Category : Science and Education
Archive   : DRUGMAN.ZIP
Filename : WATER

DRUGS THAT MODIFY WATER EXCRETION

Mechanisms
* Antidiuretic hormone (vasopressin) and its semisynthetic derivative,
desmopressin (DDAVP) act in the collecting duct of the nephron to in-
crease its permeability to water and thereby increase the reabsorption
of water. They act at specific receptors to increase the synthesis of
cAMP in the cell. They are of no value in the treatment of nephrogenic
diabetes insipidus since the defect in this condition lies distal to
the ADH receptor.
* The thiazides reduce diluting ability of the kidney by the mechanism de-
scribed in Section I.A.; loop diuretics decrease diluting ability by
reducing the osmotic gradient set up in the medulla of the kidney. Fur-
thermore, diuretic-induced reduction in blood volume stimulates sodium
and water retention in the proximal tubule. These agents can therefore
reduce the volume of urine produced in diabetes insipidus; in
nephrogenic diabetes insipidus they constitute, along with sodium
restriction, the major mode of therapy.




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* Lithium and certain antibiotics, notably demeclocyline, inhibit the ac-
tion of ADH in the kidney at some point distal to the generation of
cAMP, and produce a drug-induced nephrogenic diabetes insipidus. This
is usually an undesired effect, but in the syndrome of inappropriate
ADH secretion (SIADH), demeclocyline can be used to ameliorate the ex-
cessive water retention and hyponatremia associated with these hormone-
producing tumors.

A. Antidiuretic agents (ADH, desmopressin, lypressin):
Indications
* Pituitary diabetes insipidus: ADH or desmopressin. (In nephrogenic
diabetes insipidus use thiazides and water restriction.)

Pharmacokinetics
* Absorption: these polypeptides are hydrolyzed in the GI tract and must
be given parenterally as nasal snuff or sprays, or by IM or SC injec-
tion.
* Elimination: peptide hydrolysis in the blood and tissues is responsible
for the elimination of these compounds.



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Contraindications and Warnings
* Hypersensitivity to ADH or its analogs. Warnings: smooth muscle effects
are usually mild; use caution in patients with severe coronary artery
disease, hypertension, or pregnancy.

Adverse Reactions
* Allergic responses
* Local irritation in response to intranasal administration.
* Increased smooth muscle activity may result in diarrhea, coronary
vasoconstriction, hypertension.

Toxicity and Overdosage
* Extensions of adverse reactions.

Interactions
* Chlorpropamide, carbamazepine, and clofibrate may potentiate the
antidiuretic action of these agents.




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B. Inhibitors of ADH (Demeclocycline)

Major indications
* SIADH: demeclocycline and water restriction.

Pharmacokinetics ( and Chapter 10)
* Absorption: good absorption from the gut.
* Elimination: primarily by biliary and renal excretion.

Contraindications and Warnings
* Hypersensitivity
* Age under 8 (effects on bones and teeth, see Chapter 10).

Adverse Reactions
* Teeth, skin: Discoloration and abnormal development of teeth before
eruption. Photosensitivity.
* GI: Nausea, vomiting, diarrhea.
* Liver: Impairment of liver function, especially with large parenteral
doses (unlikely in SIADH).
* Superinfection with yeasts and normally innocuous bacteria may occur.


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Toxicity and Overdosage
* Rare, see chapter 10.

Interactions
* Demeclocycline interferes with the bactericidal action of penicillins.
* Antacids (including milk) may interfere with the absorption of
tetracyclines.














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