Domina Petric, MD Aquaretics

Introduction Aquaretics are agents that alter water excretion: Osmotic diuretics Antidiuretic hormone agonists Antidiuretic hormone antagonists

Osmotic diuretics

Osmotic diuretics The proximal tubule and descending limb of Henle´s loop are freely permeable to water. Any osmotically active agent that is filtered by the glomerulus, but not reabsorbed, causes water to be retained in these segment. That promotes a water diuresis. Glucose causes osmotic diuresis (glycosuria) in patients with hyperglycemia. Mannitol is used to reduce intracranial pressure and to promote prompt removal of renal toxins.

Pharmacokinetics Mannitol is poorly absorbed by the gastrointestinal tract. When administered orally it causes osmotic diarrhea. Mannitol must be given intravenously! It is not metabolized. It is excreted by glomerular filtration within 30-60 minutes.

Pharmacokinetics Mannitol has to be used cautiously in patients with even mild renal insufficiency.

Pharmacodynamics Osmotic diuretics have their major effect in the proximal tubule and the descending limb of Henle´s loop. Through osmotic effects, they also oppose the action of ADH in the collecting tubule. Mannitol prevents the normal absorption of water by interposing a countervailing osmotic force.

Pharmacodynamics Mannitol increases urine volume. The increase in urine flow rate decreases the contact time between fluid and the tubular epithelium. Sodium reabsorption is reduced as well as water reabsorption. Natriuresis is of lesser magnitude than the water diuresis: excessive water loss and hypernatremia.

Increase of urine volume Clinical indications Increase of urine volume Reduction of intracranial and intraocular pressure

Increase of urine volume Osmotic diuretics are used to increase water excretion in preference to sodium excretion. This is useful when avid sodium retention limits the response to conventional agents. It can be used to maintain urine volume and prevent anuria in patients with hemolysis or rhabdomyolysis (large pigment loads to the kidney).

Increase of urine volume Some oliguric patients do not respond to osmotic diuresis. A test dose of mannitol should be given before starting a continuous infusion: 12,5 g iv. Mannitol should not be continued unless there is an increase in urine flow rate to more than 50 mL/h during the 3 hours after the test dose.

Increase of urine volume Mannitol in dose 12,5-25 g iv. can be repeated every 1-2 hours to maintain urine flow rate greater than 100 mL/h. Prolonged use of mannitol is not advised.

Reduction of intracranial and intraocular pressure Osmotic diuresis alter Starling forces so that water leaves cells and reduces intracellular volume. This effect is used to reduce intraocular pressure before ophthalmologic procedures and intracranial pressure in neurologic conditions.

Reduction of intracranial and intraocular pressure A dose of 1-2 g/kg of mannitol is administered intravenously. Intracranial pressure should fall in 60-90 minutes.

Toxicity Extracellular volume expansion Dehydration Hyperkalemia Hypernatremia Hyponatremia

Extracellular volume expansion Mannitol is rapidly distributed in the extracellular comparment and extracts water from cells. Prior to the diuresis, this leads to expansion of the extracellular volume and hyponatremia. This effect can complicate heart failure and may produce florid pulmonary edema. Headache, nausea and vomiting.

Dehydration, hyperK, hyperNa Excessive use of mannitol without adequate water replacement can lead to severe dehydration, free water losses and hypernatremia. Intracellular potassium concentration rises when water is extracted from cells. That leads to cellular losses and hyperkalemia.

Hyponatremia When used in patients with severe renal impairment, parenterally administered mannitol can not be excreted. It is retained intravenously. This causes osmotic extraction of water from cells leading to hyponatremia.

Antidiuretic hormone agonists

ADH agonists Vasopressin and desmopressin are used in the treatment of central diabetes insipidus. Their renal action is mediated primarily via V2 ADH receptors. V1 ADH receptors may also be involved.

Antidiuretic hormone antagonists

ADH antagonists Congestive heart failure (CHF) and the syndrome of inappropriate ADH secretion (SIADH) cause water retention as a result of excessive ADH secretion. Patients with CHF on treatment with diuretics frequently develop hyponatremia secondary to excessive ADH secretion. Dangerous hyponatremia can occur.

ADH antagonists Vasopressin receptors are V1a, V1b and V2. V1 receptors are expressed in the vasculature and CNS. V2 receptors are expressed specifically in the kidney. Conivaptan exhibits activity aganist both V1a and V2 receptors. It is available for intravenous use.

ADH antagonists Oral agents tolvaptan, lixivaptan and satavaptan are selectively active against the V2 receptor. Tolvaptan is very effective in treatment of hyponatremia. It is an adjunct to standard diuretic therapy in patients with CHF.

Tolvaptan has half-life 12-24 hours. Pharmacokinetics The half-life of conivaptan and demeclocycline is 5-10 hours. Tolvaptan has half-life 12-24 hours.

Pharmacodynamics ADH antagonists inhibit the effects of ADH in the collecting tubule. Conivaptan and tolvaptan are direct ADH receptor antagonists. Lithium and demeclocycline reduce ADH-induced cAMP.

SIADH ADH antagonists are used to manage SIADH when water restriction has failed to correct the abnormality. Demeclocycline: 600-1200 mg/day. Tolvaptan: 15-60 mg/day. Conivaptan is administered intravenously and is not suitable for chronic use in outpatients.

Other causes of ↑ADH ADH is elevated in response to diminished effective circulating blood volume, like in CHF. When treatment by volume replacement is not desirable, hyponatremia may occur. For patients with CHF, iv. conivaptan may be useful because blockade of V1a receptors leads to decreased peripheral vascular resistance and increased cardiac output.

Nephrogenic diabetes insipidus Toxicity Nephrogenic diabetes insipidus Renal failure Other

Nephrogenic diabetes insipidus If serum sodium is not monitored, any ADH antagonist can cause severe hypernatremia and nephrogenic diabetes insipidus. Treatment of nephrogenic DI: cessation of ADH antagonist administration, thiazide diuretic or amiloride.

Renal failure Both lithium and demeclocycline have been reported to cause acute renal failure. Long-term lithium therapy may also cause chronic interstitial nephritis.

Other Dry mouth and thirst. Tolvaptan may cause hypotension. Demeclocycline should be avoided in patients with liver disease and in children younger than 12 years.

Katzung, Masters, Trevor. Basic and clinical pharmacology. Literature Katzung, Masters, Trevor. Basic and clinical pharmacology.