Tretinoin is retinoic acid and is used in acne by topical application (see p. 273). Isotretinoin is a retinoic acid isomer (t_½ 20 h) given orally for acne (see p. 273). It is also effective for preventing second tumours in patients following treatment for primary squamous cell carcinoma of the head and neck.

Acute promyelocytic leukaemia

Tretinoin can be used to induce remission in conjunction with chemotherapy in acute promyelocytic leukaemia, a subgroup of acute myeloid leukaemia (AML) involving chromosomal translocation of the retinoic acid receptor-alpha gene. Initially, it proved remarkably successful, but the high doses given caused the fatal ‘differentiation syndrome’ (previously called ‘retinoic acid syndrome’; respiratory distress, fever and hypotension) and the duration of treatment is now shorter.

Vitamin A deficiency

Primary deficiency is common in developing countries. Retinol is used to prevent and treat deficiency; 1 microgram = 3.3 IU (t_½ 7—14 days). For prevention of deficiency in susceptible individuals, supplements are given at 4–6-monthly intervals. Dosing is according to age. More frequent doses are required for treatment of xerophthalmia. Secondary deficiency resulting from fat malabsorption is seen with pancreatic insufficiency and disorders of the gastrointestinal tract. Vitamin A supplementation at pharmacological doses is standard for patients with cystic fibrosis. This can result in chronic toxicity and serum retinol levels should be monitored.

Adverse effects

Acute toxicity occurs in adults with a single dose of more than 600 000 IU/day. Symptoms include headache, nausea, vomiting and drowsiness. Travellers have become ill by eating the livers of Arctic carnivores.

Chronic toxicity occurs with prolonged high intake (in children 25 000–50 000 IU/day, 10 times the recommended daily allowance, RDA). A diagnostic sign is the presence of painful tender swellings on long bones. Anorexia, skin lesions, hair loss, hepatosplenomegaly, papilloedema, bleeding and general malaise also occur. Vitamin A accumulates in liver and fat, and effects take weeks to wear off. Chronic overdose also makes the biological membranes and the outer layer of the skin more liable to peel.

Teratogenicity

Vitamin A and its derivatives are teratogenic at pharmacological doses (for precautions, see use in acne and psoriasis, p. 273). Supplements should not exceed 8000 IU (2400 micrograms) per day.

Vitamin B complex

A number of widely differing substances are now, for convenience, classed as the ‘vitamin B complex’. Those used for pharmacotherapy include the following:

Vitamin C: ascorbic acid

Vitamin C is a powerful reducing agent (antioxidant) and is an essential cofactor and substrate in a number of enzymatic reactions, including collagen synthesis and noradrenaline synthesis. It also functions as an antioxidant, mopping up free radicals produced endogenously or in the environment, e.g. cigarette smoke (see vitamin E). There has been considerable interest in using vitamin C as an antioxidative agent to reduce oxidation of low-density lipoproteins (LDL) in atherosclerosis and prevent formation of carcinogens to reduce risk of cancer. However, randomised trials have not shown any beneficial effect thus far of vitamin C on either cancer incidence or primary or secondary prevention of coronary heart disease.

Indications

• The prevention and cure of scurvy.

• Methaemoglobinaemia.

Scurvy

Deficiency of ascorbic acid leads to scurvy, which is characterised by petechial haemorrhages, haematomas, bleeding gums (if teeth are present) and anaemia.

Methaemoglobinaemia

A reducing substance is needed to convert the methaemoglobin (ferric iron) back to oxyhaemoglobin (ferrous iron) whenever enough has formed seriously to impair the oxygen-carrying capacity of the blood. Ascorbic acid is non-toxic (it acts by direct reduction) but is less effective than methylene blue (methylthioninium chloride). Both can be given orally, intravenously or intramuscularly. Excessive doses of methylene blue can cause methaemoglobinaemia (by stimulating NADPH-dependent enzymes).

