Terlipressin

Usage

• Terlipressin is prescribed for the treatment of bleeding esophageal varices, hepatorenal syndrome type 1 (HRS-1), and in some cases, other types of gastrointestinal bleeding in patients with cirrhosis. It is sometimes used as an adjuvant therapy to endoscopic hemostasis in the case of esophageal varices.
• Pharmacological Classification: Vasoconstrictor, synthetic analog of vasopressin.
• Mechanism of Action: Terlipressin is a prodrug of lysine vasopressin (LVP). It causes vasoconstriction of the splanchnic arterial bed, reducing portal venous pressure, which helps control bleeding from esophageal varices. It also improves renal perfusion in HRS-1.

Alternate Names

• Generic Name: Terlipressin acetate
• Brand Names: Glypressin, Terlivaz

How It Works

• Pharmacodynamics: Terlipressin causes vasoconstriction primarily in the splanchnic circulation, leading to reduced portal hypertension. It also has some antidiuretic effects, though less potent than vasopressin. In HRS-1, improved renal perfusion and glomerular filtration rate (GFR) are observed.
• Pharmacokinetics: Administered intravenously, it is metabolized to LVP by tissue peptidases. LVP has a short half-life (approximately 4-6 hours).
• Mode of Action: Binds to V1 receptors in vascular smooth muscle, leading to vasoconstriction.
• Receptor Binding: Primarily V1 receptor agonist.
• Elimination Pathways: Metabolized by ubiquitous peptidases; does not rely on specific CYP enzymes. Excretion is primarily renal.

Dosage

Standard Dosage

Adults:

• Bleeding Esophageal Varices: Initially 1-2 mg IV every 4-6 hours, depending on the patient’s body weight, until bleeding is controlled (up to 48 hours). Dose may be reduced to 1 mg every 4-6 hours for patients <50kg, if adverse effects occur. Some sources suggest subsequent doses can be 1mg q4-6h for all adults and durations as long as 72 hours. Continuous infusion of 2-12 mg terlipressin acetate per 24 hours can also be considered.
• HRS-1: 1 mg IV every 4-6 hours; may be increased up to 2 mg every 4-6 hours if serum creatinine does not decrease by at least 25% after 3 days. Maximum treatment duration is 14 days. Continuous infusion is an option beginning at 2 mg/24 hours and titrating to 12 mg/24 hours if needed. This route might offer a better adverse effects profile.

Children:

• No established pediatric dosing guidelines. Use with extreme caution, considering limited experience in pediatric populations.

Special Cases:

• Elderly Patients: Use with caution due to limited experience and potential for increased sensitivity to cardiovascular side effects.
• Patients with Renal Impairment: Use with caution in advanced renal dysfunction (serum creatinine ≥ 442 μmol/L), but may still be used if benefits outweigh risks.
• Patients with Hepatic Dysfunction: No dose adjustment typically required.
• Patients with Comorbid Conditions: Caution in those with uncontrolled hypertension, asthma/COPD, cardiac disease, arrhythmias, or vascular disease.

Clinical Use Cases

Dosage is primarily determined by the indication (esophageal variceal bleeding or HRS-1) as described above. Its usage may also be indicated for acute variceal bleeding if endoscopic therapy is not immediately available. It may be employed in cases where endoscopic treatment has failed to resolve the variceal bleeding.

Dosage Adjustments

As detailed in the “Standard Dosage” and “Special Cases” sections.

Side Effects

Common Side Effects:

Abdominal pain, nausea, diarrhea, dyspnea, headache, bradycardia, ischemia-related events, pallor, hypertension, hypotension, fluid overload, pleural effusion.

Rare but Serious Side Effects:

Respiratory failure, intestinal ischemia, ventricular arrhythmias (including Torsade de pointes), cutaneous ischemia and necrosis, hyponatremia, hyperglycemia, bronchospasm, seizures, uterine ischemia.

Long-Term Effects:

Chronic complications are not typically seen, as terlipressin is used for short-term treatment. However, prolonged use may exacerbate underlying cardiovascular or respiratory issues.

Adverse Drug Reactions (ADR):

Severe circulatory adverse effects, cardiac ischemia, cerebrovascular ischemia, peripheral ischemia.

