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Autonomic Nervous System High-Yield Study Guide

Autonomic Nervous System Basics

  • Sympathetic Preganglionic Neurons & Rami

    • Location: Originate from the intermediolateral cell column of the spinal cord (segments T1-L2).

    • White Rami Communicantes:

      • Composition: Myelinated axons of preganglionic sympathetic neurons.

      • Distribution: Present exclusively at spinal levels T1-L2 where sympathetic outflow originates.

    • Gray Rami Communicantes:

      • Composition: Unmyelinated axons of postganglionic sympathetic neurons.

      • Distribution: Present at all spinal levels, allowing sympathetic innervation to all parts of the body.

    • Neurotransmitters and Receptors:

      • Preganglionic Neurotransmitter: Acetylcholine (ACh).

      • Preganglionic Receptor: Nicotinic (N_n) receptor, found on postganglionic neurons.

      • Postganglionic Neurotransmitter: Norepinephrine (NE) in most sympathetic synapses (except sweat glands and adrenal medulla).

  • Horner Syndrome

    • Classic Triad (PAM):

      • Ptosis (drooping eyelid) – due to paralysis of Muller's muscle.

      • Anhidrosis (lack of sweating) – affecting the ipsilateral face.

      • Miosis (constricted pupil) – due to unopposed parasympathetic activity.

    • Additional Finding: May include enophthalmos (sunken eye), though less consistently present.

    • Causes: Results from a lesion anywhere along the sympathetic pathway from the hypothalamus, down the spinal cord (specifically T1 segment), up to the superior cervical ganglion.

    • Classic Association: Pancoast tumor, a type of lung cancer, which can compress the sympathetic chain in the thoracic inlet.

  • Parasympathetic Pathway to Lacrimal Gland

    • Pathway: Cranial Nerve VII (Facial nerve)
      ightarrow Greater petrosal nerve
      ightarrow Pterygopalatine ganglion
      ightarrow Lacrimal gland.

    • Receptor: Muscarinic M_3 receptor is activated at the lacrimal gland, leading to glandular secretion (tears).

    • Clinical Relevance: Antimuscarinic drugs (e.g., atropine, scopolamine) block M_3 receptors and can cause the side effect of dry eyes.

Clinical Toxidromes and Receptor Responses

  • Clinical Toxidromes

    • Antimuscarinic Toxidrome (Cholinergic Blockade):

      • Mnemonic: "Hot as a hare, Dry as a bone, Red as a beet, Mad as a hatter, Blind as a bat."

      • Symptoms: Hyperthermia, dry skin/mucosa (anhidrosis, xerostomia), flushed skin (vasodilation), altered mental status (confusion, delirium), mydriasis (dilated pupils) and cycloplegia.

    • Muscarinic Toxidrome (Cholinergic Excess):

      • Mnemonic: DUMBBELSS

      • Symptoms: Diarrhea, Urination, Miosis, Bronchospasm, Bradycardia, Emesis (vomiting), Lacrimation, Sweating, Salivation.

    • Nicotinic Toxidrome:

      • Symptoms: Muscle fasciculations (involuntary twitching), generalized weakness, and potentially paralysis due* to persistent depolarization of skeletal muscle.

    • Organophosphate Poisoning:

      • Mechanism: Organophosphates (e.g., malathion, sarin) are irreversible Acetylcholinesterase (AChE) inhibitors, leading to a severe cholinergic crisis (both muscarinic and nicotinic symptoms).

      • Treatment: Atropine (blocks muscarinic receptors) + Pralidoxime (2-PAM) (reactivates AChE before aging occurs; specifically targets nicotinic effects and reverses both nicotinic and muscarinic signs, if given early).

  • M_3 Receptor Responses

    • Signaling Pathway: Gq protein-coupled receptor ightarrow activates Phospholipase C ightarrow production of Inositol Triphosphate (IP3) and Diacylglycerol (DAG)
      ightarrow ultimately leads to an increase in intracellular Ca^{2+}.

    • Physiological Effects:

      • Increased glandular secretion (e.g., salivary, gastric, lacrimal).

