Pathophysiology and Pharmacology of Opioid- induced Constipation and Irritable Bowel Syndrome (IBS)

What is the mechanism of action (MOA) of opioids?

Opioids activate the μ opioid receptors.

How many types of opioid receptors exist?

Three: mu (μ), delta (δ), and kappa (κ).

Where do opioid analgesics produce their effects in the CNS?

Opioid analgesics produce their effects mainly in the brain and spinal cord.

Why are opioids sometimes injected directly into the spinal cord?

Because the site of action is in the spinal cord, where all sensory fibers are located.

What are the effects of opioid receptor activation in the GI tract?

Activation of μ opioid receptors in the GI tract decreases acetylcholine (Ach) release, reducing GI motility.

What is the ligand for μ opioid receptors?

μ opioid receptors are activated by endorphins and enkephalins.

What happens when an opioid receptor is activated?

Activation of the μ receptor inhibits calcium channels and blocks action potentials.

Why do opioids cause constipation?

Opioids decrease propulsive motility, increase sphincter tone, and enhance fluid absorption, leading to constipation.

Do patients develop tolerance to opioid-induced constipation?

No, opioid users do not develop tolerance to constipation, even though they develop tolerance to the analgesic effects.

What happens to constipation with increasing opioid dose?

Constipation worsens with an increase in opioid dose.

Why does opioid-induced constipation lead to harder stools?

Opioids increase fluid absorption and decrease water content in stool.

What is Methyl-naltrexone?

Methyl-naltrexone is a POMARA drug that blocks opioids from binding to μ receptors in the GI tract but not in the CNS.

Why is Methyl-naltrexone used instead of Naltrexone for opioid-induced constipation?

Naltrexone crosses the blood-brain barrier and blocks central opioid effects, while Methyl-naltrexone only acts in the GI tract.

How does Methyl-naltrexone help opioid users?

It blocks opioid-induced constipation while preserving the analgesic effect of opioids.

What are prokinetic agents?

Prokinetic agents are medications that enhance coordinated GI motility and transit of material in the GI tract.

What is the mechanism of action (MOA) of Metoclopramide?

Metoclopramide is a D₂ antagonist that inhibits dopaminergic receptors in the GI tract, removing inhibition of cholinergic smooth muscle stimulation.

What is the clinical use of Metoclopramide?

It is used as a prokinetic agent to improve gastric emptying, particularly in gastroparesis.

How does Metoclopramide affect nausea and vomiting (NV)?

Metoclopramide antagonizes dopamine, which helps prevent nausea and vomiting.

How does dopamine receptor blockade enhance GI motility?

Blockade of dopamine receptors removes inhibition of acetylcholine, leading to increased acetylcholine release and enhanced GI motility.

How does serotonin influence GI motility?

Serotonin affects GI motility by acting on 5HT4 and 5HT3 receptors.

What is the role of 5HT3 receptors in GI motility?

5HT3 receptors activate neurons that inhibit cholinergic neurons, reducing GI motility.

What is the role of 5HT4 receptors in GI motility?

5HT4 receptors stimulate the release of acetylcholine, increasing GI motility.

What is the mechanism of action (MOA) of Erythromycin in GI motility?

Erythromycin acts similarly to the hormone Motilin, a 22-amino acid peptide hormone released by enterochromaffin cells in the GI tract.

What is the clinical use of Erythromycin in relation to GI motility?

Erythromycin is used to treat diabetic gastroparesis by promoting gastric emptying.

What is Irritable Bowel Syndrome (IBS)?

IBS is a gastrointestinal syndrome of chronic abdominal pain and altered bowel movements in the absence of an organic cause.

What are the two types of IBS?

IBS can be either constipation-dominant or diarrhea-dominant.

What are the primary goals of pharmacologic treatment for IBS?

To relieve abdominal pain and improve GI function.

What is the major etiology of IBS?

Anxiety and depression.

What is visceral hyperalgesia?

An exaggerated feeling of pain, which is a common feature of IBS.

How does anxiety and depression contribute to IBS?

They alter the central processing of afferent stimuli, affecting GI function.

What is post-infectious IBS?

A condition where previous gut infections lead to neuroplastic changes and visceral hyperalgesia.

How can post-infectious IBS be prevented?

By early intervention in infections (e.g., using antibiotics) or primary prevention with probiotics.

What is post-inflammatory IBS?

A chronic immune process in which immune system alterations contribute to IBS symptoms.

What is bile acid malabsorption in IBS?

A genetically determined alteration in the function of the apical ileal bile acid transporter, leading to IBS symptoms.

How common is bile acid malabsorption in IBS patients?

Up to 20% of patients with severe IBS symptoms have bile acid malabsorption.

What is the role of visceral hyperalgesia in IBS?

It involves central and peripheral mechanisms that amplify pain perception in the GI tract.

How common is visceral hyperalgesia in IBS patients?