Methaemoglobinaemia may be induced by oxidising drugs: sulphonamides, nitrites, nitrates (may also occur in drinking water), primaquine, -caine local anaesthetics, dapsone, nitrofurantoin, nitroprusside, vitamin K analogues, chlorates, aniline and nitrobenzene. Where symptoms are severe enough to warrant urgent treatment, methylene blue given intravenously at 1–2 mg/kg gives response within 30 min. Patients should be monitored for rebound methaemoglobinaemia. Methylene blue turns the urine blue and high concentrations can irritate the urinary tract, so that fluid intake should be high when large doses are used. Methlyene blue should not be administered to patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency since its action is dependent on NADPH produced by G6PD. In addition to being ineffective in this circumstance it may induce haemolysis. Ascorbic acid is inadequate for the treatment of acute methaemoglobinaemia requiring treatment.

Congenital methaemogobinaemia can be treated long term with either oral methylene blue or ascorbic acid with partial effect.

Adverse effects

High doses may cause sleep disturbances, headaches and gut upsets. Ascorbic acid is eliminated partly in the urine unchanged and partly metabolised to oxalate. Doses above 4 g/day increase urinary oxalate concentration and there is a potential risk of renal oxalate stones with chronic ascorbic acid administration. Intravenous ascorbic acid may precipitate a haemolytic attack in subjects with G6PD deficiency.

Vitamin D, calcium, parathyroid hormone, calcitonin, bisphosphonates, bone

Vitmain D is closely interrelated with calcium homeostasis and bone metabolism and these topics are therefore discussed together.

Vitamin D

Vitamin D comprises a number of structurally related sterol compounds having similar biological properties (but different potencies) in that they prevent or cure the vitamin D-deficiency diseases, rickets and osteomalacia. The most relevant form of vitamin D is vitamin D₃ (colecaciferol). This is made by ultraviolet irradiation of 7-dehydrocholesterol in the skin. It is also absorbed in the intestinal tract; however, few foods contain significant levels of vitamin D (Fig. 39.1). Vitamin D₂ (ergocalciferol) is made by ultraviolet irradiation of ergosterol in plants. This is not the naturally occurring form.

Fig. 39.1 Metabolism of vitamin D. D3, Vitamin D3 (cholecalciferol); pre-D3, pre-vitamin D3; DBP, vitamin D-binding protein; 25-OHase, liver 25-hydroxylase; 25(OH)D3, 25-hydroxycholecalciferol (25(OH)D3; 1-OHase, 25-hydroxyvitamin D3-1-hydroxylase; 1,25(OH)2D3, calcitriol; PTH, parathyroid hormone.

(From Deeb K K, Trump D L, Johnson C S 2007 Vitamin D signalling pathways in cancer: potential for anticancer therapeutics. Nature Reviews Cancer 7(9): 684.)

Vitamin D₃ (and D₂) undergo two successive hydroxylations: first in the liver to form 25-hydroxyvitamin D and second in the proximal tubules of the kidney (under the control of parathyroid hormone, PTH) to form 1α,25-dihydroxyvitamin D₃ (calcitriol), the most physiologically active form of vitamin D.

There exist also a variety of synthetic vitamin D analogues, developed to treat vitamin D deficiency and hypoparathyroidism. The vitamin D derivative 1α-hydroxycolecalciferol (alfacalcidol) requires only hepatic hydroxylation to become calcitriol. The usual adult maintenance dose, 0.25–1 micrograms/day, indicates its potency.

Other 1α-hydroxylated vitamin D analogues include paricalcitol. In addition, a structural variant of vitamins D₂ and D₃, dihydrotachysterol (ATIO, Tachyrol), is also biologically activated by hepatic 25-hydroxylation. All are effective in renal failure as they bypass the defective renal hydroxylation stage.

Pharmacokinetics

Alfacalcidol and dihydrotachysterol have a fast onset and short duration of clinical effect (days) which renders them suitable for rapid adjustment of plasma calcium, e.g. in hypoparathyroidism. Such factors are not relevant to the slower adjustment of plasma calcium (weeks) with vitamins D₂ and D₃ in the ordinary management of vitamin D deficiency.

