DISSENTEN TABLETS

Indications

• Acute diarrhea
• Chronic diarrhea
• Irritable bowel syndrome
• Traveler's diarrhea

Dosage

Children: For children aged 6 to 8 years, the recommended dose is 1 mg after each loose stool, not exceeding 3 mg per day

Adults: The usual adult dose for acute diarrhea is 4 mg initially, followed by 2 mg after each loose stool, not exceeding 16 mg per day.

Mechanism of action

Loperamide binds to mu (μ)-opioid receptors in the intestinal muscles, inhibiting enteric nerve activity. This leads to decreased neurotransmitter release, pre- and post-synaptic inhibition of excitatory and inhibitory pathways, and enhancement of fluid and electrolyte absorption. Consequently, it reduces propulsive peristalsis, increases intestinal transit time, and promotes the formation of firmer stools.

Pharmacodynamics

Loperamide decreases gastrointestinal motility and fluid secretion, leading to increased rectal tone and reduced fecal volume. It enhances the viscosity and bulk density of feces, thus alleviating symptoms of diarrhea. The onset of action is approximately one hour, with effects lasting up to three days. While it is a potent mu-opioid receptor agonist, it does not typically produce analgesic effects at standard doses. At excessive doses, loperamide may cause central nervous system effects and cardiac conduction issues.

Pharmacokinetics

Loperamide is absorbed well from the gastrointestinal tract, but it undergoes extensive first-pass metabolism in the liver. It binds to plasma proteins and is primarily metabolized by the cytochrome P450 system. The elimination half-life is variable but generally ranges from 10 to 12 hours. Renal excretion plays a minor role in its elimination, with the majority of the drug excreted as metabolites. High doses can cause the drug to cross the blood-brain barrier, potentially leading to toxicity.

Contra-indications

• Severe colitis or infectious diarrhea
• Acute abdominal pain of unknown origin
• Hypersensitivity to loperamide or any of its components

Adverse effects

• Constipation
• Dizziness
• Nausea
• Abdominal pain
• Dry mouth
• Fatigue
• Headache
• Potential for cardiac effects at high doses

Interactions

• Berotralstat+loperamide: Moderate (increases concentration)
• Eliglustat+loperamide: Moderate (increases exposure)
• Sotorasib+loperamide: Moderate (increases exposure)
• Tucatinib+loperamide: Moderate (increases exposure)
• Vemurafenib+loperamide: Moderate (increases exposure)
• Dronedarone+loperamide: Unknown (increases exposure)
• Clozapine+loperamide: Unknown (additive effect)
• Ceritinib+loperamide: Unknown (increases exposure)
• Loperamide+oral desmopressin: Unknown (increases absorption)
• Loperamide+possibly sublingual: Unknown (increases absorption)

Precautions

• Use with caution in patients with liver impairment
• Avoid exceeding recommended doses to prevent central effects
• Monitor for signs of dehydration in patients with diarrhea
• Not for use in chronic diarrhea without medical advice

Pregnancy

Loperamide should be used in pregnancy only if clearly needed, as safety in human pregnancy has not been established.

Breast-feeding

Loperamide is excreted in breast milk, and caution is advised when administered to nursing mothers.

Storage

Store at room temperature, away from moisture and light. Keep out of reach of children.

Formulations

• Oral tablets
• Oral capsules
• Oral solution

Indications

• Symptomatic treatment of acute diarrhoea
• Chronic diarrhoea management
• Control of faecal consistency after colostomy or ileostomy

Dosage

Children: For children aged 4–7 years, 1 mg 3–4 times a day for up to 3 days; for children aged 8–11 years, 2 mg 4 times a day for up to 5 days; for children aged 12–17 years, initially 4 mg, followed by 2 mg for up to 5 days, with a maximum of 6–8 mg daily.

Adults: Initially 4 mg, followed by 2 mg after each loose stool, not to exceed 16 mg per day.

Mechanism of action

Loperamide acts on the mu-opioid receptors in the myenteric plexus of the large intestine. By binding to these receptors, it decreases gastrointestinal motility and increases the time taken for substances to transit through the bowel. This leads to enhanced absorption of fluids and electrolytes and thus reduces the frequency of defecation.

Pharmacodynamics

Loperamide exhibits its effects by inhibiting peristalsis, which decreases the propulsion of intestinal contents. It affects the secretion of fluids and electrolytes, promoting reabsorption in the intestinal mucosa, and indirectly increases anal sphincter tone, which helps to control bowel movements.

Pharmacokinetics

Loperamide is well absorbed from the gastrointestinal tract, with peak plasma concentrations occurring approximately 2.5 hours after oral administration. It undergoes extensive first-pass metabolism in the liver, resulting in a bioavailability of about 0.3% to 0.5%. The elimination half-life is approximately 10.8 hours, and it is primarily excreted in the feces as metabolites. Renal impairment may prolong its effects due to reduced clearance.

