Lecture 9: Drugs Acting on Vasopressin Receptors

Arginine Vasopressin (AVP)

-main hormone that regulates body fluid osmolality

-synthesized from the neurosecretory cells in supraoptic nuclei (SON) of hypothalamus

Vssopressin

also known as Antidiuretic hormone ( ADH), Arginine vasopressin (AVP)

Antidiuretic

__________________ Effect:

-AVP bind to V2 receptor to increase cAMP

-cAMP promotes phosphorylation of aquaporin2 channel

-results in thirst stimulation

-increases water resabsorption

Vasopressor

__________________ Effect:

-AVP binds to V1a receptor on vascular smooth muscle cells

-activates PLC and formation of IP3

-increased intracellular Ca2+ concentration and vasoconstriction

Neurogenic Diabetes Insipidus

defect in synthesis/release of ADH

Nephrogenic Diabetes Insipidus

Impaired renal response to ADH

Neurogenic Diabetes Insipidus

Causes:

Hypothalamic or pituitary tumors

Head trauma

CNS infection

Inherited genetic disease: defect in ADH processing and transport to pituitary

Nephrogenic Diabetes Insipidus

Causes:

Deficient response of collecting duct to ADH

Inherited genetic disease: mutation in V2 receptor,

Drug-induced: lithium, ADH antagonists

Water Deprivation Test

-Do not drinking any liquid for several hours to see how your body responds.

-If you have DI, you will continue to pee large amounts of dilute urine when normally only pee a small amount of concentrated urine.

Vasopressin Receptor Agonists

treatment of Von Willdebrand Disease

-Thiazide diuretics

-Amiloride

treatment which can cause polydipsia, polyuria, and pollakiuria

Synthetic AVP

-vasopressin agonist

-- V1a receptors --> Vasoconstriction

- V2 receptors --> Antidiuresis

Synthetic AVP

Emergency use: rapid blood loss, hypovolemic hypotension and septic shock

To control bleeding due to esophageal varices or colonic diverticula Administration route: iv or i.m. injection

Synthetic AVP

AEs:

-water intoxication and hyponatremia when overdose

-headache, nausea, bronchoconstriction, and tremor

-caution in pts with CAD and asthma

Desmopressin

Vasopressin agonist most commonly used for Neurogenid Diabetes insipidus

Desmopressin

-A synthetic modified human vasopressin with longer plasma half life

-Selective action on V2 receptor --> antidiuresis

-Action on extrarenal V2-like receptors ---> increased release of coagulation factor VIII and von Willebrand factor

Desmopressin

selective vasopressin V2 agonist with a minimal effect on V1 receptors

Desmopressin

Indications:

-neurogenic diabetes insipidus

-nocturnal enuresis

-treatment of mild hemophilia A and Von Willebrand Disease

AEs:

-water intoxication and hyponatremia when overdose

-headache, nausea, abdominal cramps, local irritation

Thiazide diuretics + dietary Na+ restriction (

-inhibits Na+ reabsorption in distal tubules to induce natiuresis and mild ECF volume deficit

-end goal is to decrease urine output by 50%

Thiazide diuretics + dietary Na+ restriction (

First line for nephrogenic Diabetes insipidus

NSAIDs (Indomethacin)

-can potentiate AVP

-decreases GFR, increases medullary solute concentration, increases proximal fluid reabsorption

Indication: adjunct for central and nephrogenic Diabetes insipidus

Amiloride

-DI: Inhibits lithium uptake in the cortical collecting duct

• Indication: Adjunct for lithium-induced nephrogenic DI

-Stabilize vital signs with NS

-Free water replacement

therapy for hypovolemic hypernatremia

-Free water replacement

-Nephrogenicc DI: Thiazide diuretic and Na restriction

-Central DI: AVP analog

therapy for euvolemic hypernatremia

-Loop diuretics + free water

-Dialysis if necessary

therapy for hypervolemic hypernatremia

Hypotonic

• D5W

• ½ 0.9% NS (0.45% NaCl)

Fluids used for free-water deficit are _________________

Syndrome of Inappropriate Antidiuresis (SIADH)

Causes:

-SSRIs, TCAs, vinca

alkaloids, sulfonylureas

-Small cell carcinoma of the lung

-Head trauma or damage to hypothalamus or pituitary during surgery

-meningitis, brain abscess

Demeclocycline

-Vasopressin Receptor Antagonist for SIADH

-semisynthetic tetracycline

-prevents the V2R mediated increase in cAMP formation

Demeclocycline

Indications:

-SIADH

-no longer used bc of side effects

AEs:

-GI problems, rash and acute renal failure

Lithium

Nephrogenic diabetes insipidus (NDI) is the most common renal side effect of ____________ therapy.

Conivaptan

-Vasopressin Receptor Antagonist for SIADH

-V1a and V2 receptor competitive antagonist ---> vasodilation and increased water excretion

Conivaptan

Indications:

-Euvolemic and hypervolemic hyponatremia in hospitalized patients (SIADH)

AEs:

-infusion site reactions

-phlebitis

Osmotic Demyelination Syndrome (ODS)

due to overly rapid correction of hyponatremia (i.e., >12 mEq/L/24 hrs)

dysarthria, mutism, dysphagia, lethargy, seizure, coma, death

closely monitor serum sodium and neurologic status

Tolvaptan

-Orally active, non-peptide vasopressin antagonist

-Selective V2 receptor antagonist increased water excretion

Tolvaptan

Indications:

-Euvolemic and hypervolemic hyponatremia in hospitalized pts (heart failure, liver cirrhosis, SIADH)

-should not be used longer than 30 days

Tolvaptan

AEs:

-dry mouth and constipation

-thirst, asthenia

-Hyperglycemia, polyuria, pollakiuria

-Osmotic demyelination syndrome

-liver injury

Vasoconstriction

V1 receptors are associated with _____________________

Replace fluid losses

management of hypovolemic hyponatremia

Decrease TBW

management of euvolemic hyponatremia

-Therapies which remove fluid and/or Na to decrease TBW and/or Na

Managment of hypervolemic hyponatremia