Prucalopride - Mechanism of Action, Indications, Dosage, and Adverse Drug Reactions

Overview

Prucalopride is a drug that stimulates the muscles in the walls of the intestines to speed up the transit of food, therefore treating chronic constipation (long-term complex bowel movements). It eases symptoms such as straining, hard stools, and irregular bowel motions. Prucalopride is a selective serotonin 5-HT4 receptor (5-hydroxytryptamine receptor 4) agonist. On December 17, 2018, the Food and Drug Administration (FDA) authorized Prucalopride to treat adult chronic constipation. The medical condition, reaction to treatment, and co-occurring drugs influence the dosage. It does not, however, alleviate constipation. Constipation management also requires frequent exercise, drinking water, and eating a balanced diet.

Drug Group

Prucalopride is a 5-HT4 receptor agonist in the class of drugs known as serotoninergic neuroenteric modulators. It works by selectively stimulating the gastrointestinal tract's 5-HT4 receptors, increasing waste material passage through the intestine, and helping cure chronic idiopathic constipation.

Indications

Prucalopride functions as a serotonin-4 (5-HT4) receptor agonist and is indicated in the treatment of chronic idiopathic (unknown cause) constipation in adults.

Contraindications

Prucalopride is contraindicated in patients with:

• A prior history of Prucalopride hypersensitivity (exaggerated immune response). There have been reports of reactions such as dyspnea (shortness of breath), rash, pruritus (itchiness), urticaria (skin rash), and facial edema (swelling).

• Digestive perforation or obstruction brought on by toxin-filled megacolon (an abnormal dilation or enlargement of the colon) or megarectum (an abnormal enlargement or dilation of the rectum), obstructive ileus (a bowel condition where there is a blockage preventing normal digestive flow), or severe inflammatory disorders of the digestive system such as Crohn's disease (a disease that causes inflammation of the digestive tract) or ulcerative colitis (a disease that causes inflammation and ulcers in the large intestine).

Dosage Forms and Available Strengths

Tablet forms of Prucalopride are available in 1 mg (milligram) and 2 mg concentrations.

Warnings and Precautions

• Suicidal Ideation and Behavior: Patients should be closely watched for signs of persistently worsening depression (prolonged sadness) and suicidal thoughts. They should be advised to stop taking Prucalopride immediately and to get in touch with the healthcare provider if the depression gets worse or if suicidal intentions or behaviors start to emerge.

For Patients

What Is Chronic Constipation?

A frequent condition known as chronic constipation is characterized by hard, dry, or lumpy stools, pain or straining, and a feeling of having a plugged rectum. It also results in less than three stools per week. It is regarded as chronic if it persists for three months or more. Chronic constipation can be brought on by a variety of factors, such as a low dietary fiber intake, dehydration, a lack of fluids, and exercise, as well as specific medical disorders and prescription use.

How Does Prucalopride Work?

Prucalopride is a drug that promotes peristalsis, or the natural movement of colon muscles, to increase waste passage through the intestine. The three stages of functioning are ready, set, and move. The medicine targets a particular colon receptor, releases the active substance, and the bowels move. Since it encourages colonic movement, Prucalopride is referred to as a "prokinetic" medication.

What Are the Benefits of Prucalopride?

The key benefits, such as

• Effective Treatment: Prucalopride is prescribed when other drugs, including laxatives, have failed to relieve constipation. The treatment of chronic (long-term) constipation works especially well.

• Better Digestion: Prucalopride enhances the passage of food through the intestines and stomach during digestion. It promotes the release of certain molecules that facilitate better food flow in the intestine·. It aids in speeding up the emptying of both liquid and solid substances in the stomach.

• Targeted Action: Prucalopride is an intrinsically active, selective 5-HT4 receptor agonist. It improves the motility of the gut by indirectly stimulating the production of acetylcholine, a chemical messenger.

• Easy Use: Prucalopride is easy to use because it can be taken with or without food. This allows patients to incorporate it into their routine easily.

How Is Prucalopride Administered?

Prucalopride tablets are taken orally, usually once daily, with or without food. It should be taken as directed on the prescription label at the same time each day. Never take more or less of Prucalopride or take it more frequently than the physician has instructed.

What Are the Side Effects of Prucalopride?

If patients have any of the following symptoms of a Prucalopride allergic reaction:

• Hives (skin rash).

• Trouble breathing.

• Swelling of the neck, tongue, lips, or face.

Patients having Prucalopride allergic reactions should seek emergency medical attention.

