Calcium Laevulinate
A white crystalline or amorphous powder with a faint odour
suggestive of burnt sugar. Each g of calcium laevulinate (di-
hydrate) represents approximately 3.3 mmol of calcium. Cal-
cium laevulinate (dihydrate) 7.64 g is approximately
equivalent to 1 g of calcium.
Freely soluble in water; slightly soluble or very slightly solu-
ble in alcohol; practically insoluble in chloroform and in
ether. The USP states that a 10% solution in water has a pH of
7.0 to 8.5; Ph. Eur. requires a pH of 6.8 to 7.8.
The properties are similar to calcium, so see below at calcium record for the details.
Calcium
Calcium is a cation administered as various calcium containing salts. Calcium salts have been reported to be incompatible with a wide range of drugs. Complexes may form resulting in the formation of a precipitate.
Adverse effects and Treatment
[ministration of some calcium salts by mouth can
cause gastro-intestinal irritation: calcium chloride is
generally considered to be the most irritant of the
commonly used calcium salts.
injection of calcium salts can also produce irritation
and in particular intramuscular or subcutaneous inject-
ion can cause local reactions including sloughing
or necrosis of the skin; solutions of calcium
chloride are extremely irritant and should not be in-
jected intramuscularly or subcutaneously. Soft-tissue-,
calcification has also followed the use of calcium
salts parenterally.
excessive amounts of calcium salts may lead to hyperc-
alcaemia. This complication is usually associated
with the parenteral route of administration, but
patients with renal failure or who are taking vitamin D
concurrently. Symptoms of hypercalcaemia may in-
clude anorexia, nausea, vomiting, constipation, ab-
dominal pain. muscle weakness, mental
disturbances, polydipsia. polyuria. nephrq~ilcino-
sis, renal calculi, and, in severe cases, cardiac
arrhythmia and coma. Too rapid intravenous injec-
tion of calcium salts may also lead to many of the
symptoms of hypercalcaemia as well as a chalky
taste, hot flushes, and peripheral vasodilatation.
Mild asymptomatic hypercalcaemia will usually re-
solve on stopping administration of calcium and
other contributory drugs such as vitamin D.
Precautions
Solutions of calcium salts, particularly calcium
chloride, are irritant, and care should be taken to
prevent extravasation during intravenous injection.
Calcium salts should be given cautiously to patients
with impaired renal function, or diseases associated
with elevated vitamin D concentrations such as sar-
coidosis. In addition, they should generally be
avoided in patients with calcium renal calculi, or a
history of renal calculi. Calcium chloride, because
of its acidifying nature, is unsuitable for the treat-
ment of hypocalcaemia caused by renal insufficien-
cy or in patients with respiratory acidosis or failure.
Plasma-calcium concerntration should be moni-
tored closely in patients with renal insufficiency and
during parenteral administration and if large doses
of vitamin- D are used concurrently.
Interactions:
Hypercalcemia has occurred when calcium salts
Are coadministered with thiazide diuretics or vita-
min D. Vitamin D increases the gastro-intestinal ab-
sorption of calcium and thiazide diuretics decrease
its urinary excretion. Plasma-calcium concentra-
tions should be monitored in patients receiving the
drugs concurrently.
Bran decreases the gasiro-intestinal absorption of
calcium, and may therefore decrease the efficacy of
calcium supplements.
Calcium enhances the effects of digitalis glycosides
on the heart and may precipitate digitalis intoxica-
tion, parenteral calcium therapy is best avoided in
patients receiving cardiac glycosides. Citrate sails
increase the absorption of aluminium from the gas-
tro-intestinal tract, therefore patients with
renal failure taking aluminium phosphate should
avoid taking calcium citrate. Calcium salts reduce
the absorption of a number of other drugs such a.s
bisphosphonales. fluoride, some fluoroquinolones,
and tetracyclines: administration should be separat-
ed by at least 3 hours.
Pharmacokinetics
Calcium is absorbed predominantly from the small
intestine by active transport and passive diffusion.
About one-third of ingested calcium is absorbed al-
though this can vary depending upon dietary factors,
and the state of the small intestine; also absorption
is increased in calcium deficiency and during peri-
ods of high physiological requirement such as dur-
ing childhood or pregnancy and lactation. 1.25-
Dihydroxycholecalciferol (calcitriol), a metabolite
of vitamin D. enhances the active phase of absorp-
tion.
excess calcium is predominantly excreted renally
unabsorbed calcium is eliminated in the faeces, to-
gather with that secreted in the bile and pancreatic juice.
