is sometimes caused by drugs, notably the anticonvulsant
carbamazepine, which stimulates ADH release from the pos-
terior pituitary, and sulphonylureas, which potentiate its
action on the renal collecting ducts. Antidiuretic hormone
secretion results in a concentrated urine, while continued
drinking (as a result of dietary habit) leads to progressive dilu-
tion of the plasma, which becomes hypo-osmolar and hypo-
natraemic. The plasma volume is slightly increased and
urinarysodium loss continues. Some causes of SIADH resolve
spontaneously (e.g. some cases of head injury), whereas others
may improve after specific treatment of the underlying cause
(e.g. following chemotherapy for small-cell carcinoma of the
bronchus). Hyponatraemia that has arisen gradually can be
corrected gradually by restricting fluid intake. This does not
cause thirst (because the plasma is hypo-osmolar), but may
not be well tolerated because of habit. Rapid correction of
hyponatraemia to levels greater than 125 mmol/L is poten-
tially harmful and is associated with central pontine myelino-
lysis, with resultant devastating loss of brainstem function.
Demeclocyclineinhibits adenylyl cyclase and renders the
collecting ducts insensitive to ADH (thereby producing a form
of nephrogenic diabetes insipidus). It has been used to treat
SIADH. In common with other tetracyclines, it increases
plasma urea levels and can produce deterioration of renal func-
tion and increased loss of sodium in the urine. Electrolytes and
renal function must be monitored during treatment.
VOLUME DEPLETION
PRINCIPLES OF FLUID REPLACEMENTVolume depletion is seldom treated with drugs. Even in
Addisonian crisis, where the definitive treatment is replacement
with glucocorticoid and mineralocorticoid hormones, emer-
gency treatment pivots on replacement of what is depleted, i.e.
salt and water, usually in the form of adequate volumes of iso-
tonic 0.9% sodium chloride solution (Chapter 40). The same is
true of diabetic ketoacidosis, where the critical life-saving inter-
vention is the rapid infusion of large volumes of isotonic saline,
as well as insulin (Chapter 37). In patients with hypovolaemia
due to acute and rapid blood loss, the appropriate fluid with
which to replace is blood. In some situations, particularly when
hypoalbuminaemia and oedema coexist with acute blood vol-
ume depletion, infusion of solutions of high-molecular-weight
colloid (e.g. gelatin) may be preferable to isotonic saline. Ana-
phylactoid reactions are an unusual but severe adverse effect of
such treatment. Lactate is metabolized aerobically with the pro-
duction of bicarbonate and Ringer’s lactate solution is used to
avoid hyperchloraemic acidosis. Bicarbonate-containing solu-
tions for i.v. use are being developed.
DIABETES INSIPIDUS AND VASOPRESSIN‘Pure’ water deprivation (i.e. true dehydration) is much less
common than loss of salt and water (i.e. desalination). Plasma
osmolality rapidly increases if fluid intake is inadequate. This
causes thirst, which leads to drinking and restoration of plasma
osmolality, and to secretion of antidiuretic hormone (ADH,
arginine vasopressin) by the posterior pituitary, which results in
the formation of a small volume of concentrated urine. ADH
combines with receptors coupled to G-proteins. The most
physiologically important actions of vasopressin, including its
antidiuretic effect, are mediated by V 2 -receptors which are cou-
pled to adenylyl cyclase. V 1 -receptors activate the phosphatidyl
inositol signalling system in vascular smooth muscle, mobiliz-
ing cytoplasmic calcium and causing vasoconstriction.
Vasopressin renders the collecting ducts permeable to
water. Consequently, water leaves the collecting ducts pas-
sively down its osmotic gradient from tubular fluid (which is
hypotonic at the beginning of the distal tubule) into the highly
concentrated papillary interstitium. This process results in the
formation of a small volume of highly concentrated urine
under the influence of vasopressin.
Control of plasma osmolarity via thirst fails when a patient is
denied oral fluid, usually because of surgery (‘nil by mouth’).
Fluid must then be administered parenterally if dehydration
with increased plasma sodium ion concentration is to be pre-
vented. An isotonic (5%) solution of glucose is used in these cir-
cumstances, as the glucose is rapidly metabolized to carbon
dioxide, leaving water unaccompanied by solute. Surgical
patients also lose salt, but unless they have been vomiting or
losing electrolyte-rich fluid from the gastro-intestinal tract
via a drain or fistula, salt is lost at a lower rate than water.
Consequently, post-operative patients are often given two or
three volumes of 5% glucose for every volume of isotonic saline,
adjusted in the light of serial serum electrolyte determinations.
Diabetes insipidus is an uncommon disorder in which
either the secretion of ADH is deficient (‘central’ diabetes
insipidus which can follow neurosurgery or head injury or
complicate diseases such as sarcoid that can infiltrate the pos-
terior pituitary), or in which the sensitivity of the collecting
ducts to ADH is deficient (‘nephrogenic’ diabetes insipidus).
Nephrogenic diabetes insipidus is sometimes drug induced,
lithiumbeing a common cause. Severe nephrogenic diabetes
insipidus is a rare X-linked disease caused by a mutation in the
V 2 -receptor gene. In such cases, exogenous vasopressinor
desmopressin(see below) is ineffective. Paradoxically, thi-
azide diuretics (see above) reduce polyuria in nephrogenic dia-
betes insipidus by reducing the hypotonicity of fluid entering
the distal tubule, and are combined with mild salt restriction.
Dehydration is not a problem in diabetes insipidus pro-
vided the patient has access to water, because increasing
plasma osmolality stimulates thirst. The consequent polydip-
sia prevents dehydration and hypernatraemia. However,
patients with diabetes insipidus are at greatly increased risk of
dehydration if they become unconscious for any reason (e.g.
anaesthesia for an intercurrent surgical problem).
Polydipsia and polyuria in central diabetes insipidus can
be prevented by vasopressin. Treatment with ADH necessi-
tates repeated injections. Currently, the usual treatment is
therefore with a stable analogue, namely desamino-D-arginine
vasopressin (DDAVP, desmopressin). This is sufficiently wellVOLUMEDEPLETION 277