If patients experience the following: stop taking Prucalopride and contact the physician immediately.

• Unexpected alterations in behavior or emotions.

• Persistent or getting worse depression.

• Intentions to harm oneself or commit suicide.

• If patients are depressed or hopeful.

Typical adverse effects of Prucalopride could be:

• Vomiting.

• Diarrhea.

• Nausea.

• Stomach ache.

• Gas.

• Bloating.

• Headache.

• Lightheadedness.

• Feeling tired.

What Are the Things to Inform the Doctor Before Taking Prucalopride?

1. If patients have Prucalopride allergies, they should not take Prucalopride. Additionally, if patients have:

• Gastrointestinal obstruction.

• Extreme constipation.

• Ulcerative colitis, Crohn's disease, and other inflammatory bowel disorders.

• Toxic megacolon.

• Intestinal perforation (a hole in the gastrointestinal tract's wall), or a hole or tear.

2. For Prucalopride to be safe for the patient, let the doctor know if the patient has any of the following conditions:

• Illness of the kidneys.

• Depression.

• Psychological condition.

• Suicide ideas.

3. Inform the doctor if a patient is pregnant or nursing.

4. Anyone under 18 is not permitted to use Prucalopride.

Dietary Considerations

Any dietary, beverage, or exercise limitations should be adhered to as directed by the doctor.

Missed Dose

When the next dose of Prucalopride approaches, take it as soon as possible, omit the missed dose, and avoid taking two doses at once.

Overdose

Headache, nausea, and diarrhea can be signs of a Prucalopride overdose. There is no specific treatment for Prucalopride overdose. If an overdose occurs, treat the symptoms and put supportive measures in place. If vomiting or diarrhea causes fluid loss, correct electrolyte imbalances.

Storage and Handling

Keep Prucalopride out of children's reach and store it at room temperature, between 68°F (degrees Fahrenheit) and 77°F (20°C (degrees Celsius) and 25°C), in its original container.

Disposal

It is imperative to appropriately dispose of unnecessary Prucalopride to avoid consumption by children, pets, and other individuals. To guarantee proper disposal, use an FDA drug take-back program rather than flushing them down the toilet.

For Doctors

Description:

Prucalopride is a Dihydrobenzofuran Carboxyamide derivative belonging to the benzofurane family. It has enterokinetic effects because it stimulates 5-HT4 receptors explicitly. Since Prucalopride eliminated the cardiac adverse events linked to previous medicines' non-target effects, its superior selectivity enabled continued development.

What Are the Pharmacological Actions of Prucalopride?

Pharmacodynamics

Prucalopride promotes small bowel, gastric, and colonic transit. At supratherapeutic concentrations, it interacts with L-type calcium channels (a class of voltage-gated calcium channels) and hERG (human ether-a-go-go related gene) potassium channels (an ion channel that contributes to the electrical activity of the heart). According to clinical research, it improves colonic transit time, total bowel movements, and spontaneous bowel movements without appreciably altering anorectal function. Eighty-six percent of test subjects in phase III trials finished the study, and 67 percent reported higher satisfaction levels. Over three complete spontaneous bowel movements per week were achieved by a significantly greater percentage of patients in the final batch of trials submitted for approval.

Mechanism of Action

Prucalopride lowers the risk of cardiovascular disease by selectively stimulating 5-HT4 receptors in the gastrointestinal system. Acetylcholine, a key excitatory neurotransmitter, is released when it activates enterochromaffin cells, smooth muscle cells, and the myenteric plexus. The release of acetylcholine, which causes colon muscle contraction and relaxation, and the propulsion of luminal material, enhances motility. The hERG channel and 5-HT1 receptors are unaffected by Prucalopride.

Pharmacokinetics

• Absorption: Prucalopride has good absorption, with a maximum plasma concentration of 3.79 ng/ml (nanograms per milliliter), a tmax (time to peak drug concentration) of 2.77 hours, an AUC (area under the curve) of 109 ng.h/ml (nanograms. hour per milliliter), and a bioavailability of more than 90 percent that is unaffected by meal ingestion.

• Distribution: Prucalopride has a mean volume of 623 L (liters) and a 30 percent affinity for plasma proteins.

• Metabolism: Prucalopride does not interact with P glycoprotein or cytochrome P450 enzymes and is not substantially metabolized in the body. Only six percent of the total dose was given; the other 94 percent is unaltered. Research has indicated the recovery of eight metabolites, the primary metabolite being R107504, which is generated when alcohol is oxidized to carboxylic acid and undergoes O-demethylation.