      • Increased gut motility (peristalsis).

      • Miosis (pupil constriction).

      • Bronchoconstriction (narrowing of airways).

      • Bladder contraction (detrusor muscle).

    • Clinical Use of Agonists: Muscarinic agonists like pilocarpine and carbachol are used in the treatment of glaucoma to promote aqueous humor outflow.

  • Acetylcholine (ACh) on Endothelium

    • Intact Endothelium:

      • Mechanism: ACh binds to M_3 receptors on endothelial cells
        ightarrow stimulates Nitric Oxide (NO) release
        ightarrow NO diffuses to vascular smooth muscle
        ightarrow causes vasodilation.

    • Damaged Endothelium:

      • Mechanism: When the endothelium is damaged, ACh acts directly on M_3 receptors on vascular smooth muscle cells (bypassing NO release)
        ightarrow leads to vasoconstriction.

    • Clinical Implication: An ACh infusion typically causes a decrease in blood pressure (BP) due to vasodilation. However, in patients with endothelial dysfunction (e.g., atherosclerosis), it can paradoxically cause vasospasm.

Adrenergic Receptor Pharmacology

  • Alpha-1 (\alpha_1) Receptor Agonist

    • Mechanism: Agonists (e.g., phenylephrine) activate \alpha_1 receptors
      ightarrow primarily cause vasoconstriction.

    • Physiological Effect: Leads to an increase in Blood Pressure (BP).

    • Clinical Use of Blockers: Blockade of \alpha_1 receptors (e.g., prazosin) prevents vasoconstriction and lowers BP.

    • Therapeutic Applications: \alpha_1 blockers are used in conditions like Benign Prostatic Hyperplasia (BPH) and hypertension.

  • Alpha-2 ( \alpha_2) Receptor Agonist

    • Mechanism: Presynaptic \alpha_2 agonists (e.g., clonidine, methyldopa) act on autoreceptors
      ightarrow inhibit the release of norepinephrine (NE) from nerve terminals.

    • Physiological Effect: Reduces sympathetic outflow from the central nervous system, leading to a decrease in BP.

    • Antagonist Action: \alpha_2 antagonists (e.g., yohimbine) block these presynaptic receptors
      ightarrow lead to an increase in NE release.

  • Beta-2 ( \beta_2) Receptor Agonist

    • Mechanism: Agonists (e.g., albuterol, salmeterol) stimulate \beta_2 receptors.

    • Physiological Effects: Primarily cause bronchodilation in the lungs and vasodilation in skeletal muscle vasculature.

    • Therapeutic Applications: Used extensively in the treatment of asthma and Chronic Obstructive Pulmonary Disease (COPD).

    • Other Use: Terbutaline (a \beta_2 agonist) is used in tocolysis to relax uterine smooth muscle and inhibit premature labor.

    • Drug Interactions: The effects of \beta_2 agonists can be blocked by nonselective \beta-blockers.

Vasomotor Responses and Clinical Scenarios

  • Dale’s Vasomotor Reversal

    • Concept: A classic experimental pharmacology concept demonstrating the shift in epinephrine's pressor response after \alpha-receptor blockade.

    • Before \alpha-blockade: Epinephrine administration leads to an increase in BP because its \alpha1 vasoconstrictive effects dominate over \beta2 vasodilatory effects.

    • After Irreversible \alpha-blockade: If epinephrine is given after an irreversible \alpha-blocker (e.g., phenoxybenzamine), the \alpha1 effects are eliminated. The unopposed \beta2 vasodilatory effects then dominate, leading to a decrease in BP.

  • Low-dose Epinephrine Effects

    • Cardiovascular Changes:

      • Increases Systolic Blood Pressure (SBP).

      • Decreases Diastolic Blood Pressure (DBP).

      • Results in a widened Pulse Pressure (PP).

      • Increases Heart Rate (HR).

    • Mechanism: At low doses, \beta2-receptor effects (vasodilation) tend to dominate over \alpha1-receptor effects.

  • Norepinephrine (NE) Infusion

    • Cardiovascular Changes:

      • Increases both SBP and DBP.

