NOVAPRESSIN INJECTION

Indications

• Hepatorenal syndrome type 1
• Acute variceal bleeding

Dosage

Children: Refer to the BNF for Children for appropriate paediatric dosing guidelines, as specific dosing for children is not provided in the general BNF.

Adults: The usual adult dose of terlipressin for hepatorenal syndrome type 1 is 1 mg administered intravenously every 4 to 6 hours, with a maximum daily dose of 12 mg. Doses may be adjusted based on clinical response.

Mechanism of action

Terlipressin acts by binding to V1 receptors on vascular smooth muscle, leading to vasoconstriction. It enhances blood pressure by increasing arterial pressure while also demonstrating antidiuretic effects through its action on V2 receptors, although it has a higher affinity for V1 receptors, which contributes to its therapeutic effects in conditions like hepatorenal syndrome.

Pharmacodynamics

As a vasopressin analog, terlipressin has a longer half-life than natural vasopressin and provides sustained cardiovascular effects. It is effective in increasing diastolic, systolic, and mean arterial pressure, while simultaneously decreasing heart rate. The onset of action is rapid, with cardiovascular effects observable within five minutes, peaking at 1.2 to 2 hours post-administration, and lasting for several hours.

Pharmacokinetics

Terlipressin is administered intravenously and has a prolonged duration of action due to its structural modifications which enhance receptor selectivity and reduce degradation. It undergoes metabolism primarily in the liver, and its pharmacokinetic profile allows for effective management of acute conditions with limited intravenous access. The pharmacokinetics can be influenced by individual patient factors, including the severity of underlying liver conditions.

Contra-indications

• Hypersensitivity to terlipressin or any of its components
• Severe renal impairment
• Cardiovascular disease
• Pregnancy

Adverse effects

• Abdominal cramps
• Diarrhea
• Nausea
• Hypertension
• Bradycardia
• Ischemia
• Peripheral vasoconstriction
• Headache

Interactions

• Concomitant use with other vasopressors may increase the risk of hypertension
• Drug interactions affecting hepatic metabolism may alter terlipressin effectiveness
• Diuretics may counteract the effects of terlipressin

Precautions

• Monitor blood pressure and heart rate regularly during treatment
• Use with caution in patients with a history of cardiovascular disease
• Consider renal function before initiating therapy
• Gradual withdrawal is recommended to avoid rebound hypotension

Pregnancy

Terlipressin is contraindicated in pregnancy due to potential risks to the fetus.

Breast-feeding

It is unknown if terlipressin is excreted in human breast milk; caution should be exercised.

Storage

Store at room temperature, away from light and moisture. Do not freeze.

Formulations

• Intravenous injection solution

Indications

• Bleeding from oesophageal varices
• Acute massive hemorrhage of the gastrointestinal tract

Dosage

Children: Refer to the BNF for Children for specific dosing information.

Adults: 1–2 capsules three times a day, to be taken before food.

Mechanism of action

Terlipressin acetate exerts its effects primarily by acting on V1 vasopressin receptors, leading to increased vascular resistance and subsequent elevation of blood pressure. It also promotes renal vasoconstriction, enhances glomerular filtration, and facilitates the excretion of sodium, which contributes to its role in managing hypotensive states.

Pharmacodynamics

Terlipressin increases systemic vascular resistance and reduces portal pressure, which is beneficial in conditions such as oesophageal varices. Its vasopressor effect can improve hemodynamic stability during acute bleeding episodes. The drug's renal effects help in maintaining renal perfusion in patients with compromised renal function, ensuring better outcomes during therapeutic interventions.

Pharmacokinetics

Terlipressin is administered intravenously and is rapidly distributed throughout the body. It has a short half-life, requiring multiple doses for sustained effect. The drug is primarily metabolized in the liver, and its effects can be influenced by hepatic function. Renal elimination is minimal, but caution is advised in patients with chronic renal impairment to avoid accumulation.

