VITAMINS. ENZYMES
DRUGS. ANGIOPROTECTORS. (Thiamimi bromidum,
Riboflavinum, Calcii pangamanas, Acidum folicum, Acidum nicotinicum, Piridoxinum, Cyanocobalaminum, Calcii pantotenas, Acidum ascorbinicum, Rutinum, Cvercitinum, Retinoli acetas, Ergocalcipherolum, Tocopheroli acetas, Vicasolium)
Vitamins
History:
Approximately 40 vitamin and mineral nutrients are required by man. Vitamins
can be defined as organic substances that must be provided in not more than
small amounts from the environment to sustain healthy life.
Vitamins are either not synthesized at all by the body
or are synthesized in quantities too small to fulfill daily nutritional needs.
For centuries, some diseases have been known to be related to deficient intake
of a specific vitamin including night blindness (vitamin A deficiency),
beriberi (thiamine deficiency), pellagra (niacin deficiency), scurvy (ascorbic
acid deficiency), and rickets (vitamin D deficiency). Folic acid deficiency
during gestation has recently been associated with neural tube defects in the
fetus.
Vitamins
were originally identified through animal experiments. Animal were fed a diet
that was thought to cause a particular disease in man and then treated with the
nutrient that was deficient in the diet producing the disease. Funk, in 1911,
was able to identify an extract that prevented beriberi and coined the term
"vitamine" because he believed the
substance to be an amine that was vital to life. It was later confirmed by
McCollum and Davis that a number of factors were present in fats (fat-soluble
A) which were different from water-soluble factors they called a
"water-soluble B" fraction. The B vitamins were found in an extract
from rice husks and continue to be classified together even though they have
different chemical structures and biologic functions.
Today, the fat-soluble vitamins are known as vitamins
A, D, E, and K. Water-soluble vitamins include thiamine, riboflavin, nicotinic
acid (niacin), pyridoxine, pantothenic acid, biotin, folic acid, and cyanocobalamin.
The
daily requirements for vitamins are estimated in the
The
RDA document also discusses substances that have not been proven essential by
man. These substances are grouped into four categories: (1) those known to be
essential for some animals but not shown to be needed by man (e.g., nickel,
vanadium, and silicon); (2) substances that act as growth factors for lower
forms of life (e.g., para-aminobenzoic acid, carnitine, and pimelic acid); (3)
substances that are in foods but whose actions are probably pharmacologic or non-existent
and; (4) substances for which scientific proof of a nutrient action has not
been established (e.g., pangamic acid, laetrile).
This latter category includes substances often promoted by the health-food
industry.
Vitamin
products are regulated by the US FDA primarily as foods and not as drugs.
Therefore, most vitamin products are not subject to the same requirements to
establish safety and efficacy as are OTC and prescription drugs. The
distinction as to whether a vitamin is a drug or a food supplement is
determined by its intended use. If the vitamin is intended to treat or prevent
disease, it is considered a drug.
If,
however, its use is simply as a nutritional supplement, then the vitamin is
considered a food supplement and is not subject to the strict guidelines as
mandated in the Food, Drug, and Cosmetic Act. Vitamin products must contain
ingredients as labeled but there is no requirement to establish that the
ingredients in the product are able to be absorbed from the product or are
active after oral administration. In part to remedy this situation, the USP has
published voluntary standards governing in
vitro dosage form disintegration and dissolution. Vitamin and mineral
supplement manufacturers may choose to test their products against these
standards and indicate that they passed the tests on their product labels.
Mechanism of
Action: Since vitamins represent a diverse collection of
biologically active compounds, they exert their effects through a wide range of
mechanisms. Their classification as vitamins is not because they have similar
biochemical effects but because all are needed for continued good health. In
general, most vitamins exert their effect by binding to a specific cofactor.
Because it is thought that binding to the cofactor can be saturated at some
vitamin concentration, increasing the dose of the vitamin,
does not produce proportionately greater physiologic effects.