Actions

are complex. Vitamin D promotes the active transport of calcium and phosphate in the gut (increased absorption) and renal tubule (reduced excretion), and thus controls, with PTH, the plasma calcium concentration and the mineralisation of bone (see Fig. 39.1). After a dose of D₂ or D₃ there is a lag of about 21 h before the intestinal effect begins; this is probably due to the time needed for its metabolic conversion to the more active forms. With the biologically more active calcitriol, the lag is only 2 h.

A large single dose of vitamin D has biological effects for as long as 6 months (because of metabolism and storage). Thus, the agent is cumulative (see toxicity).

Indications

• The prevention and cure of rickets of all kinds and osteomalacia (vitamin D deficiency).

• Osteoporosis.

• Hypoparathyroidism.

• Psoriasis.

• CKD-MBD (renal osteodystrophy).

Vitamin D deficiency

This can be treated with a variety of vitamin D analogues. Selecting the appropriate preparation requires a knowledge of the underlying aetiology. There are no absolute criteria for vitamin D deficiency; however, serum 25(OH)VitD3 levels are used as a guide to vitamin D levels and there is a general consensus that a 25(OH)D concentration of 50–75–nmol/L reflects insufficiency, and concentrations of less than 50–nmol/L indicate deficiency.

Although rickets due to primary vitamin D deficiency is rare in developed countries, subclinical vitamin D deficiency and vitamin D insufficiency are now recognised to be extremely common in the UK and in other populations with limited exposure to sunlight, particularly in individuals with increased skin pigmentation, in whom greater amounts of sun exposure are required for adequate synthesis, or in those with excessive body cover. There is accumulating evidence that subclinical vitamin D deficiency has adverse effects on health. Vitamin D deficiency in pregnancy is a significant public health issue: babies born to mothers with low vitamin D levels are at increased risk of neonatal hypocalcaemia and other vitamin D deficiency-related symptoms. Vitamin D deficiency can be prevented in susceptible individuals by taking an oral supplement of ergocalciferol 20 micrograms (800 units) daily. All pregnant and lactating women should receive vitamin D supplementation. Breast milk contains negligible amounts of vitamin D thus breast-fed infants receiving less than 500 mL of formula should be supplemented with vitamin D: Abidec and Dalivit are two paediatric multivitamin preparations, both containing colecalciferol 400 IU.

For the treatment of simple nutritional vitamin D deficiency oral doses of either colecalciferol or ergocalciferol, 10 000 units daily or 60 000 units weekly, should be given for 12 weeks. Infants and children should receive between 1000 and 5000 units of vitamin D₃ daily, depending on age (usually ergocalciferol), for 12 weeks. Where there are concerns with regards to compliance, ‘Stoss’ therapy – a single dose of intramuscular ergocalciferol 500–000 units – can be given. Nutritional vitamin D insufficiency can be treated with 800–1000 units daily for 12 weeks. 25(OH)-vitamin D₃ levels should be measured after 12 weeks of treatment. Alfacalcidol should not be given for the treatment of vitamin D deficiency as it does not replete vitamin D stores.

Vitamin D deficiency resulting from intestinal malabsorption or chronic liver disease usually requires vitamin D in pharmacological doses, e.g. ergocalciferol tablets up to 50 000 units daily. The maximum antirachitic effect of vitamin D occurs after 1–2 months, and the plasma calcium concentration reflects the dosage given days or weeks before. Frequent changes of dose are therefore not required. Vitamin D deficiency resulting from chronic renal failure is discussed below (see renal osteodystrophy).

Epileptic patients taking enzyme-inducing drugs long term can develop osteomalacia (adults) or rickets (children). This may arise from the accelerated metabolism, increasing vitamin D breakdown and causing deficiency, or from inhibition of one of the hydroxylations that increase biological activity.

Osteoporosis

Calcitriol is licensed for the management of post-menopausal osteoporosis (see below).

Hypoparathyroidism

The hypocalcaemia of hypoparathyroidism requires 1000–1500 mg of elemental calcium daily in divided doses as well as vitamin D. Ergocalciferol may be required in doses up to 100 000 units daily to achieve normocalcaemia, but the dose is difficult to titrate and hypercalcaemia from overdose may take weeks to resolve. Alfacalcidol (0.5–2.0 micrograms daily) or calcitriol (0.5–1.0 micrograms daily) are therefore preferred, as their rapid onset and offset of action makes for easier control of plasma calcium levels.