Minor amounts are lost in the sweat, skin, hair,and nails.
Calcium crosses the placenta and is distributed into breast milk.
Human Requirements
Calcium is the most abundant mineral in the body
and is an essential body electrolyte. However, defin-
ing individual calcium requirements has proved dil-
ticult and guidelines vary widely by country and
culture. Some authorities have adopted a factorial
approach. For example, in the UK the dietary refer-
ence value (DRV) represents the apparent calcium
requirements of healthy people under the prevailing
dietary circumstances. The amount of calcium ab-
sorbed varies according to several factors including
ihe requirements of the body, but is normally only
about 30 to 40% of the dietary intake.
The richest dietary sources of calcium are milk and
milk products. Significant amounts can also be con-
sumed in green leafy vegetables, fortified flour, and
hard water.
In the United Kingdom dietary reference values
have been published for calcium.' In the USA recommended
dietary allowances (RDA) had been set and have recently
been replaced by dietary reference intakes .' In
the UK the estimated average requirement (EAR) for adults is
S25 mg (13.1 mmol) daily and the reference nutrient intake
(RNI) for adults is 700 mg (17.5 mmol) daily; these figures
are based on a mean absorption of calcium of 30% from
mixed diets. In the USA the traditional RDA was 800 mg dai-
ly for adults aged over 25 years, this figure was based on an
absorption rate of 40%. Under the new dietary reference in-
lakes, adequate intakes (Al) for calcium have been set, which
are higher in some age groups than the previous RDAs.' For
adults aged up to 50 years the Al is I g daily, and for those 51
years or older, it is 1.2 g daily.)
Uses and Administration
Calcium salts are used in the management of hypo-
calcaemia and calcium deficiency states
resulting from dietary deficiency or ageing. Doses may be expressed in
terms of mmol or mEq of calcium, mass (mg) of cal-
cium. or mass of calcium salt (for comparative pur-
poses, see Table I, below).
Table I, Some calcium salts and their calcium content.
Calcium content per g
Calcium salt mg mmol mEq
Calcium acetate (anhydrous) 253 6.3 12.6
Calcium carbonate 400 10.0 20.0
Calcium chloride (dehydrate) 273 6.8 13.6
Calcium citrate (tetrahydrate) 211 5.3 10.5
Calcium glubionate (monohydrate) 66 1.6 3.3
Calcium gluceptate (anhydrous) 82 2.0 4.1
Calcium gluconate (monohydrate) 89 2.2 4.5
Calcium glycerophosphate 191 4.8 9.5
(anhydrous)
Calcium lactate (anhydrous) 184 4.6 9.2
Calcium lactate (trhydrate) 147 3.7 7.3
Calcium lactate (pentahydrate) 130 3.2 6.5
Calcium lactate gluconate(dihydrate) 129 3.2 6.4
Calcium laciobionate(dihydrate) 51 1.3 2.5
Calcium laevulinate(dihydrate) 131 3.3 6.5
Calcium hydrogen phosphate 233 5.8 11.6
{dihydrate)
Calcium phosphate 399 10.0 19.9
Calcium pidolate (anhydrous) 135 3.4 6.7
Calcium sodium lactate (tetrahydrate) 78 1.9 3.9
in simple deficiency states calcium salts may be giv-
en by mouth, usually in doses of 10 to 50mmol
i400 mg to 2 g) of calcium daily adjusted to the in-
dividual patient's requirements.
In severe acute hypocalcaemia or hypocalcaemic
ictany parenteral administration is necessary, gener-
al ly by slow intravenous injection or continuous in-
lusion of calcium chloride or calcium gluconate (see
also Administration, below). A typical dose is
2.25 mmol of calcium by slow intravenous injec-
tion, either repeated as required, or followed by con-
tinuous intravenous infusion of about 9 mmol daily.
2.25 mmol of calcium is provided by 10 mL of cal-
cium gluconate 10%. Calcium gluceptate and calci-
um glycerophosphate with calcium lactate have
been given by the intramuscular route; the chloride
and gluconate are unsuitable for this route because
of their irritancy. The intravenous route is used in
children.
Intravenous calcium salts are also used to reverse the
toxic cardiac effects of potassium in the emergency
treatment of severe hyperkalaemia, and as
an antidote to magnesium in severe hypennagne-
saemia. For these indications, 2.25 to
4.5 mmol of calcium (10 to 20 mL of calcium glu-
conate 10%) is commonly used.