Rather,
pharmacologic or toxic effects of the vitamin may occur. An example of an
effect of a pharmacologic effect for a vitamin is the cholesterol lowering
action of niacin (vitamin B3) when used in doses at least 40 times
the RDA. Nevertheless, many individuals attribute near magical qualities to
vitamins despite the fact that they merely represent dietary nutrients in
tablet or capsule form. Recently, however, great interest in the antioxidant
properties of vitamins C and E and beta-carotene has arisen. These data have
been reviewed by Jha et al. It is thought that the
body, particularly in smokers, generates highly reactive oxidative molecules
which can be damaging to tissues unless neutralized. Adequate
concentrations of the "antioxidant" vitamins affords the
protection from these molecules the body needs. Oxidation of LDL cholesterol is
an important step in the pathogenesis of atherosclerotic lesions. Vitamins with
antioxidant properties include vitamin E (alpha-tocopherol),
beta-carotene, and vitamin C. Other pharmacologic actions of vitamins are
discussed in detail on the respective monographs for each vitamin.
Distinguishing
Features: Although dissimilar in function, fat- and
water-soluble vitamins share some general characteristics.
The body stores only limited amounts of water-soluble vitamins as these are
easily eliminated by the kidneys. Fat-soluble vitamins are readily stored in
large quantities and can accumulate to toxic concentrations. Health-food
outlets and literature often promote the benefits of natural source products, however, products that are equally bioavailable
are equally effective regardless of origin (natural or synthetic).
Besides
satisfying the body's daily needs to prevent the development of a deficiency
state, some vitamins have therapeutic uses: pyridoxine can be used in the
treatment of sideroblastic anemia and to offset
certain drug-induced neuropathies, niacin exerts an antilipemic
action, and ascorbic acid can be used to acidify the urine. Some derivatives of
vitamin A - though not nutrients in the strict definition - exert powerful
effects on the skin and the hematopoetic system,
underscoring how important vitamins are to general health. Although more data
are needed, preliminary results indicate that routine intake of doses of
vitamins with antioxidant properties in excess of the standard RDA may indeed
be protective against myocardial infarction. Data is most convincing for
vitamin E, however, results from randomized trials has tempered enthusiasm
generated from earlier epidemiologic cohort studies. The beneficial effects of
beta-carotene on risk of myocardial infarction appear to be limited to smokers.
Vitamin C was found to reduce risk in only one cohort study. Clinicians should
also consider that subjects using antioxidant vitamins in these studies were
less likely to be smokers and have hypertension, more likely to exercise
regularly, and consumed more alcohol.
Adverse
Reactions: Due to their prompt elimination via the kidneys,
sweat glands, and other sites of excretion, water-soluble vitamins are
generally considered to be non-toxic even when taken in larger than physiologic
doses. Various toxicities, however, have been associated with water-soluble
vitamins. In doses greater than the RDA, niacin can be hepatotoxic, ascorbic
acid has been associated with nephrolithiasis, and pyridoxine, paradoxically,
in very high doses has caused peripheral neuropathy. Fat soluble vitamins, on
the other hand, can readily accumulate to toxic levels when taken in doses
substantially greater than the RDA. The liver is highly efficient in storing
vitamin A and even modest doses of vitamin D taken in combination with calcium
supplements can lead to hypercalcemia severe enough
produce coma. Since there is no established benefit of taking vitamins in
excess quantities, the AMA Council on Scientific Affairs has recommended that
the daily intake of vitamins be limited to 150% of the RDA for any single
vitamin in patients with no documented need for therapeutic doses.
VItamin B12
Vitamin B12 serves
as a cofactor for several essential biochemical reactions in humans. Deficiency
of vitamin B12 leads to anemia, gastrointestinal symptoms, and neurologic
abnormalities.
While
deficiency of vitamin B12 due to an inadequate supply in the diet is unusual,
deficiency of B12 in adults—especially older adults—due to abnormal absorption
of dietary vitamin B12 is a relatively common and easily treated disorder.
Chemistry
Vitamin B12
consists of a porphyrin-like ring with a central
cobalt atom attached to a nucleotide.
Various
organic groups may be covalently bound to the cobalt atom, forming different cobalamins. Deoxyadenosylcobalamin
and methylcobalamin are the active forms of the
vitamin in humans.