Psoriasis

Calcipotriol and tacalcitol are vitamin D analogues available as creams or ointments for the treatment of psoriasis (see p. 269).

Renal osteodystrophy

(See below.)

Adverse effects

Vitamin D toxicity has been reported in children accidentally overdosed on vitamin D supplements. Symptoms of overdosage are due mainly to an excessive increase in plasma calcium concentration and include anorexia, nausea and vomiting, diarrhoea, constipation, weight loss, polyuria and thirst. Other long-term effects include ectopic calcification almost anywhere in the body, renal damage and an increased calcium output in the urine; renal calculi may form. Recent research has suggested that the safe upper limit of vitamin D therapy be revised. It was previously considered dangerous to exceed 10 000 units daily of vitamin D in an adult for more than about 12 weeks; however, it has now become apparent that such doses are required to render a vitamin D-deficient individual replete. In general, use of vitamin D at pharmacological doses requires monitoring of plasma calcium.

Treatment of calcium and bone disorders

Hypocalcaemia

In acute hypocalcaemia requiring systemic therapy, give a slow intavenous infusion of 10 mL of 10% calcium gluconate injection over 10 min. This should not be given at a faster rate because of the risk of cardiac arrhythmias and arrest. Correction of hypocalcaemia is temporary and this should be followed by a continuous intravenous infusion containing ten 10 mL ampoules of 10% calcium gluconate in 1 L of 0.9% saline given at an initial infusion rate of 50 mL/h. Plasma calcium should be monitored and the rate adjusted accordingly. Oral calcium therapy should be initiated meanwhile and the intravenous infusion stopped once the oral agents take effect. Avoid infusing with solutions containing bicarbonate or phosphate, which cause calcium to precipitate. Intramuscular injection is contraindicated as it is painful and causes tissue necrosis. Calcium glubionate (Calcium Sandoz) can be given by deep intramuscular injection in adults. Concurrent hypomagnesaemia should be corrected as hypocalcaemia is resistant to treatment without normal serum magnesium levels.

Treatment of chronic hypocalcaemia is with 1500–2000 mg of oral elemental calcium daily in divided doses, as either calcium carbonate or calcium citrate. Additional treatment depends on the cause. Hypocalcaemia secondary to vitamin D deficiency should be treated with vitamin D as described above and there are preparations which combine calcium tablets with colecalciferol. Hypocalcaemia secondary to hypoparathyroidism requires alfacalcidol or calcitriol as PTH is required for hydroxylation of 25-hydroxy-vitamin D₃, thus ergocalciferol or colecalciferol have reduced efficacy.

Adverse effects

of intravenous calcium may be very dangerous. An early sign is a tingling feeling in the mouth and of warmth spreading over the body. Serious effects are those on the heart, which mimic and synergise with digitalis, and it is advisable to avoid intravenous calcium administration in any patient taking a digitalis glycoside (except in severe symptomatic hypocalcaemia). The effect of calcium on the heart is antagonised by potassium, and similarly the toxic effects of hyperkalaemia in acute renal failure may be to an extent counteracted by calcium.

Hypercalcaemia

Treatment of severe acute hypercalcaemia causing symptoms is needed whether or not the cause can be removed; generally a plasma concentration of 3.0 mmol/L (12 mg/100 mL) needs urgent treatment if there is also clinical evidence of toxicity (individual tolerance varies greatly).

Temporary measures

After taking account of the patient’s cardiac and renal function, the following measures may be employed selectively:

• Physiological saline solution is important, firstly to correct sodium and water deficit, and secondly to promote sodium-linked calcium diuresis in the proximal renal tubule. Initially, 500 mL 0.9% saline should be given intravenously over 4 h and then adjusted to maintain urine output at 100-150 mls/hour until the plasma Ca^2 + level falls below 3.0 mmol/L and the oral intake is adequate. The regimen requires careful attention to fluid and electrolyte balance, particularly in patients with renal insufficiency secondary to hypercalcaemia or heart failure who are unable to excrete excess sodium. The use of furosemide to enhance renal Ca^2 + excretion has been largely abandoned owing to the exacerbation of electrolyte disturbances and the increased availability of newer agents.