Contra-indications

• Antibiotic-associated colitis
• Gastrointestinal obstruction
• Intestinal atony
• Myasthenia gravis
• Paralytic ileus
• Prostatic enlargement (in adults)
• Pyloric stenosis
• Severe ulcerative colitis
• Significant bladder outflow obstruction
• Toxic megacolon
• Urinary retention

Adverse effects

• Abdominal discomfort
• Angioedema
• Cardiac disorder
• Depression
• Dysuria
• Fever
• Gastrointestinal disorders
• Malaise
• Mucosal dryness
• Restlessness
• Vision disorders

Interactions

• Atropine
• Opioids

Precautions

• Cardiac arrhythmias
• Pancreatitis
• Severe pulmonary conditions
• Renal impairment

Pregnancy

Manufacturer advises caution during pregnancy

Breast-feeding

Therapeutic doses unlikely to affect infant

Storage

Store in a cool, dry place, away from light

Formulations

• Tablets
• Oral suspension

Mechanism of action

Enteric neurons synthesize and release endogenous opioid peptides and other neurotransmitters, such as acetylcholine and substance P. Endogenous opioids bind to opioid receptors expressed on these neurons to regulate gastrointestinal signalling, motility, and balance of fluids and electrolytes. Loperamide acts on the mu (μ)-opioid receptor expressed on the circular and longitudinal intestinal muscle. Receptor binding leads to the recruitment of G-protein receptor kinases and the activation of downstream molecular cascades that inhibit enteric nerve activity. By inhibiting the excitability of enteric neurons, loperamide suppresses neurotransmitter release, pre-synaptic and post-synaptic inhibition of transmission of excitatory and inhibitory motor pathways, and secretomotor pathways. Loperamide inhibits the release of acetylcholine and prostaglandins, thereby reducing propulsive peristalsis and increasing intestinal transit time. Loperamide stimulates the intestinal absorption of water and electrolytes by inhibiting calmodulin. Loperamide can bind to and hyperpolarize submucosal secretomotor neurons, promoting dry, hard stools. ... The present study investigates the mechanism of the central analgesic effect of loperamide. Adult male Sprague-Dawley rats were subjected to surgery for catheter placement. Following baseline testing, different groups of rats were administered fixed intrathecal doses (1 ug, 3 ug, 10 ug and 30 ug) of loperamide and morphine. Analgesia was compared employing Hargreaves paw withdrawal apparatus at 15 min, 30 min, 60 min, 90 min and 120 min. Additionally, CTOP, a specific mu-opioid receptor antagonist was co-administered with loperamide to examine the mu-opioid receptor mediated loperamide analgesia. Furthermore, nefiracetam, a calcium channel opener, was co-administered with loperamide or morphine to evaluate the involvement of Ca(2+) channels in loperamide showed an analgesic effect which was comparable to morphine. However, loperamide produced longer analgesia and the analgesic effect was significantly better at 42 hr and 49 hr compared to morphine. CTOP completely reversed loperamide analgesia. Though nefiracetam significantly reversed loperamide analgesia, it did not have any effect on morphine induced analgesia. Our findings suggest that loperamide administered intrathecally produces analgesia which is mediated through mu-opioid receptor and subsequent blockade of downstream calcium channels. The effects of the antidiarrheal agent loperamide on high-voltage-activated (HVA) calcium channel activity and excitatory amino acid-evoked responses in two preparations of cultured hippocampal pyramidal neurons were examined. In rat hippocampal neurons loaded with the calcium-sensitive dye fura-2, rises in intracellular free calcium concentration ([Ca2+]i) evoked by transient exposure to 50 mM K(+)-containing medium [high extracellular potassium concentration ([K+]o)] were mediated by Ca2+ flux largely through nifedipine-sensitive Ca2+ channels, with smaller contributions from omega-conotoxin GVIA (omega-CgTx)-sensitive Ca2+ channels and channels insensitive to both nifedipine and omega-CgTx. Loperamide reversibly blocked rises in [Ca2+]i evoked by high [K+]o in a concentration-dependent manner, with an IC50 of 0.9 +/- 0.2 microM. At the highest concentration tested (50 microM), loperamide eliminated rises in [Ca2+]i evoked by high [K+]o, a result otherwise achieved only in Ca(2+)-free medium or by the combined application of nifedipine, omega-CgTx, and funnel web spider venom to Ca(2+)-containing medium. The action of loperamide was neither naloxone sensitive nor mimicked by morphine and was seen at concentrations substantially less than those required to block influx of Ca2+ through the N-methyl-D-aspartate (NMDA) receptor-operated ionophore. Similar results were obtained in cultured mouse hippocampal pyramidal neurons under whole-cell voltage clamp. Voltage-activated Ca2+ channel currents carried by bariu

Pharmacodynamics

Loperamide is an anti-diarrheal agent that provides symptomatic relief of diarrhea. It decreases peristalsis and fluid secretion in the gastrointestinal tract, delays colonic transit time, and increases the absorption of fluids and electrolytes from the gastrointestinal tract. Loperamide also increases rectal tone, reduces daily fecal volume, and increases the viscosity and bulk density of feces. It also increases the tone of the anal sphincter, thereby reducing incontinence and urgency. The onset of action is about one hour and the duration of action can be up to three days. While loperamide is a potent mu-opioid receptor agonist, it does not mediate significant analgesic activity at therapeutic and supratherapeutic doses. However, at high doses of loperamide, inhibition of P-glycoprotein-mediated drug efflux may allow loperamide to cross the blood-brain barrier, where loperamide can exert central opioid effects and toxicity. At very high plasma concentrations, loperamide can interfere with cardiac conduction. Because loperamide inhibits the Na⁺-gated cardiac channels and ether-a-go-go–related gene potassium channels, the drug can prolong the QRS complex and the QTc interval, which can lead to ventricular dysrhythmias, monomorphic and polymorphic ventricular tachycardia, torsade de pointes, ventricular fibrillation, Brugada syndrome, cardiac arrest, and death.