That's Dope-a-minergic
How do D₂ receptors regulate motility within the myenteric plexus?
D₂ activation inhibits ACh release → ↓ smooth muscle contraction; antagonism reverses this
What is the main serotonin receptor subtype that promotes peristalsis?
5-HT₄ receptor
What receptor family mediates erythromycin’s GI effects?
Motilin receptors (Gq-coupled on smooth muscle
What dual mechanism makes ranitidine and nizatidine unique among H₂ antagonists?
H₂ blockade + acetylcholinesterase inhibition
How does lidocaine act as a prokinetic beyond sodium-channel blockade?
Suppresses sympathetic reflex arcs and decreases inflammatory cytokine release → restores excitatory tone.
Explain why metoclopramide’s dopaminergic effect is limited to the upper GI tract.
Dopaminergic neurons are concentrated in gastric and pyloric regions; minimal distribution distally
What dual serotonergic mechanism explains cisapride’s superior motility effect compared to metoclopramide?
5-HT₄ agonism + 5-HT₁/₃ antagonism → increased ACh release and reduced inhibition
What is erythromycin’s secondary receptor activity that contributes to antiemetic benefit?
5-HT₃ receptor antagonism
How does acetylcholinesterase inhibition potentiate motility?
Increases ACh persistence → prolonged M₃ receptor activation → smooth-muscle contraction.
Explain how prokinetic therapy can indirectly improve mucosal barrier integrity.
Restores luminal flow and nutrient delivery → stimulates epithelial turnover + reduces bacterial overgrowth and endotoxin exposure.
How does metoclopramide’s MOA improve efficacy compared with pure D₂ blockers?
Dual D₂-antagonism + 5-HT₄-agonism --> Simultaneous removal of dopaminergic inhibition and direct facilitation of cholinergic output.
What effect does 5-HT₄ activation have at the presynaptic terminal?
Stimulates ACh release from postganglionic cholinergic neurons
What species difference explains why erythromycin is more effective in dogs than cats?
Cats have fewer motilin receptors in distal small intestine
Which muscarinic receptor subtype mediates GI smooth-muscle contraction?
M₃ receptor (Gq-coupled → ↑ IP₃ → Ca²⁺ release).
Explain the interplay between histaminergic and cholinergic pathways in gastric motility, including how H₂ blockade might indirectly influence peristaltic activity.
Histamine --> H₂ receptors (Gs-coupled) in parietal cells increases gastric acid secretion; antral motility via duodenal negative feedback.
H₂ antagonists (ranitidine, nizatidine) reduce acid-mediated inhibition, allowing enhanced antral contractions and improved gastric emptying.
Additionally, their AChE-inhibiting effect potentiates cholinergic tone, reinforcing motility enhancement through dual mechanisms.
How does adrenergic signaling interact with dopaminergic tone to influence GI motility in critical illness?
Excess sympathetic (α₂-adrenergic) stimulation inhibits ACh release and potentiates D₂-mediated suppression of motility.
D₂ antagonists may partially offset this effect, but persistent adrenergic dominance (e.g., from catecholamine CRIs) maintains ileus.
What is the MOA of cisapride.
Cisapride is a serotonin 5-HT₄ receptor agonist that acts presynaptically on myenteric cholinergic neurons to enhance ACh release, also 5-HT₁ and 5-HT₃ antagonism, which reduces inhibitory reflexes and sensory feedback.
Cisapride enhances colonic motility primarily through 5-HT₄ receptor agonism in the myenteric plexus of the distal bowel and may exert mild direct stimulation of 5-HT₂B receptors on colonic smooth muscle.,
The result is increased excitatory cholinergic tone, improved esophageal clearance, gastric emptying, and colonic peristalsis without direct smooth-muscle stimulation.
Why is the prokinetic effect of erythromycin lost with chronic administration?
Receptor desensitization and motilin-receptor down-regulation.
How does systemic inflammation alter cholinergic tone in the enteric nervous system during critical illness?
Inflammatory cytokines (TNF-α, IL-1β) suppress ACh synthesis and release by enteric neurons, while nitric oxide and reactive oxygen species decrease receptor responsiveness.
This leads to depressed peristalsis and contributes to sepsis-associated ileus.
How does inflammation alter NO signaling in smooth muscle?
Inducible NOS (iNOS) upregulated → excessive NO → cGMP accumulation → sustained relaxation.
Explain the mechanism behind extrapyramidal signs seen in animals receiving high-dose or prolonged metoclopramide therapy.
Metoclopramide crosses the blood–brain barrier and blocks central D₂ receptors in the basal ganglia (especially the caudate nucleus). This disrupts dopaminergic–cholinergic balance within extrapyramidal motor pathways, leading to involuntary muscle rigidity, tremors, hyperactivity, and restlessness. Signs are dose-dependent and reversed with anticholinergic or antihistaminic agents (e.g., diphenhydramine).
Which intracellular messenger is increased when 5-HT₄ receptors on myenteric neurons are stimulated?
↑ cAMP → enhanced ACh release and excitatory motor neuron firing.
What is the mechanism of erythromycin-induced retrograde peristalsis at high doses?
Excess motilin activation → uncoordinated contractions between antrum and duodenum.
How does vagal efferent firing pattern (tonic vs. phasic) determine the type of ACh release and motility pattern generated and how does critical illness change this.
Tonic firing: low-frequency baseline → promotes segmental contractions for mixing and nutrient absorption.
Phasic bursts: high-frequency firing → triggers propagating peristaltic waves.
Critical illness blunts phasic firing due to impaired vagal–nucleus tractus solitarius integration, shifting motility toward atony and stasis.
How does vagal stimulation influence acetylcholine-mediated motility, and what is the pharmacologic implication of reduced vagal tone in critical illness?
The vagus nerve enhances coordinated ACh release within the myenteric plexus, promoting peristalsis and gastric emptying. In critical illness or anesthesia, reduced vagal tone and sympathetic dominance suppress cholinergic transmission, decreasing motility. Prokinetic efficacy (e.g., of AChE inhibitors or metoclopramide) is diminished under these conditions.