quiz 2 choli review

• Autonomic Nervous System (ANS) is responsible for regulating the internal environment, including sweating, respiration, secretions, metabolism, and body temperature
• ANS is composed of neurons and bundled axons, and it includes:

  • Sympathetic (thoracolumbar T1-12, L1-5)
  • Parasympathetic (craniosacral CN3, 7, 9, 10, S3-4)
  • Enteric
• Organ responses to sympathetic (Fight or Flight) and parasympathetic (Rest or Digest) stimulation:

  • Pupils: Mydriasis (𝛼1, 𝛽 - radial, 𝛽 - ciliary) vs. Miosis (M3 - radial, M3 - ciliary)
  • Heart: (+) Inotropy, Chronotropy, Dromotropy (𝛽1, 𝛽2) vs. (-) Inotropy, Chronotropy, Dromotropy (M2)
  • Bronchioles: Dilation (𝛽2) vs. Constriction (M2)
  • GIT: Decreased peristalsis and secretions (𝛼2, 𝛽2) vs. Increased peristalsis and secretions (M3)
  • Urinary Bladder: Relaxed detrusor muscle (𝛽2) vs. Constricted sphincter (𝛼1) vs. Contracted detrusor muscle (M3) vs. Relaxed sphincter (M3)
• • Peripheral Blood Vessels: Vasoconstriction (𝛼1) vs. Vasodilation (M3)
  • Penis: Ejaculation vs. Erection
  • Skin/Sweat Glands: Arector Pili muscle contraction (𝛼) vs. Stressful sweating (𝛼)
• Cholinergic Agonists promote cholinergic transmission activation through:

  • Direct activation of cholinergic receptors (Choline esters, cholinomimetic alkaloids)
  • Prevention of acetylcholine degradation (Edrophonium, Carbamates, Organophosphates)
• Cholinergic receptors include:

  • Muscarinic (M1-M5) found in visceral organs
  • Nicotinic neural (Nn) in post-synaptic neurons of sympathetic and parasympathetic ANS
  • Nicotinic muscular (Nm) in skeletal muscle
• Mechanism of Action for Cholinergic Agonists:

  • Direct-Acting Agents: Muscarinic receptors are G-protein coupled, leading to altered organ function through secondary messengers like IP3, DAG, cGMP. Nicotinic receptors are ligand-gated ion channels allowing Na+, K+, and Ca+ influx.
  • Indirect-Acting Agents: Inhibit AChE, preventing acetylcholine degradation, and increasing available acetylcholine levels
• Direct-Acting Cholinergic Agonists:

  1. Choline Esters: Acetylcholine, Carbachol, Metacholine, Bethanechol

  2. Cholinomimetic Alkaloids: Nicotine, Lobeline, Muscarine, Pilocarpine
• Indirect-Acting Cholinergic Agonists:

  1. Edrophonium: Forms electrostatic bond with AChE, short duration of action

  2. Carbamates: Neostigmine, Physostigmine, Pyridostigmine, Rivastigmine, Carbaryl, inhibit AChE activity by binding covalently to the active site
• Drugs with a carbamate group (ROCONR2) have longer activity than edrophonium
• These drugs bind covalently to the active site of AChE, preventing access to acetylcholine
• The drug is hydrolyzed, but the carbamoyl-enzyme complex remains
• The carbamylated enzyme is resistant to the 2nd process, and the enzyme remains bound for a longer duration (30 mins to 6 hours)
• Duration of action is determined by the stability of the carbomylated enzyme
• Organophosphates are highly lipid-soluble and absorbed through the skin, lung, gut, and conjunctiva
• Echothiophate is highly polar and stable in aqueous solutions
• Organophosphates are distributed even in the CNS and are crucial during poisoning
• Malathion can be metabolized by humans, but Parathion is not effectively detoxified in humans, making it more dangerous
• Organophosphates contain a phosphate group (-PO4) that binds with AChE in an extremely stable covalent bond
• Bond aging with organophosphates and AChE interaction involves an oxygen-phosphorus bond break to strengthen the bond with the enzyme
• Oxime regenerator PRALIDOXIME can prevent the bonding process similar to carbamates, but the phosphorylated enzyme is more stable, hard to break, and hydrolyzes very slowly
• Cholinergic agonists are used for various clinical indications
• Cholinergic antagonists are divided into Muscarinic and Nicotinic antagonists
• Muscarinic antagonists work on M1, M2, and M3 receptors
• Nicotinic antagonists work on ganglionic (Nn) and neuromuscular (Nm) sites
• Muscarinic antagonists block parasympathetic signals similar to the sympathetic ANS
• Atropine is the prototype muscarinic antagonist derived from Atropa belladonna or Datura stramonium
• Scopolamine is another anti-muscarinic alkaloid derived from Hyoscyamus niger
• Atropine is a competitive pharmacologic antagonist at muscarinic receptors
• Atropine is used in Parkinson's disease, motion sickness, and ophthalmic disorders
• Atropine decreases airway secretion during general anesthesia
• Atropine produces tachycardia by slowing the vagus nerve
• Atropine is used in respiratory, cardiovascular, gastrointestinal, urinary disorders, and cholinergic poisoning
• Atropine (large doses) is used as an antidote to reduce muscarinic signs of poisoning with AChE inhibitors (e.g., organophosphates)
• Pralidoxime is an oxime regenerator used to create active AChE during organophosphate poisoning
• Atropine surpasses thermoregulatory sweating, leading to hyperthermia called "atropine fever"
• Oxybutynin and Benztropine partially reduce sweating, with activity mostly towards apocrine rather than eccrine glands
• ADRs and toxicity to anti-muscarinic agents will show via predictive toxicities, including flushing of the skin, moderate to severe tachycardia, reduced sweating, lacrimation, & salivation, mydriasis and blurred vision, agitation and delirium, blockade of thermoregulation sweating (most dangerous), constipation, and urinary retention
• Physostigmine is used for severe tachycardia
• Cooling blankets / Evaporative cooling are used for hyperthermia