Contraindications

• Absolute: Hypersensitivity to terlipressin, pregnancy, unstable angina, recent myocardial infarction, septic shock with low cardiac output, ongoing coronary, peripheral or mesenteric ischemia, hypoxia/worsening respiratory symptoms.

Drug Interactions

• Non-selective beta-blockers: Increased hypotensive effect on the portal vein.
• Drugs prolonging the QT interval (e.g., Class IA and III antiarrhythmics, erythromycin, certain antihistamines and tricyclic antidepressants): Increased risk of Torsade de pointes.
• Medications that cause hypokalemia or hypomagnesemia (e.g., some diuretics): Increased risk of Torsade de pointes.
• Medications with known bradycardic effects (e.g., propofol, sufentanil): Increased bradycardia.

Pregnancy and Breastfeeding

• Pregnancy Safety Category: Contraindicated (Category D - Australia, unclassified - USA). May cause uterine contractions, increased intrauterine pressure, and decreased uterine blood flow. Embryotoxic and teratogenic in animal studies.
• Breastfeeding: Unknown if excreted in breast milk. Not recommended during breastfeeding.

Drug Profile Summary

• Mechanism of Action: Prodrug converted to lysine vasopressin, causing splanchnic vasoconstriction and reduced portal pressure.
• Side Effects: Abdominal pain, nausea, diarrhea, dyspnea, bradycardia, ischemia-related events (common); respiratory failure, arrhythmias, cutaneous ischemia (serious).
• Contraindications: Hypersensitivity, pregnancy, unstable angina, recent MI, septic shock.
• Drug Interactions: Non-selective beta-blockers, QT prolonging drugs, bradycardic drugs.
• Pregnancy & Breastfeeding: Contraindicated in pregnancy; not recommended while breastfeeding.
• Dosage: See detailed dosage section above.
• Monitoring Parameters: Blood pressure, heart rate, serum creatinine, electrolytes (especially sodium and potassium).

Popular Combinations

Often used in combination with albumin for HRS-1, but this does not alter terlipressin dosing.

Precautions

• General Precautions: Monitor vital signs, renal function, electrolytes. Screen for cardiac, respiratory, and vascular diseases.
• Specific Populations: Use with caution in elderly patients and those with renal impairment. Contraindicated in pregnancy.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Terlipressin?

A: See detailed dosage guidelines above, which vary according to indication and patient factors.

Q2: What are the major side effects of Terlipressin?

A: Common side effects include abdominal pain, nausea, diarrhea, and dyspnea. Serious side effects may include respiratory failure, cardiac arrhythmias (including Torsade de pointes), and cutaneous ischemia.

Q3: Is Terlipressin safe to use during pregnancy?

A: No, Terlipressin is contraindicated in pregnancy. It can cause uterine contractions and reduce uterine blood flow, potentially harming the fetus.

Q4: How does Terlipressin work in hepatorenal syndrome?

A: Terlipressin constricts splanchnic vessels, which can improve renal perfusion and increase glomerular filtration rate in HRS-1.

Q5: What are the contraindications for using Terlipressin?

A: Contraindications include hypersensitivity to terlipressin, pregnancy, unstable angina, recent myocardial infarction, and septic shock with low cardiac output. Caution should be used in patients with other cardiovascular or respiratory issues. Ongoing coronary, peripheral, or mesenteric ischemia and hypoxia/worsening respiratory function are also contraindications.

Q6: How is Terlipressin administered?

A: Terlipressin is administered intravenously, either as a bolus injection or as a continuous infusion.

Q7: Are there any significant drug interactions with Terlipressin?

A: Yes. Terlipressin can interact with non-selective beta-blockers, drugs that prolong the QT interval (like certain antiarrhythmics and antibiotics), and medications causing hypokalemia or hypomagnesemia. Concomitant use with other bradycardic agents should also be avoided.

Q8: What monitoring is necessary during Terlipressin therapy?

A: Close monitoring of blood pressure, heart rate, serum creatinine, and electrolytes (especially sodium and potassium) is recommended. Respiratory function and cardiovascular stability also require careful observation during administration.

Q9: What is the duration of Terlipressin treatment?

A: The treatment duration varies. For bleeding esophageal varices, it’s usually up to 48-72 hours. For HRS-1, it can be up to 14 days.