and view all the answers

    What type of side effects is usually observed with methacholine at clinical doses?

    <p>Minimal cardiovascular side effects</p> Signup and view all the answers

    What physiological response can carbachol trigger through its ganglion-stimulating activity?

    <p>Release of adrenaline and noradrenaline</p> Signup and view all the answers

    Which medication is primarily used in the diagnosis of myasthenia gravis due to its rapid effects?

    <p>Edrophonium</p> Signup and view all the answers

    What is the typical duration of action for pyridostigmine?

    <p>3 to 6 hours</p> Signup and view all the answers

    Which of the following is an adverse effect associated with neostigmine?

    <p>Bronchospasms</p> Signup and view all the answers

    Why was tacrine replaced by other anticholinesterases in treating Alzheimer's disease?

    <p>Hepatotoxicity</p> Signup and view all the answers

    What is the antidote used in cases of excess edrophonium administration?

    <p>Atropine</p> Signup and view all the answers

    Which of the following statements regarding irreversible anticholinesterases is correct?

    <p>They bind covalently to AChE, causing lasting effects.</p> Signup and view all the answers

    What is a common primary adverse effect of the anticholinesterases used for Alzheimer's disease?

    <p>Gastrointestinal distress</p> Signup and view all the answers

    What is the action of isoflurophate regarding acetylcholinesterase?

    <p>It phosphorylates the enzyme permanently.</p> Signup and view all the answers

    Which organophosphate is mentioned as a prototype agent for irreversible anticholinesterases?

    <p>Isoflurophate</p> Signup and view all the answers

    Which of the following is a characteristic of edrophonium's action compared to neostigmine?

    <p>More rapid absorption</p> Signup and view all the answers

    What process is primarily responsible for the synthesis of acetylcholine?

    <p>The reaction of choline with acetyl CoA</p> Signup and view all the answers

    Which substance can inhibit the uptake of choline?

    <p>Hemicholinium</p> Signup and view all the answers

    What is the effect of black widow spider venom on acetylcholine stores?

    <p>It causes the emptying of all ACh stores into the synaptic gap</p> Signup and view all the answers

    Which type of receptors are classified as muscarinic cholinergic receptors?

    <p>7 transmembrane proteins coupled to G-proteins</p> Signup and view all the answers

    What effect do M1 and M3 receptors produce upon activation?

    <p>Increased intracellular calcium levels</p> Signup and view all the answers

    What happens when acetylcholine binds to nicotinic receptors?

    <p>Depolarization of the effector cell</p> Signup and view all the answers

    The degradation of acetylcholine in the synaptic cleft is primarily facilitated by which enzyme?

    <p>Acetylcholinesterase</p> Signup and view all the answers

    How do M2 receptors influence cardiac function?

    <p>They inhibit adenylyl cyclase activity</p> Signup and view all the answers

    What ions are required for the storage of acetylcholine in vesicles?

    <p>Calcium and magnesium</p> Signup and view all the answers

    Which of the following statements about M receptors is correct?

    <p>M1, M3, and M5 subtypes lead to cellular excitation.</p> Signup and view all the answers

    Study Notes

    Cholinergic Agonists Overview

    • Cholinergic agonists mimic the actions of acetylcholine (ACh).
    • There are two main types: ACh-R (Acetylcholine Receptor) stimulants and Cholinesterase inhibitors.
    • ACh-R stimulants are further categorized by the type of receptors they stimulate: Muscarinic cholinomimetics and Nicotinic cholinomimetics.
    • Another classification considers their mechanism of action: Direct acting (binding directly to the ACh-R) and Indirect acting (inhibiting the hydrolysis of endogenous ACh).

    The Cholinergic Neuron

    • ACh is the neurotransmitter in:
      • Autonomic ganglia (both parasympathetic and sympathetic)
      • Preganglionic fibers terminating in the adrenal medulla
      • Postganglionic fibers of the parasympathetic division
      • Somatic muscle innervations

    Neurotransmission at the Cholinergic Neuron

    • The six steps of neurotransmission in cholinergic neurons include:
      • Synthesis
      • Storage
      • Release
      • Binding of ACh to a receptor
      • Degradation of the neurotransmitter (NT) in the synaptic gap
      • Recycling of choline

    Synthesis of ACh

    • Choline is transported from plasma into the neuron by a high-affinity choline transporter (Na+ dependent).
    • Choline acetyltransferase catalyzes the formation of ACh from choline and acetyl CoA in the cytosol.
    • The uptake of choline is the rate-limiting step in ACh synthesis.
      • This process can be inhibited by hemicholinium.

    Storage of ACh

    • ACh is packaged into vesicles called vesiculin by an active transport process.
    • These vesicles also contain adenosine triphosphate (ATP), ions (Ca2+ & Mg2+), and proteoglycan.

    Release of ACh

    • Action potentials stimulate voltage-sensitive Ca2+ channels in the presynaptic membrane.
    • Increased Ca2+ levels promote the fusion of synaptic vesicles with the cell membrane and release of ACh into the synaptic cleft.
      • This release can be blocked by botulinum toxin.
      • Black widow spider venom causes the emptying of all ACh stores in synaptic vesicles into the synaptic gap.