Contra-indications

• Uncontrolled hypertension
• Septic shock
• Severe heart disease
• History of QT interval prolongation
• Severe electrolyte and fluid disturbances
• Acute abdominal conditions

Adverse effects

• Abdominal cramps
• Arrhythmias
• Hypotension
• Pallor
• Nausea
• Vomiting
• Dyspnoea
• Skin necrosis
• Pulmonary oedema
• Hyperglycaemia
• Stroke
• Seizures

Precautions

• Use with caution in elderly patients
• Caution in patients with chronic renal failure
• Monitor for potential arrhythmias
• May cause uterine contractions and increased intra-uterine pressure in early pregnancy

Pregnancy

Avoid unless benefits outweigh risks; uterine contractions and decreased uterine blood flow reported.

Breast-feeding

Avoid unless benefits outweigh risks; no information available.

Storage

Store in a cool, dry place away from light. Keep out of reach of children.

Formulations

• Capsules: 120 micrograms
• Solution for injection: 1 mg/8.5 ml

Mechanism of action

Endogenous vasopressin, also referred to as antidiuretic hormone (ADH) or arginine vasopressin (AVP), regulates important physiological processes such as osmotic balance, blood pressure regulation, sodium homeostasis, and kidney functioning. It is a nonapeptide synthesized in the hypothalamus and stored in the posterior pituitary. Vasopressin mediates its biological effects by binding to three subtypes of vasopressin receptors. V1 receptors are expressed on vascular smooth muscle and many other cells such as hepatocytes: activating these G-protein-coupled receptors leads to vasoconstriction. V2 receptors are predominantly expressed on the basolateral membrane of the distal tubule and collecting ducts of the kidney: these receptors are responsible for the antidiuretic effect of vasopressin, regulating water permeability of kidney tubules and therefore maintaining water homeostasis. V3 receptors mediate the effects of vasopressin on the central nervous system. Vasopressin is considered a stress hormone as it is released into the bloodstream in response to various volume and pressure stimuli, such as pain, surgery, syncope and shock. Shock conditions such as hypovolemia initially cause an increase in the release of vasopressin to maintain organ perfusion; however, as the shock state progresses, plasma vasopressin concentrations decrease due to several causes such as depleted stores of vasopressin in refractory shock and a central inhibitory effect of initially elevated vasopressin levels on further vasopressin release. Terlipressin is a synthetic vasopressin analogue that can cause sustained increases in blood pressure in patients with shock conditions. It exhibits twice the selectivity for vasopressin V1 receptors versus V2 receptors. Terlipressin is pharmacologically active but acts as a prodrug for [lypressin] (also known as lysine vasopressin), a vasoconstrictor and antidiuretic agent. The exact mechanism of action of terlipressin is not fully understood; however, terlipressin works to cause vasoconstriction in shock and other conditions associated with vasodilation. Hepatorenal syndrome (HRS) is caused by splanchnic and systemic arterial vasodilation along with a reduced mean arterial pressure (MAP) and cardiac output, resulting in a marked decrease in effective circulating volume. Terlipressin is thought to increase renal blood flow in patients with HRS-1 by reducing portal hypertension and blood circulation in portal vessels and increasing effective arterial volume and mean arterial pressure (MAP).

Pharmacodynamics

Terlipressin mimics the biological effects of endogenous vasopressin, but it displays increased selectivity for the V1 receptor and a longer half-life than vasopressin. These pharmacokinetic and molecular properties of terlipressin give it several advantages, such as the prevention of rebound hypotension when the drug is stopped and convenience in patients with limited intravenous access. Terlipressin increases arterial pressure (diastolic, systolic, and mean) and decreases heart rate in patients with hepatorenal syndrome type 1 (HRS-1). After the administration of a single 0.85 mg dose of terlipressin in patients with HRS-1, cardiovascular effects were observed within five minutes after dosing and were maintained for at least six hours after dosing. The maximum change in blood pressure and heart rate occurred at 1.2 to two hours post-dose.