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Assays / Trace
Metals/ Lithium
Lithium salts are used predominantly in the acute and short-term
treatment of manic states and as prophylactic long-term treatment
of recurrent manic and depressive illness. The metal is administered
orally as either the carbonate or citrate in doses of 10 to 80 mmol
per day. Absorption from the gut is complete within 8 hours and
peak plasma concentrations are seen 2-4 hours after dosage. The
distribution volume of lithium approximates to the body water volume,
although concentrations in white matter, thyroid and bones are several-fold
higher than the plasma concentration. Penetration into the cerebrospinal
fluid takes place at a relatively slow rate and at equilibrium the
concentration is about 40% of that in plasma. There is no binding
to plasma proteins and excretion is almost entirely by the kidneys.
Lithium is handled like sodium in the proximal tubule with about
80% being reabsorbed. The elimination half-life varies with age
and ranges from 8-20 hours in younger patients with normal renal
function to 30-40 hours in elderly patients or in those with renal
impairment.
The optimum maintenance dosage is usually established
by monitoring the serum lithium concentrations and these are measured
subsequently to check compliance, prevent sub-therapeutic dosing
and to diagnose impending or manifest lithium toxicity.
Toxicity
Lithium therapy is frequently associated with
mild side effects such as weight gain, polyuria, tremor, diarrhoea
and oedema of the face and legs which resolve when the treatment
stops. A small proportion of patients develop a benign enlargement
of the thyroid and it is recommended that thyroid function tests
are carried out when treatment starts and at six month intervals
thereafter. Usually there is a fall in total and free thyroxine
levels and a rise in thyroid stimulating hormone (TSH), but hypothyroidism
is rarely so severe as to need thyroxine therapy. Lithium has diuretic
properties due to its antagonism of the renal response to ADH and
can induce nephrogenic diabetes insipidus, although the full pathogenesis
of the condition, which persists for some time after medication
is withdrawn, is uncertain.
Since lithium is excreted almost exclusively by the
kidneys, any impairment of this route induced by, for example, mild
dehydration, reduced salt intake, sliming diets, intercurrent kidney
disease and the use of interacting medications such as diuretics
or non-steroidal anti-inflamatory drugs, can lead to intoxication
at any stage during long-term treatment. If moderate renal impairment
is not detected or drugs are given which reduce lithium excretion
and lithium intake continues,m the intoxication escalates so that
the patient may develop a life threatening illness within a few
days.
The clinical effects of acute and chronic lithium poisoning
are similar, although these tend to be milder in overdose cases
despite higher plasma levels and diminish more rapidly. The prime
effect is on the central nervous system and the kidneys. At an early
stage the patient may look ill with a greyish yellow complexion.
Other characteristic features include nausea, vomiting, diarrhoea,
drowsiness, ataxia, blurred vision, seizures and coma. These may
be accompanied by progressive acute renal failure with oliguria.
The symptoms are reversible with haemodialysis if instituted in
time, but usually persist for a prolonged period and there is a
danger that these patients will be left with permanent neurological
damage.
Laboratory Indices of Lithium Therapy and Toxicity
When monitoring lithium therapy, it is most
important to measure the serum lithium concentration as close as
possible to 12 hours after the last dose by which time the drug's
absorption is complete and distribution will have stabilised. This
standardised measurement is commonly referred to as the 12h-stSLi
and should preferably be taken always at the same time of day to
mitigate the effect of diurnal variation of serum lithium levels.
When a patient begins therapy, it is usual to carry out one or two
12h-stSLi measurements with appropriate adjustment of the dose regime
and to check the serum lithium concentration one week after any
change of dose or formulation. If treatment with diuretics and other
drugs which affect renal function is instituted or the patient moves
to a low salt diet, more intensive monitoring is indicated.
There is substantial inter individual variation in
the relationship between serum lithium concentrations and effective
therapy. However, it is generally accepted that in patients with
acute mania levels of up to 1.3 mmol/L may be needed to gain a satisfactory
response, whereas effective prophylaxis with minimum side effects
can be achieved in most patients with serum lithium concentrations
in the range 0.5 to 0.8 mmol/L.
There is a marked risk of oliguria and acute renal
failure if the serum lithium concentration rises above 1.4 mmol/L
and levels of over 3.5 mmol/L after chronic accumulation are associated
with serious and possibly fatal toxicity.
References:
Aronson JK and Reynolds DJM. ABC of monitoring drug
therapy; Lithium. BMJ, 1992; 305: 1273-1276
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