• Bisphosphonates are the agents of choice in moderate to severe hypercalcaemia, There are a number of bisphosphonates licensed for this indication but pamidronate and zoledronic acid are the most widely used agents. Pamidronate² is infused according to the schedule in Table 39.1; it is active in a wide variety of hypercalcaemic disorders. A fall in the serum calcium concentration begins within the first day, reaches a nadir in 5–6 days and lasts for 20–30 days. Zoledronic acid has the advantage of being more potent and it can be administered over a shorter time (4 mg over 15 min versus 2 h). It is a convenient regimen for patients with hypercalcaemia of malignancy where repeat courses may be required every 3–4 weeks.

• Calcitonin. When the hypercalcaemia is at least partly due to mobilisation from bone, calcitonin (4 units/kg) can be used to inhibit bone resorption, and may enhance urinary excretion of calcium. The effect develops in a few hours but responsiveness is lost over a few days owing to tachyphylaxis. Calcitonin is not as effective as the bisphosphonates; however, its shorter onset of action makes it a valuable agent for initial management of hypercalcaemia until the peak onset of action of the bisphosphonate at 2–4 days.

• An adrenocortical steroid, e.g. prednisolone 20–40 mg/day orally, is effective in particular situations; it reduces the hypercalcaemia of hypervitaminosis D (which is due to excessive intestinal absorption of calcium either secondary to intoxication or granulomatous disease, e.g. sarcoidosis). Corticosteroid may be effective in the hypercalcaemia of malignancy where the disease itself is responsive, e.g. myeloma of lymphoma. Patients with hyperparathyroidism do not respond.

• Dialysis is quick and effective and is likely to be needed in severe cases or in those with renal failure.

Table 39.1 Treatment of hypercalcaemia with disodium pamidronate

Calcium (mmol/L)	Pamidronate (mg)
< 3.0	15–30
3.0–3.5	30–60
3.5–4.0	60–90
> 4.0	90

Infuse slowly, e.g. 30 mg in 250 mL 0.9% saline over 1 h. Expect a response in 2–4 days.

The above measures are only temporary, giving time to tackle the cause.

Longer-term treatment

Sodium cellulose phosphate

(Calcisorb) is an oral ion exchange substance with a particular affinity for calcium which is bound in the gut, and the complex eliminated in the faeces. It is effective for patients who over-absorb dietary calcium and develop hypercalciuria and renal stones.

Inorganic phosphate

e.g. sodium acid phosphate (Phosphate Sandoz), taken orally, also binds calcium in the gut. It is of particular use for hypercalcaemia resulting from increased intestinal absorption of calcium, e.g. vitamin D intoxication, or increased calcitriol production (as seen with chronic granulomatous disease).

Hypercalciuria

In renal stone formers, in addition to general measures (low calcium diet, high fluid intake), urinary calcium may be diminished by a thiazide diuretic (with or without citrate to bind calcium) and oral phosphate (see above). See also Nephrolithiasis, p. 463.

Parathyroid hormone

Parathyroid hormone (PTH) acts chiefly on the kidney, increasing renal tubular reabsorption of calcium and excretion of phosphate; it increases calcium absorption from the gut, indirectly, by stimulating the renal synthesis of 1α,25-vitamin D (see above and Fig. 39.1). PTH increases the rate of bone remodelling (mineral and collagen) and osteocyte activity with, at high doses, an overall balance in favour of resorption (osteoclast activity) with a rise in plasma calcium concentration (and fall in phosphate); but, at low doses, the balance favours bone formation (osteoblast activity).

Calcitonin

Calcitonin is a peptide hormone produced by the C cells of the thyroid gland (in mammals). It acts on bone (inhibiting osteoclasts) to reduce the rate of bone turnover, and on the kidney to reduce reabsorption of calcium and phosphate. It is obtained from natural sources (pork, salmon, eel) or synthesised. The t_½ varies according to source; the human t_½ is 10 min. Antibodies develop particularly to pork calcitonin and neutralise its effect; synthetic salmon calcitonin (salcatonin) is therefore preferred for prolonged use; loss of effect may also be due to down-regulation of receptors.

