ANTIDIURETIC HORMONE

AGONISTS & ANTAGONISTS

A. Prototypes and Mechanis o! Action
Antidi"retic horone (ADH) and desopressin are prototypical
ADH agonists. They are peptides and must be given parenterally. Coni#aptan and to$#aptan are ADH
antagonists.
Demeclocycline was previously used for this purpose. Lithium
also has ADH-antagonist effects but is never used for this purpose.
ADH facilitates water reabsorption from the collecting tubule
by activation of ! receptors" which stimulate adenylyl cyclase via
#s. The increased cyclic adenosine monophosphate (cA$%) causes
the insertion of additional a&uaporin A'%! water channels into
the luminal membrane in this part of the tubule ((igure )*+,).
-onivaptan is an ADH inhibitor at )a and ! receptors. Tolvaptan
is a more selective ! bloc.er with little ) affinity. Demeclocycline
and lithium inhibit the action of ADH at some point distal to the
generation of cA$% and presumably interfere with the insertion of
water channels into the membrane.
%. E!!ects and C$inica$ Uses
&. A'onists(ADH and desmopressin reduce urine volume
and increase its concentration. ADH and desmopressin are useful
in pituitary diabetes insipidus. They are of no value in the
nephrogenic form of the disease" but salt restriction" water restriction"
thia/ides" and loop diuretics may be used. These therapies
reduce blood volume" a very strong stimulus to pro0imal tubular
reabsorption. The pro0imal tubule thus substitutes1in part1for
the deficient concentrating function of the collecting tubule in
nephrogenic diabetes insipidus.
). Anta'onists(ADH antagonists oppose the actions of
ADH and other naturally occurring peptides that act on the same
! receptor. 2uch peptides are produced by certain tumors (eg"
small cell carcinoma of the lung) and can cause significant water
retention and dangerous hyponatremia. This syndroe o!
inappropriate ADH secretion *SIADH+ can be treated with
demeclocycline and conivaptan. Lithium also wor.s but has
greater to0icity.
C. To,icity
3n the presence of ADH or desmopressin" a large water load may
cause dangerous hyponatremia. Large doses of either peptide may
cause hypertension in some persons.
-onivaptan and tolvaptan may cause demyelination with
serious neurologic conse&uences if hyponatremia is corrected too
rapidly. -onivaptan may cause infusion site reactions. 3n children
younger than 4 years" demeclocycline (li.e other tetracyclines)
causes bone and teeth abnormalities. Lithium causes nephrogenic
diabetes insipidus as a to0ic effect5 because of its other to0icities"
the drug is never used to treat 23ADH.