Vitamin B12
and folate metabolism
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Cyanocobalamin and
hydroxocobalamin (both available for
therapeutic use) and other cobalamins found in food
sources are converted to the above active forms. The ultimate source of vitamin
B12 is from microbial synthesis; the vitamin is not synthesized by animals or
plants. The chief dietary source of vitamin B12 is microbially
derived vitamin B12 in meat (especially liver), eggs, and dairy products. Vitamin B12 is sometimes called extrinsic
factor to differentiate it from intrinsic factor, a protein normally
secreted by the stomach.
Pharmacokinetics
The
average diet in the
The vitamin
is avidly stored, primarily in the liver, with an average adult having a total
vitamin B12 storage pool of 3000–5000 g. Only trace amounts of vitamin B12 are
normally lost in urine and stool. Since the normal daily requirements of
vitamin B12 are only about
Vitamin B12
in physiologic amounts is absorbed only after it complexes with intrinsic
factor, a glycoprotein secreted by the parietal cells of the gastric
mucosa. Intrinsic factor combines with the vitamin B12 that is liberated from
dietary sources in the stomach and duodenum, and the intrinsic factor-vitamin
B12 complex is subsequently absorbed in the distal ileum by a highly specific
receptor-mediated transport system.
Vitamin B12
deficiency in humans most often results from malabsorption
of vitamin B12, due either to lack of intrinsic factor or to loss or malfunction
of the specific absorptive mechanism in the distal ileum. Nutritional
deficiency is rare but may be seen in strict vegetarians after many years
without meat, eggs, or dairy products. Once absorbed, vitamin B12 is
transported to the various cells of the body bound to a plasma glycoprotein, transcobalamin II. Excess vitamin B12 is transported to the
liver for storage. Significant amounts of vitamin B12 are excreted in the urine
only when very large amounts are given parenterally,
overcoming the binding capacities of the transcobalamins
(50–100 g).
Pharmacodynamics
Two essential
enzymatic reactions in humans require vitamin B12 (Figure 33–1). In one, methylcobalamin serves as an intermediate in the transfer
of a methyl group from N_5- methyltetrahydrofolate to methionine (Figure 33–1 A; Figure
33–2, reaction 1).
In the
absence of vitamin B12, conversion of the major dietary and storage folate, N5-methyltetrahydrofolate, to tetrahydrofolate, the precursor of folate
cofactors, cannot occur. As a result, a deficiency of folate
cofactors necessary for several biochemical reactions involving the transfer of
one-carbon groups develops. In particular, the depletion of tetrahydrofolate
prevents synthesis of adequate supplies of the deoxythymidylate
(dTMP) and purines required for DNA synthesis in
rapidly dividing cells as shown in Figure 33–3, reaction 2.
The
accumulation of folate as N5-methyltetrahydrofolate
and the associated depletion of tetrahydrofolate
cofactors in vitamin B12 deficiency have been referred to as the "methylfolate trap." This is the biochemical step
whereby vitamin B12 and folic acid metabolism are linked and explains why the megaloblastic anemia of vitamin B12 deficiency can be
partially corrected by ingestion of relatively large amounts of folic acid.
Folic acid can be reduced to dihydrofolate by the
enzyme dihydrofolate reductase
(Figure 33–2, reaction 3) and thus serve as a source of the tetrahydrofolate
required for synthesis of the purines and dTMP that
are needed for DNA synthesis.
The other
enzymatic reaction that requires vitamin B12 is isomerization of methylmalonyl-CoA to succinyl-CoA
by the enzyme methylmalonyl-CoA mutase
(Figure 33–1 B). In vitamin B12 deficiency, this conversion cannot take place,
and the substrate, methylmalonyl-CoA, accumulates.
In the past,
it was thought that abnormal accumulation of methylmalonyl-CoA
causes the neurologic manifestations of vitamin B12 deficiency. However, newer
evidence instead implicates the disruption of the methionine synthesis pathway
as the cause of neurologic problems. Whatever the biochemical explanation for
neurologic damage, the important point is that administration of folic acid in
the setting of vitamin B12 deficiency will not prevent neurologic manifestations even though it will largely correct
the anemia caused by the
vitamin B12 deficiency.
Clinical
Pharmacology
Vitamin
B12 is used to treat or prevent deficiency. There is no evidence that vitamin
B12 injections have any benefit in persons who do not have vitamin B12
deficiency. The most characteristic clinical manifestation of vitamin B12
deficiency is megaloblastic anemia.