30% to 40% of IBS patients experience visceral hyperalgesia.

What is the significance of SCN5A mutations in IBS?

SCN5A encodes the sodium channel NaV1.5, and mutations are linked to constipation-predominant IBS.

How can SCN5A mutations be treated in IBS patients?

Anti-arrhythmic drugs like mexiletine may help alleviate symptoms.

What is the role of serotonin in GI motility?

Ligands of 5-HT₃ and 5-HT₄ receptors modulate GI motility.

What happens when 5-HT₃ receptors are blocked?

Blocking 5-HT₃ receptors slows down GI motility.

What happens when 5-HT₄ receptors are activated?

Activating 5-HT₄ receptors increases acetylcholine release, enhancing GI motility.

What is Alosetron and what receptor does it target?

Alosetron is a 5-HT₃ receptor antagonist.

How does Alosetron affect GI motility?

It slows colonic transit and enhances small intestine fluid reabsorption.

What is the clinical use of Alosetron?

It is used to treat IBS-D in women by reducing visceral pain and slowing motility.

What is Tegaserod and what receptor does it target?

Tegaserod is a 5-HT₄ receptor partial agonist.

How does Tegaserod affect GI motility?

It stimulates GI peristalsis, increases intestinal fluid secretion, and reduces visceral sensation.

What is the clinical use of Tegaserod?

It is used to treat IBS-C in women.

Why is Tegaserod only available for emergency use?

Due to cardiovascular (CV) risks associated with its use.

How do serotonin modulators help in IBS treatment?

They regulate GI motility by either slowing (5-HT₃ antagonists) or stimulating (5-HT₄ agonists) bowel movements.

What drug is used to treat diarrhea-dominant IBS (IBS-D)?

Eluxadoline (Viberzi).

What is the mechanism of action (MOA) of Eluxadoline?

Eluxadoline is a peripherally-acting μ opioid receptor (MOR) agonist and a δ opioid receptor (DOR) antagonist in the myenteric plexus.

How does Eluxadoline affect the μ opioid receptor (MOR)?

It activates MOR, leading to K+ channel activation and Ca²+ channel inhibition in cajal cells and enteric neurons, which slows GI motility.

How does Eluxadoline affect intestinal secretion?

It inhibits intestinal secretion by reducing chloride (Cl⁻) secretion and passive water movement.

What is the function of the δ opioid receptor (DOR) in the GI tract?

Similar to MOR, DOR activation slows GI motility and affects secretion.

Why is Eluxadoline preferred over a MOR-only agonist for IBS-D?

Eluxadoline is an agonist for MOR (which reduces pain and slows motility) but an antagonist for DOR, reducing the likelihood of opioid-induced constipation.

What is the advantage of Eluxadoline over traditional opioids for diarrhea control?

It provides pain relief via MOR agonism while controlling diarrhea with less risk of constipation due to DOR antagonism.

Eluxadoline works on two different receptors, what are they and what effects do they have?

It acts on both the μ (MOR) and δ (DOR) receptors but with different effects—agonist at MOR, antagonist at DOR.

What tricyclic antidepressants (TCAs) are used for IBS-D management?

Amitriptyline and Desipramine.

How do TCAs help in IBS-D?

They slow GI motility due to their anticholinergic effects.

What are anticholinergic agents used for in IBS-D?

They help reduce bowel motility and secretions.

What is Loperamide and how does it help in IBS-D?

Loperamide is an opioid receptor agonist that slows GI motility, acting as a "poor man's Viberzi."

How does Loperamide work?

It activates μ opioid receptors in the gut to slow peristalsis and reduce diarrhea.

What is the mechanism of action (MOA) of Lubiprostone (Amitiza)?

Lubiprostone stimulates type 2 chloride channels (ClC-2) in the small intestine, increasing Cl⁻-rich intestinal fluid.

What is the clinical use of Lubiprostone?

It is used to treat constipation in women with IBS-C and chronic idiopathic constipation.

How does Lubiprostone increase intestinal hydration?

It activates Cl⁻ channels, causing chloride secretion into the lumen, followed by sodium and water.

What is the mechanism of action (MOA) of Linaclotide (Linzess)?

Linaclotide is a 14-amino acid peptide agonist on guanylate cyclase-C (GC-C) receptors, increasing cGMP levels.

What are the downstream effects of Linaclotide?

It activates CFTR chloride channels, leading to Cl⁻ and bicarbonate secretion, which draws water into the intestinal lumen.

What additional benefit does Linaclotide provide besides treating constipation?

It decreases activity in pain-sensing afferent neurons, helping with abdominal pain relief.

What conditions is Linaclotide used to treat?

IBS-C and chronic idiopathic constipation.

How does Linaclotide's action compare to Lubiprostone?

Both drugs increase chloride and water secretion into the lumen, but Linaclotide works via cGMP signaling, whereas Lubiprostone directly activates chloride channels.