Calcitonin is used (subcutaneously, intramuscularly or intranasally) for Paget’s disease of bone (relief of pain, and compression of nerves, e.g. auditory cranial), metastatic bone cancer pain, post-menopausal osteoporosis, and for initial control of hypercalcaemia (see above).

Adverse effects

include allergy, nausea, flushing and tingling of the face and hands.

Bisphosphonates

Bisphosphonates are synthetic, non-hydrolysable analogues of pyrophosphate (an inhibitor of bone mineralisation) in which the central oxygen atom of the -P-O-P- structure is replaced with a carbon atom to give the -P-C-P- group. There are two classes of bisphosphonates: nitrogen containing (alendronate, risedronate, ibandronate, pamidronate and zoledronate) and non-nitrogen containing (clodronate, etidronate and tiludronate).

Actions

These compounds are effective calcium chelators that rapidly target exposed bone mineral surfaces, are imbibed by bone-resorbing osteoclasts, inhibit their function and cause osteoclast apoptosis. An additional action may be to stimulate bone formation by osteoblasts, but the therapeutic utility of bisphosphonates rests on their capacity to inhibit bone resorption.

Bisphosphonate binding to hydroxyapatite crystals can, in high doses, inhibit bone mineralisation (potentially causing osteomalacia), an effect that is unrelated to their anti-resorptive efficacy. This disadvantageous effect, prominent with non-nitrogen containing bisphosphonates, is less with newer nitrogen containing members.

Pharmacokinetics

Bisphosphonates are poorly absorbed after ingestion. Absorption is further impaired by food, drinks, and drugs containing calcium, magnesium, iron or aluminium salts. A proportion of bisphosphonate that is absorbed is rapidly incorporated into bone; the remaining fraction is excreted unchanged by the kidneys. Once incorporated into the skeleton, bisphosphonates are released only when the bone is resorbed during turnover. They may be given orally or intravenously. One trial has shown that bioavailability of oral bisphosphonates are greatest if the drug is administered in the early morning, before the first meal of the day.

Indications

• Osteoporosis (see below).

• Paget’s disease of bone (see below).

• Hypercalcaemia due to malignancy (see above) and metastatic bone disease Bisphosphonates reduce skeletal fractures and loss of skeletal integrity associated with metastatic bone disease. The best evidence for such a benefit comes from use of intravenous zoledronic acid in patients with metastatic lung cancer, prostate cancer or breast cancer. There is no evidence that bisphosphonates can prevent bone metastases in these cancers.

Adverse effects

of orally administered bisphosphonates include gastrointestinal disturbances, and oesophageal irritation – a particular problem with alendronate. This drug should be taken at least 30 min before food, with the patient remaining erect during this period. Oral bisphosphonates should not be used in patients with Barrett’s oesophagus. Disturbances of calcium and mineral metabolism (e.g. vitamin D deficiency, PTH dysfunction) should be corrected before starting a bisphosphonate. Increased bone pain (as well as relief) and fractures (high dose, prolonged use only) can occur due to bone demineralisation. Potential nephrotoxicity is a concern with bisphosphonate therapy although zoledronic acid has been used in patients with severe renal impairment. Intravenous administration can cause acute ‘flu-like symptoms (fever, myalgia, malaise). Repeated courses of intravenous bisphosphonates for treatment of hypercalcaemia of malignancy is associated with increased risk of osteonecrosis of the jaw in patients with metastatic bone disease or multiple myeloma. The risk may be slightly greater with zoledronic acid compared with pamidronate.

Osteoporosis

Osteoporosis is a disease characterised by increased skeletal fragility, low bone mineral density (less than 2.5 standard deviations below the mean for young people; Fig. 39.2) and deterioration of bone microarchitecture. It occurs most commonly in post-menopausal women and patients taking long-term corticosteroid. Exclude underlying causes such as hyperthyroidism, hyperparathyroidism and hypogonadism (in both sexes) before treatment is initiated.