The typical
clinical findings in megaloblastic anemia are
macrocytic anemia (MCV usually > 120 fL), often
with associated mild or moderate leukopenia or thrombocytopenia (or both), and
a characteristic hypercellular bone marrow with megaloblastic maturation of erythroid
and other precursor cells.
Figure 33–1.
Vitamin
B12 deficiency also causes a neurologic syndrome that usually begins with paresthesias and weakness in peripheral nerves and
progresses to spasticity, ataxia, and other central nervous system
dysfunctions. A characteristic pathologic feature of the neurologic syndrome is
degeneration of myelin sheaths followed by disruption of axons in the dorsal and
lateral horns of the spinal cord and in peripheral nerves. Correction of
vitamin B12 deficiency arrests the progression of neurologic disease, but it
may not fully reverse neurologic symptoms that have been present for several
months.
Although most patients with neurologic
abnormalities caused by vitamin B12 deficiency have full-blown megaloblastic anemias when first
seen, occasional patients have few if any hematologic abnormalities. Once a
diagnosis of megaloblastic anemia is made, it must be
determined whether vitamin B12 or folic acid deficiency is the cause. (Other
causes of megaloblastic anemia are very rare.)
Figure 33–2.
This can
usually be accomplished by measuring serum levels of the vitamins. The
Schilling test, which measures absorption and urinary excretion of
radioactively labeled vitamin B12, can be used to further define the mechanism
of vitamin B12 malabsorption when this is found to be
the cause of the megaloblastic anemia.
The most
common causes of vitamin B12 deficiency are pernicious anemia, partial or total
gastrectomy, and diseases that affect the distal
ileum, such as malabsorption syndromes, inflammatory
bowel disease, or small bowel resection.
Pernicious anemia results from defective secretion of intrinsic factor by the gastric
mucosal cells.
Patients with
pernicious anemia have gastric atrophy and fail to secrete intrinsic factor (as
well as hydrochloric acid). The Schilling test shows diminished absorption of
radioactively labeled vitamin B12, which is corrected when hog intrinsic factor
is administered with radioactive B12, since the vitamin can then be normally
absorbed.
Vitamin
B12 deficiency also occurs when the region of the distal ileum that absorbs the
vitamin B12-intrinsic factor complex is damaged, as when the ileum is involved
with inflammatory bowel disease, or when the ileum is surgically resected. In
these situations, radioactively labeled vitamin B12 is not absorbed in the
Schilling test, even when intrinsic factor is added. Other rare causes of
vitamin B12 deficiency include bacterial overgrowth of the small bowel, chronic
pancreatitis, and thyroid disease. Rare cases of vitamin B12 deficiency in
children have been found to be secondary to congenital deficiency of intrinsic
factor and congenital selective vitamin B12 malabsorption
due to defects of the receptor sites in the distal ileum. Since almost all
cases of vitamin B12 deficiency are caused by malabsorption
of the vitamin, parenteral injections of vitamin B12 are required for therapy.
For patients with potentially reversible diseases, the underlying disease
should be treated after initial treatment with parenteral vitamin B12. Most
patients, however, do not have curable deficiency syndromes and require lifelong
treatment with vitamin B12 injections.
Vitamin B12
for parenteral injection is available as cyanocobalamin
or hydroxocobalamin. Hydroxocobalamin
is preferred because it is more highly protein-bound and therefore remains
longer in the circulation. Initial therapy should consist of 100–1000 g of
vitamin B12 intramuscularly daily or every other day for 1–2 weeks to replenish
body stores.
Maintenance
therapy consists of 100–1000 g intramuscularly once a month for life. If
neurologic abnormalities are present, maintenance therapy injections should be
given every 1–2 weeks for 6 months before switching to monthly injections.
Oral vitamin
B12-intrinsic factor mixtures and liver extracts should not be used to treat
vitamin B12 deficiency; however, oral doses of
Folic Acid
Reduced
forms of folic acid are required for essential biochemical reactions that
provide precursors for the synthesis of amino acids, purines, and DNA. Folate deficiency is not uncommon, even though the
deficiency is easily corrected by administration of folic acid. The
consequences of folate deficiency go beyond the
problem of anemia because folate deficiency is
implicated as a cause of congenital malformations in newborns and may play a
role in vascular disease (see Folic Acid Supplementation: A Public Health
Dilemma).
