Search. Learn. Save

Platform for Pharmaceutical Products for Healthcare Professionals
Search By
☰ Generic Formulas

Generic Formulas X

Terlipressin

Terlipressin: A Comprehensive Overview of a Life-Saving Drug

Introduction

Terlipressin is a synthetic vasopressin analog that has found a crucial role in the management of several life-threatening conditions, particularly in critical care and hepatology. As an analog of vasopressin, it has potent vasoconstrictive properties that make it indispensable in the treatment of conditions like variceal bleeding, hepatorenal syndrome (HRS), and septic shock. Approved for various uses around the world, terlipressin continues to be a vital tool in the therapeutic arsenal of healthcare professionals.

1. What is Terlipressin?

Terlpressin (brand names: Glypressin, Terlivaz, among others) is a synthetic long-acting analog of the endogenous hormone vasopressin. It acts primarily on vasopressin V1 receptors located on vascular smooth muscle, causing vasoconstriction.

Originally developed in the 1980s, terlipressin was designed to address the limitations of vasopressin, particularly its short half-life and widespread systemic effects. By modifying the structure and pharmacokinetics of vasopressin, researchers created a compound that offers targeted vasoconstriction with fewer adverse effects.

2. Mechanism of Action

Terlipressin is a prodrug, which means it requires enzymatic conversion in the body to become active. After administration, it is gradually cleaved by endothelial peptidases into lysine vasopressin, the active metabolite.

Receptor Binding:

V1 receptors: Located on vascular smooth muscle; stimulation leads to vasoconstriction, particularly in the splanchnic (intestinal) circulation.

V2 receptors: Found in the kidney; while terlipressin has minimal activity here, vasopressin analogs can affect water retention.

V3 receptors: Involved in ACTH release from the pituitary; terlipressin has minimal activity here as well.

The selective action on V1 receptors leads to decreased blood flow in the portal venous system, making it ideal for treating portal hypertension-related complications.

3. Pharmacokinetics

Administration: Intravenous (IV) bolus or infusion

Onset of action: Within minutes

Half-life: 6 hours (much longer than vasopressin's 10–20 minutes)

Duration of action: 4–6 hours

Metabolism: Enzymatic cleavage to lysine vasopressin

Excretion: Renal and hepatic pathways

This prolonged duration of action allows for less frequent dosing and sustained therapeutic effects, reducing the need for continuous infusions.

4. Clinical Uses of Terlipressin

Terlipressin is primarily used in the management of advanced liver disease complications and certain types of shock. Here are the most common indications:

a. Acute Esophageal Variceal Bleeding (EVB)

One of the most life-threatening complications of portal hypertension in cirrhosis is esophageal variceal bleeding. Terlipressin reduces portal venous pressure by vasoconstriction of splanchnic arterioles.

Evidence:

Studies have shown that terlipressin is as effective as endoscopic band ligation in controlling acute variceal bleeding.

It also reduces mortality and rebleeding when used early.

Dosing:

Initial: 2 mg IV every 4 hours

Maintenance: 1 mg IV every 4–6 hours for up to 48–72 hours

b. Hepatorenal Syndrome (HRS-AKI)

HRS is a severe complication of liver failure, marked by rapid deterioration of kidney function due to intense renal vasoconstriction.

Mechanism:

Terlipressin counteracts the vasodilation of splanchnic circulation, improving effective arterial blood volume and renal perfusion.

Evidence:

Clinical trials (e.g., CONFIRM trial) demonstrated that terlipressin, combined with albumin, improves renal function in HRS patients.

Dosing:

0.5–2 mg IV every 4–6 hours, titrated based on response

c. Septic Shock

Although not yet approved universally for septic shock, terlipressin has been investigated as an adjunct to catecholamines in vasodilatory shock. Its selective V1 receptor action may lead to better hemodynamic stability with fewer side effects compared to vasopressin.

5. Comparative Effectiveness

Terlipressin has often been compared with other vasoactive agents like octreotide, somatostatin, and vasopressin. It tends to outperform these alternatives in certain indications due to its:

Longer half-life

Highr splanchnic selectivity

Ability to reverse HRS-AKI effectively

However, its use should always be tailored to patient-specific factors, including hemodynamic status and liver function.

6. Adverse Effects and Safety Concerns

Terlipressin, while effective, can cause several side effects, particularly due to its vasoconstrictive action.

Common Side Effects:

Abdominal cramps

Headache

Hypertension

Bradycardia

Pale or cold extremities

Serious Adverse Effects:

Ischemia (myocardial, skin, bowel, peripheral)

Respirtory failure

Cardiac arrhythmias

Black Box Warning (U.S.):

In 2022, the FDA approved terlipressin (Terlivaz) for HRS-AKI but added a boxed warning about serious respiratory failure, particularly in those with hypoxia or pre-existing respiratory issues.

Monitoring Parameters:

Blood pressure

Heart rate

Oxygen saturation

Renal function (creatinine, urine output)

Liver function tests

ECG (n patients with cardiac history)

7. Contraindications and Precautions

Contraindications:

Hypersensitivity to terlipressin or vasopressin

Hypoxia or respiratory distress

Active ischemic heart disease or peripheral arterial disease

Precautions:

Use caution in patients with cardiovascular disease

Monitor closely in patients with asthma or chronic lung disease

8. Special Populations

Pregnancy and Lactation:

Terlipressin is not recommended in pregnancy due to uterine vasoconstriction and potential for fetal hypoxia.

It is unknown if terlipressin is excreted in breast milk.

Pediatrics:

Limited data available; not commonly used

Geriatrics:

Increased sensitivity to vasoactive drugs; start with lower doses

9. Clinical Guidelines and Recommendations

Terlipressin has been incorporated into several clinical practice guidelines:

EASL (European Association for the Study of the Liver): Recommends terlipressin for the treatment of HRS and variceal bleeding.

AASLD (American Association for the Study of Liver Diseases): Supports terlipressin use in variceal bleeding and in combination with albumin for HRS-AKI.

NIkE (UK): Endorses terlipressin for HRS treatment when available.

10. Recent Research and Future Directions

a. CONFIRM Trial (2021):

A pivotal phase 3 trial in the U.S. that led to FDA approval for HRS.

Showed significant improvement in renal function and reduction in need for renal replacement therapy.

b. New Delivery Methods:

Intraenous infusions vs. bolus dosing: Continuous infusions may have fewer side effects.

Subcutaneous delivery under research.

c. Expanding Use Cases:

Exploring utility in sepsis, cardiac surgery, and pediatric cirrhosis.

Investigating combination therapies with norepinephrine or midodrine.

11. Cost and Availability

Terlipressin is relatively expensive compared to other vasoconstrictors.

Availability may vary by region; not approved in all countries.

Branded versions (e.g., Terlivaz in the U.S.) have brought more visibility to the drug.

12. Conclusion

Terlipressin represents a significant advancement in the management of portal hypertension and hepatorenal syndrome. With its selective vasoconstrictive effects, longer half-life, and proven efficacy, it continues to be a critical intervention in intensive care and hepatology.

References

1. Sanyal A, et al. "Terlipressin plus albumin for the treatment of type 1 hepatorenal syndrome." NEJM, 2021.

2. European Association for the Study of the Liver (EASL) Clinical Practice Guidelines.

3. U.S. FDA Label for Terlivaz (Terlipressin).

4. Krag A, et al. "Terlipressin in acute-on-chronic liver failure." Journal of Hepatology, 2020.

5. NICE Clinical Guidelines on Liver Disease and HRS Management.