TOLVAPTANPRESENTED BY

SHREYA JHA

also known as OPC-41061

is a selective, competitive vasopressin receptor 2 antagonist

Mainly used to treat hyponatremia (euvolemic and hypervolemic) in cases of congestive cardiac failure, cirrhosis of liver and SIADH.

Tolvaptan was approved by the U.S. Food and Drug Administration (FDA) on May 19, 2009.

is sold by Otsuka Pharmaceutical Co. under the trade name Samsca

In India is manufactured & sold by MSN laboratories Ltd. under the trade name Tolsama & Tolvat and by Lupin under the brand name Resodim

MECHANISMselective vasopressor V2 receptor antagonist

without intrinsic agonist properties.29 times more affinity for v2 receptors than v1

receptors.Produces adequate aquaresis (water diuresis

without electrolyte excretion)Antagonism at the V2 receptor causes a decrease in

the number of aquaporin-2 channels in the renal collecting tubules, resulting in decreased water reabsorption, a net increase in free water excretion and an increase in serum sodium concentrations.

Advantages of TolvaptanImproves signs and symptoms of congestionImproves hyponatremiaNo effect on renal functionsNo effect on blood pressureNo effect on electrolytesOral route of administrationNo adverse effect on mortality

PHARMACOKINETICSThe absolute bioavailability of a dose of

tolvaptan is unknown, but at least 40% of the drug is absorbed after oral administration.

The onset of effect is two to four hours after a dose is taken, and peak effects occur four to eight hours after administration.

After absorption, it is 99% bound to circulating plasma proteins.

Volume of distribution is approximately 3 L/kg

Tolvaptan is eliminated by the liver almost entirely by CYP 3A4 to inactive metabolites, and it is an inhibitor of P-glycoprotein.

The plasma half-life is 12 hours;

Increased serum sodium concentrations persist at 24 hours post-dose despite a return to baseline free water excretion.

INDICATIONUsed in patient with hyponatremia < 125 meq /l

in heart failure (NYHA class III and IV)

Used in SIADH for fluid restriction

Patients with a serum sodium level of 125 to 134 mEq/L may be treated if they have symptoms and have not responded to fluid restriction

Tolvaptan is also in fast-track clinical trials for polycystic kidney disease

Starting dose is 15 mg per day and may be increased to 30 to 60 mg per day.

Initiate therapy only in a hospital where serum sodium levels can be monitored

Too rapid correction of serum sodium can cause serious neurologic sequel

Do not administer it for more than 30 days to minimize the risk of liver injury

During initiation and titration, frequently monitor for changes in serum electrolytes and volume

Too rapid correction of serum sodium can cause osmotic demyelination resulting in dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, coma and death.

In susceptible patients, including those with severe malnutrition, alcoholism or advanced liver disease, slower rates of correction may be advisable.

ADVERSE EFFECTSMost common are thirst(7.8 -16 %), dry

mouth(4.2 – 13%) and polyuria(3.3%).It may cause fatal liver injury.GI bleeding may occur when prescribed in

cirrhosis of liverconstipationHyperglycemia

Should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

CONTRA-INDICATIONHypovolemic hyponatremiaAnuric patientConcomitant use of strong or moderate CYP

3A inhibitor (mainly grapefruit)Urgent need to raise serum sodium acutely

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