Chemistry
Folic acid (pteroylglutamic acid) is a compound composed of a heterocycle, p-aminobenzoic
acid, and glutamic acid (Figure 33–3). Various numbers of glutamic acid
moieties may be attached to the pteroyl portion of
the molecule, resulting in monoglutamates, triglutamates, or polyglutamates.
Folic acid can undergo reduction, catalyzed by
the enzyme dihydrofolate reductase
("folate reductase"),
to give dihydrofolic acid (Figure 33–2, reaction 3). Tetrahydrofolate can subsequently be transformed to folate cofactors possessing one-carbon units attached to
the 5-nitrogen, to the 10- nitrogen, or to both positions (Figure 33–2). The folate cofactors are interconvertible
by various enzymatic reactions and serve the important biochemical function of
donating one-carbon units at various levels of oxidation. In most of these, tetrahydrofolate is regenerated and becomes available for
reutilization.
Pharmacokinetics
The average
diet in the
Folates are excreted
in the urine and stool and are also destroyed by catabolism, so serum levels
fall within a few days when intake is diminished. Since body stores of folates are relatively low and daily requirements high,
folic acid deficiency and megaloblastic anemia can
develop within 1–6 months after the intake of folic acid stops, depending on
the patient's nutritional status and the rate of folate
utilization. Unaltered folic acid is readily and completely absorbed in the
proximal jejunum. Dietary folates, however, consist
primarily of polyglutamate forms of N_5-methyltetrahydrofolate.
Before
absorption, all but one of the glutamyl residues of
the polyglutamates must be hydrolyzed by the enzyme
-1-glutamyl transferase ("conjugase")
within the brush border of the intestinal mucosa The monoglutamate N_5-methyltetrahydrofolate
is subsequently transported into the bloodstream by both active and passive
transport and is then widely distributed throughout the body. Inside cells, N_5-methyltetrahydrofolate
is converted to tetrahydrofolate by the demethylation reaction that requires vitamin B12 (Figure
33–2, reaction 1).
Pharmacodynamics
Tetrahydrofolate
cofactors participate in one-carbon transfer reactions. As described above in
the section on vitamin B12, one of these essential reactions produces the dTMP needed for DNA synthesis. In this reaction, the enzyme
thymidylate synthase catalyzes the transfer of the
one-carbon unit of N_5,N_10-methylenetetrahydrofolate
to deoxyuridine monophosphate (dUMP)
to form dTMP (Figure 33–2, reaction 2). Unlike all of
the other enzymatic reactions that utilize folate
cofactors, in this reaction the cofactor is oxidized to dihydrofolate,
and for each mole of dTMP produced, one mole of tetrahydrofolate is consumed. In rapidly proliferating
tissues, considerable amounts of tetrahydrofolate can
be consumed in this reaction, and continued DNA synthesis requires continued
regeneration of tetrahydrofolate by reduction of dihydrofolate, catalyzed by the enzyme dihydrofolate
reductase. The tetrahydrofolate
thus produced can then reform the cofactor N_5,N_10-methylenetetrahydrofolate
by the action of serine transhydroxy- methylase and thus allow for the continued synthesis of dTMP. The combined catalytic activities of dTMP synthase, dihydrofolate reductase, and serine transhydroxymethylase
are often referred to as the dTMP synthesis cycle.
Enzymes in the dTMP cycle are the targets of two
anticancer drugs; methotrexate inhibits dihydrofolate
reductase, and a metabolite of 5-fluorouracil
inhibits thymidylate synthase. Cofactors of tetrahydrofolate participate in several other essential
reactions. As described above, N_5-methy- lenetetrahydrofolate
is required for the vitamin B12-dependent reaction that generates methionine
from homocysteine (Figure 33–1 A; Figure 33–2,
reaction 1). In addition,
tetrahydrofolate
cofactors donate one-carbon units during the de novo synthesis of essential
purines.
In these
reactions, tetrahydrofolate is regenerated and can
reenter the tetrahydrofolate cofactor pool.
Clinical Pharmacology
Folate deficiency results in a megaloblastic anemia that is microscopically
indistinguishable from the anemia caused by vitamin B12 deficiency (see above).