      • Causes reflex bradycardia (slowing of heart rate) due to the baroreceptor reflex responding to the increased BP.

      • Does not cause a widening of Pulse Pressure.

    • Key Difference from Epinephrine: Norepinephrine has minimal \beta2-receptor activity, primarily acting on \alpha1 and \beta_1 receptors, leading to widespread vasoconstriction and increased cardiac contractility.

  • Phentolamine in Hypertensive Crisis

    • Scenario: Hypertensive crisis can be triggered by the consumption of tyramine-rich foods in patients taking Monoamine Oxidase Inhibitors (MAOIs), leading to a significant increase in catecholamine release.

    • Treatment: Phentolamine (an intravenous \alpha-blocker) is used to reverse the severe vasoconstriction and rapidly lower BP.

    • Mnemonic: "Tyrant tyramine blocked by Phento."

  • Labetalol in Pregnancy

    • Pharmacology: Labetalol is a combined \alpha1 and \beta1/\beta_2 blocker.

    • Clinical Use: Administered intravenously in hypertensive emergencies, including those during pregnancy.

    • Safety in Pregnancy: Labetalol is considered safe for use in preeclampsia/eclampsia and gestational hypertension.

    • Other Safe Antihypertensives in Pregnancy: Hydralazine, methyldopa, and nifedipine.

    • Contraindicated Antihypertensives in Pregnancy: ACE inhibitors and Angiotensin II Receptor Blockers (ARBs) are contraindicated due to potential fetal harm.

  • Vasovagal Syncope

    • Mechanism: Involves an increase in vagal tone (parasympathetic activity) coupled with a decrease in sympathetic activity.

    • Physiological Effects: This imbalance leads to bradycardia (slow heart rate) and hypotension (low blood pressure).

    • Clinical Outcome: The decrease in cerebral blood flow results in fainting (syncope).

    • Triggers: Commonly triggered by stress, pain, or prolonged standing.

    • Diagnosis: Can be clinically tested using a tilt-table test.

Extra High-Yield Nuggets

  • Nicotinic Receptors:

    • Voltage-gated ion channels.

    • N_m (muscle type): Located at the skeletal neuromuscular junction. Blocked by curare, causing skeletal muscle paralysis.

    • N_n (neuronal type): Located in autonomic ganglia and the adrenal medulla. Blocked by hexamethonium, affecting ganglionic transmission.

  • Muscarinic Antagonists:

    • Atropine: The prototype antimuscarinic agent. Causes mydriasis (pupil dilation), tachycardia (increased heart rate), and dry secretions (xerostomia, decreased sweating).

    • Scopolamine: Primarily used for motion sickness.

    • Ipratropium/Tiotropium: Used in the treatment of COPD and asthma as bronchodilators by blocking muscarinic receptors in the airways.

  • Anticholinesterases (AChE Inhibitors):

    • Mechanism: Inhibit the enzyme acetylcholinesterase, leading to increased levels of ACh in the synaptic cleft.

    • Reversible Inhibitors:

      • Edrophonium: Short-acting, used diagnostically for myasthenia gravis.

      • Neostigmine: Used for myasthenia gravis and reversal of neuromuscular blockade.

      • Physostigmine: Crosses the blood-brain barrier, used to treat central anticholinergic toxicity.

    • Irreversible Inhibitors: Organophosphates. Their binding to AChE can become permanent ("aging") over time, which prevents reactivation by drugs like pralidoxime (2-PAM).

  • Adrenergic Receptor Mnemonics:

    • \alpha_1: Constriction (vasoconstriction, pupils, sphincters).

    • \alpha_2: Decreases NE release (presynaptic feedback inhibition).

    • \beta_1: 1 heart (increases heart rate, contractility, renin release).

    • \beta_2: 2 lungs (bronchodilation, vasodilation in skeletal muscle, uterine relaxation).

    • \beta_3: Bladder relaxation, lipolysis.

  • Safe Antihypertensives in Pregnancy (Mnemonic: Hypertensive Moms Love Nifedipine):

    • Hydralazine

    • Methyldopa

    • Labetalol

    • Nifedipine