    Binding to a Receptor

    • Released ACh diffuses across the synaptic space and binds to postsynaptic receptors (M & N) on the target cell.
    • Presynaptic (auto-) receptors can also bind to ACh in the membrane of the neuron.
    • Binding to a receptor leads to a biological response within the cell.

    Degradation

    • Acetylcholinesterase (AChE) rapidly terminates the signal at the postsynaptic effector site by cleaving ACh into choline and acetate in the synaptic cleft.

    Recycling of Choline

    • A Na+-coupled, high-affinity choline uptake system recaptures choline and transports it back into the neuron for further ACh synthesis.

    Cholinergic Receptors (Cholinoreceptors)

    • Muscarinic cholinergic receptors (M) are 7 transmembrane proteins coupled to a G-protein (GPCRs).
      • They bind to both ACh and muscarine but only have a weak affinity for nicotine.
      • There are five subclasses: M1-5.
        • M1, M3, and M5 lead to cellular excitation.
        • M2 and M4 inhibit cellular excitability.

    Location of M-Receptors

    • All five subtypes have been found on neurons.
    • M1 receptors are also found on gastric parietal cells (controlling gastric acid secretion).
    • M2 receptors are on cardiac cells and smooth muscle (slowing heart rate and force of contraction).
    • M3 receptors are on the bladder, exocrine glands, and smooth muscle.

    ACh Signal Transduction Mechanisms (M1 & M3)

    • When M1 or M3 receptors are activated, they interact with a G protein (Gq).
    • This activates phospholipase C, hydrolyzing phosphatidylinositol-(4,5)-bisphosphate (PIP2) into diacylglycerol (DAG) and inositol (1,4,5)-trisphosphate (IP3).
    • IP3 causes an increase in intracellular Ca2+ from intracellular stores (sarcoplasmic reticulum).
    • Ca2+ stimulates or inhibits enzymes, or causes hyperpolarization, secretion, or contraction.

    ACh Signal Transduction Mechanisms (M2 & M4)

    • Activation of M2 subtypes on the myocardium muscle stimulates a G protein (Gi).
    • This inhibits adenylyl cyclase (AC) activity, which normally converts ATP to cAMP (second messenger).
    • The inhibition leads to an increased K+ conductance, resulting in decreased heart rate and force of contraction.

    Nicotinic Cholinergic Receptors (N)

    • These receptors bind to both ACh and nicotine, but only have a weak affinity for muscarine.
    • N cholinergic receptors consist of five transmembrane polypeptide subunits and function as ligand-gated ion channels.
    • Binding causes conformational changes that allow Na+ entry, depolarizing the effector cell (excitatory post-synaptic potential; EPSP).

    Carbachol

    • Carbachol has both M and N actions (not selective).
    • It's an ester of carbamic acid and a poor substrate for AChE.
    • Its long duration of action allows for a single administration to persist for approximately one hour.
    • It's primarily used topically in the eye as a miotic agent to treat glaucoma.

    Bethanechol

    • Bethanechol is a direct-acting cholinergic agonist with selective M activity.
    • It's used for urinary retention and postoperative ileus.

    Methacholine

    • Methacholine is a synthetic choline ester that is highly active at all M receptors, but has little effect on N receptors.
    • It is primarily used to diagnose bronchial hyper-reactivity in asthma.

    Neostigmine

    • Neostigmine is a reversible AChE inhibitor used to treat myasthenia gravis.

    Pyridostigmine and Ambenonium

    • These are also reversible AChE inhibitors used to manage myasthenia gravis.

    Edrophonium

    • Edrophonium is a short-acting reversible AChE inhibitor used in the diagnosis of myasthenia gravis.

    Tacrine, Donepezil, Rivastigmine, & Galantamine

    • These drugs are reversible AChE inhibitors used to treat Alzheimer's disease.

    Anticholinesterases (Irreversible)

    • Organophosphates bind covalently to AChE, increasing ACh levels at all sites.
      • Many are highly toxic and were developed as nerve agents (e.g., Sarin).
      • Related compounds like parathion are used as insecticides.

    Isoflurophate

    • Isoflurophate is an organophosphate that covalently binds to AChE, inactivating it permanently.
    • It is used topically in the eye for the chronic treatment of open-angle glaucoma.

    Cholinesterase Reactivators

    • Oximes (e.g., pralidoxime and obidoxime) can reactivate inhibited AChE.
    • They displace the organophosphate and regenerate the enzyme.
    • Their effectiveness decreases with time as the enzyme undergoes "aging", which strengthens the bond between the organophosphate and the enzyme, making it impossible for reactivators to break the bond.

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    Description

    This quiz covers the essential concepts of cholinergic agonists, including their types and mechanisms of action. You'll learn about ACh-Receptor stimulants, cholinesterase inhibitors, and the neurotransmission process involved in cholinergic neurons. Test your knowledge on this crucial topic in pharmacology today!

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