However, folate deficiency does not cause the
characteristic neurologic syndrome seen in vitamin B12 deficiency. In patients
with megaloblastic anemia, folate
status is assessed with assays for serum folate or
for red blood cell folate.
Red
blood cell folate levels are often of greater
diagnostic value than serum levels, since serum folate
levels tend to be quite labile and do not necessarily reflect tissue levels.
Folic acid deficiency, unlike vitamin B12 deficiency, is often caused by
inadequate dietary intake of folates. Alcoholics and
patients with liver disease develop folic acid deficiency because of poor diet
and diminished hepatic storage of folates. There is
also evidence that alcohol and liver disease interfere with absorption and
metabolism of folates. Pregnant women and patients
with hemolytic anemia have increased folate
requirements and may become folic acid-deficient, especially if their diets are
marginal. Evidence implicates maternal folic acid deficiency in the occurrence
of fetal neural tube defects, eg, spina
bifida.
Patients
with malabsorption syndromes also frequently develop
folic acid deficiency. Folic acid deficiency is occasionally associated with
cancer, leukemia, myeloproliferative disorders,
certain chronic skin disorders, and other chronic debilitating diseases.
Patients who require renal dialysis also develop folic acid deficiency, because
folates are removed from the plasma each time the
patient is dialyzed. Folic acid deficiency can be caused by drugs that
interfere with folate absorption or metabolism.
Phenytoin, some other anticonvulsants, oral contraceptives, and isoniazid can
cause folic acid deficiency by interfering with folic acid absorption. Other
drugs such as methotrexate and, to a lesser extent, trimethoprim and pyrimethamine, inhibit dihydrofolate
reductase and may result in a deficiency of folate cofactors and ultimately in megaloblastic
anemia.
Parenteral
administration of folic acid is rarely necessary, since oral folic acid is well
absorbed even in patients with malabsorption
syndromes.
A
dose of 1 mg of folic acid orally daily is sufficient to reverse megaloblastic anemia, restore normal serum folate levels, and replenish body stores of folates in almost all patients.
Therapy
should be continued until the underlying cause of the deficiency is removed or
corrected. Therapy may be required indefinitely for patients with malabsorption or dietary inadequacy.
Folic acid
supplementation to prevent folic acid deficiency should be considered in
high-risk patients, including pregnant women, alcoholics, and patients with
hemolytic anemia, liver disease, certain skin diseases, and patients on renal
dialysis.
By January
1998, all products made from enriched grains in the
Clinical data
suggest that the folate supplementation program has
improved the folate status and reduced the prevalence
of hyperhomocysteinemia in a population of
middle-aged and older adults who did not use vitamin supplements. It is
possible, though as yet unproved, that the increased ingestion of folic acid
will also reduce the risk of vascular disease in this population. While these
two potential benefits of supplemental folic acid are compelling, the decision
to require folic acid in grains was—and still is—controversial. As described in
the text, ingestion of folic acid can partially or totally correct the anemia
caused by vitamin B12 deficiency. However, folic acid supplementation will not prevent the potentially
irreversible neurologic damage caused by vitamin B12 deficiency. People with
pernicious anemia and other forms of vitamin B12 deficiency are usually
identified because of signs and symptoms of anemia, which tend to occur before
neurologic symptoms. The opponents of folic acid supplementation are concerned
that increased folic acid intake in the general population will mask vitamin
B12 deficiency and increase the prevalence of neurologic disease in our elderly
population. To put this in perspective, approximately 4000 pregnancies,
including 2500 live births, in the
VItamin D
Vitamin D is a secosteroid
produced in the skin from 7-dehydrocholesterol under the influence of
ultraviolet irradiation. Vitamin D is also found in certain foods and is used
to supplement dairy products. Both the natural form (vitamin D3, cholecalciferol) and the plant-derived form (vitamin D2, ergocalciferol) are present in the diet. These forms differ
in that ergocalciferol contains a double bond
(C22–23) and an additional methyl group in the side chain
(Figure
42–2).
Vitamin D is
a prohormone that serves as precursor to a number of
biologically active metabolites (Figure 42–2).