• Excretion: Prucalopride concentration declines biphasically after reaching the peak plasma concentration, with 84 percent of the dosage eliminated in the urine. Its renal clearance rate of 17 L/h (liters per hour) surpasses the kidney's glomerular filtration rate, and its half-life is 18 to 20 hours. The dosage retrieved in feces is only 13 percent.

Toxicity

When used over ten times the prescribed dosage, Prucalopride is well tolerated; overdose symptoms may include headaches, nausea, and diarrhea. Studies on carcinogenicity reveal that rats treated with 80 mg/kg/day (milligrams per kilogram per day) had a higher incidence of mammary gland adenocarcinoma, as well as benign adrenal pheochromocytoma, hepatocellular adenoma, pituitary adenoma, pancreatic adenoma, and thyroid follicular tumors. Prucalopride had no negative impacts on fertility and just one weak positive result in a bacterial strain reverse mutation test at high dosages.

What Are the Drug Interactions of Prucalopride?

Effect of Prucalopride on Other Drugs:

• Fosfomycin: When Prucalopride is used with Fosfomycin, a medicine for urinary tract infections (UTIs), there is a chance that the body fails to utilize the full dose, which would reduce the drug's effectiveness in treating UTIs.

• Erythromycin: The study discovered that taking Prucalopride and oral Erythromycin together raised the drug's mean Cmax (maximum concentration) and AUC0-24h (hours) by 28 percent and 40 percent, respectively; however, the exact mechanism remains unknown.

• Other Drugs: When co-administered with Prucalopride, there were no clinically significant variations in the pharmacokinetics (no more than a 10 percent shift in AUC) of Warfarin, Digoxin, Paroxetine, or oral contraceptives (Ethinyl estradiol and Norethisterone).

Effect of Other Drugs on Prucalopride:

• Ketoconazole: The Cmax and AUC of Prucalopride were markedly elevated by about 40 percent by Ketoconazole, a strong CYP3A inhibitor as well as a P-gp and BCRP inhibitor; however, this effect is unlikely to be clinically relevant.

• Other Drugs: When co-administered with Erythromycin, Probenecid, Cimetidine, or Paroxetine, the study demonstrated no significant alterations in the pharmacokinetics of Prucalopride, with a 10 percent change in AUC.

Clinical Studies

Prucalopride's effectiveness was assessed in six randomized, multicenter, double-blind, placebo-controlled clinical trials and 12 weeks happened for Studies 1 to 5 and 24 weeks for Study 6. 2,484 adult patients with chronic idiopathic constipation (CIC) were included in the studies. The primary efficacy endpoint was the percentage of patients who experienced more than three complete spontaneous bowel movements (CSBMs) on average per week during the 12-week treatment period.

Compared to patients who got a placebo, more people who received Prucalopride had an increase in CSBMs to at least three bowel movements per week. In a further analysis, throughout the 12-week treatment period, a higher proportion of patients on Prucalopride (47.0 percent versus 29.9 percent) experienced a mean increase of more than one CSBM per week compared to placebo. Improvements persisted for the entire 12-week course of treatment, with a prompt response evident as early as the first week. Patients taking Prucalopride had their first CSBM 1.4 to 4.7 days into treatment, versus 9.1 to 20.6 days for those taking a placebo.

Use in Specific Populations

• Pregnancy: Prucalopride belongs to category B in terms of pregnancy. This category is used for drugs for which adequate and carefully conducted studies in pregnant women have not been conducted and where studies on animal reproduction have not shown harm to the fetus. It is crucial to remember that even though studies have not revealed any hazards, this does not mean the drug is entirely risk-free.

• Breastfeeding: Prucalopride excretes very little in breast milk, so it should be taken cautiously during nursing. However, there is insufficient research on infant risk, and how it affects nursing infants is unclear. It is advised to speak with a healthcare professional if symptoms such as diarrhea are noticed.

• Pediatric Use: It is unknown if Prucalopride is safe and effective for use with children or adolescents.

• Geriatric Use: Compared to younger patients, elderly individuals are exposed to higher levels of Prucalopride; however, this impact is associated with decreased renal function, suggesting that dosage should be adjusted based on renal function.

• Renal Impairment: Dosage adjustments are unnecessary for patients with mild to moderate renal impairment. However, because of the possibility of adverse effects, people with severe renal impairment ought to take a lower dosage. Because Prucalopride is eliminated through the kidney, it is not recommended for people with end-stage renal disease who need dialysis.