Individual calcium salts have specific uses. Calcium
carbonate or acetate are effective phosphate binders
and are given by mouth to reduce phosphate absorp-
tion from the gut in patients with hyperphospha-
taemia; this is particularly relevant to patients with
chronic renal failure in order to prevent the develop-
ment of renal osteodystrophy. The initial
dose of calcium carbonate is 2.5 g daily titrated to a
maximum of 17 g daily. The initial dose of calcium
acetate is 3 or 4 g daily: most patients require 6 to
12 K daily.
Calcium carbonate, administered by mouth, is also
widely used for its antacid properties.
The calcium salts discussed here also havepharma-
ct'uilcal uses. Calcium carbonate is employed as a
diluent in capsules and tablets and as a buffer and
dissolution aid in dispersible tablets. Other applica-
tions include its use as a basis for some dental for-
mulations. Calcium phosphate is also used as a
diluent for solid dose forms and sometimes as a dis-
iniegrant and anticaking agent. Calcium hydrogen
phosphate is another tablet or capsule diluent and is
employed for its abrasive properties in toothpastes.
Calcium phosphate (Calcarea Phosphorica; Calc.
Phos.) is used in homoeopathic medicine.
Administration. Views have been expressed that calcium
chloride rather than calcium gluconate is the calcium salt of
choice for parenteral preparations.'" This opinion is based on
the tact that the body's retention of calcium chloride is greater
and more predictable than its retention of calcium gluconate
and that the increase in extracellular ionised calcium concen-
tration is unpredictable for the gluconate.
It should, however, be remembered that calcium chloride is
considered to be the most irritant of the calcium salts in gen-
eral use (see under Adverse Effects, above).
Calcium gluconate has also been administered by the intra-
pentoneal route) for the treatment of chronic hypocalcaemia
after parathyroidectomy in a patient undergoing continuous
ambulatory peritoneal dialysis, resulting in improved system-
ic bioavailability compared with oral and intravenous admin-
istration.
Bites and stings. Calcium gluconate 10% solution has been
administered intravenously as an alternative to the use of con-
ventional muscle relaxants for neurotoxic spider envenoma-
tion . Mention has been made of such use of calcium
in the management of Lairodectus mactans (black widow spi-
der) envenomation.' Although the precise mechanism of ac-
tion of calcium. in the alleviation of neuromuscular symptoms
calcium stores in the sarcoplasmic reticulum of muscle de-
pleted by stimulation.
Bone disease. Calcium is essential for the development and
maintenance of normal bone. and calcium salts may be indi-
cated in the treatment of some bone disorders associated with
calcium deficiency, such as certain types of osteomalacia and
rickets. Doses of I to 3 g of calcium daily are used in
osteomalacia.
Oral calcium supplements can also be used as an adjunct in
the management of osteoporosis .
Fluoride toxicity. Inorganic fluoride is corrosive to skin and
mucous membranes and acute intoxication disrupts many
physiological systems and severe burns and profound hypoc-
alcaemia may ensue. Absorption of the fluoride can be pre-
vented by conversion to an insoluble form such as calcium
fluoride and thus irrigation of skin (or gastric lavage as appro-
priate) with lime water, milk. or a i % solution of calcium glu-
conate is recommended. Immediate treatment should also
consist of 10 mL of calcium gluconate 10% intravenously re-
peated after one hour. 30 mL should be given if tetany is
present. In the short term affected skin and tissue should be
injected with a 10% solution of calcium gluconate at a dose
of 0.5 mL per cm2 and burned skin treated with a calcium glu-
conate 2.5% gel.'
Hypertention. Two recent meta-analyses report that calci-
um supplementation results in a small reduction in systolic,
but not diastolic, blood pressure.lΒ·2 Both studies concluded
that the effect was too small to support the use of calcium
supplementation for preventing or treating hypertension,
but the authors of the second study considered it pos-
sible that calcium supplementation might have beneficial ef-
fects on blood pressure in those with an inadequate intake.'
PREGNANCY. A meta-analysis of 14 trials involving 2459 wom-
en concluded that calcium supplementation during pregnancy
reduced systolic and diastolic blood pressure and the inci-
dence of pre-eclampsia and hypertension.' However, inclu-
sion criteria for this meta-analysis have been criticised.
Moreover, results from a double-blind, placebo-controlled tri-
al in a total of 4589 women indicated that calcium supple-
mentation during normal pregnancy did not prevent pre-
eclampsia. pregnancy-associated hypertension without pre-
eclampsia. and a number of other related disorders'
For discussions of hypertension in pregnancy and eclampsia
and pre-eclampsia.