Vitamin D is
first hydroxylated in the liver to form
25-hydroxyvitamin D (25[OH]D). This metabolite is
further converted in the kidney to a number of other forms, the beststudied of which are 1,25-dihydroxyvitamin
D (1,25[OH]2D) and 24,25-dihydroxyvitamin D (24,25[OH]2D). Of the natural
metabolites, only vitamin D, 25(OH)D (as calcifediol),
and 1,25(OH)2D (as calcitriol)
are available for clinical use (see Table 42–1)
Moreover, a number of analogs of 1,25(OH)2 are being synthesized in an effort to extend the
usefulness of this metabolite to a variety of nonclassic
conditions. Calcipotriene (calcipotriol),
for example, is currently being used to treat psoriasis, a hyperproliferative
skin disorder. Doxercalciferol and paricalcitol have recently been approved for the
treatment of secondary hyperparathyroidism in patients with renal failure.
source de vitamines D-3) ...
Other analogs
are being investigated for the treatment of various malignancies. The
regulation of vitamin D metabolism is complex, involving calcium, phosphate,
and a variety of hormones, the most important of which is PTH, which stimulates
the production of 1,25(OH)2D by the kidney. mechanism of action of the vitamin D metabolites remains
under active investigation. However, calcitriol is
well established as the most potent agent with respect to stimulation of
intestinal calcium and phosphate transport and bone resorption.
Calcitriol
appears to act on the intestine both by induction of new protein synthesis (eg, calcium-binding protein) and by modulation of calcium
flux across the brush border and basolateral
membranes by a means does not require new protein synthesis. The molecular
action of calcitriol on bone has received less
attention. However, like PTH, calcitriol can induce
RANK ligand in osteoblasts and proteins such as osteocalcin,
which may regulate the mineralization process. The metabolites 25(OH)D and 24,25(OH)2D are far less potent stimulators of
intestinal calcium and phosphate transport or bone resorption.
However, 25(OH)D appears to be more potent than
1,25(OH)2D in stimulating renal reabsorption of calcium and phosphate and may
be the major metabolite regulating calcium flux and contractility in muscle.
Specific receptors for 1,25(OH)2D exist in target The
issues. However, the role and even the existence of receptors for 25(OH)D and 24,25(OH)2D remain controversial.
A summary of
the principal actions of PTH and vitamin D on the three main target tissues—
intestine, kidney, and bone—is presented in Table 42–2. The net effect of PTH
is to raise serum calcium and reduce serum phosphate; the net effect of vitamin
D is to raise both. Regulation of calcium and phosphate homeostasis is achieved
through a variety of feedback loops. Calcium is the principal regulator of PTH
secretion. It binds to a novel ion recognition site that is part of a Gq protein–coupled receptor and
links changes in intracellular free calcium concentration to changes in
extracellular
calcium. As serum calcium levels rise and bind to this receptor, intracellular
calcium levels increase and inhibit PTH secretion. Phosphate regulates PTH
secretion indirectly by forming complexes with calcium in the serum. Since it
is the ionized concentration of calcium that is detected by the parathyroid
gland, increases in serum phosphate levels reduce the ionized calcium and lead
to enhanced PTH secretion. Such feedback regulation is appropriate to the net
effect of PTH to raise serum calcium and reduce serum phosphate levels.
Likewise, both calcium and phosphate at high levels reduce the amount of 1,25(OH)2D produced by the kidney and increase the amount of
24,25(OH)2D produced. Since 1,25(OH)2D raises serum
calcium and phosphate, whereas 24,25(OH)2D has less effect, such feedback
regulation is again appropriate. 1,25(OH)2D itself
directly inhibits PTH secretion (independently of its effect on serum calcium)
by a direct action on PTH gene transcription. This provides yet another negative
feedback loop, because PTH is a major stimulus for 1,25(OH)2D
production. This ability of 1,25(OH)2D to inhibit PTH
secretion directly is being exploited using calcitriol
analogs that have less effect on serum calcium.
Such
drugs are proving useful in the management of secondary hyperparathyroidism
accompanying renal failure and may be useful in selected cases of primary
hyperparathyroidism.
A number of hormones modulate the actions of PTH
and vitamin D in regulating bone mineral homeostasis. Compared with that of PTH
and vitamin D, the physiologic impact of such secondary regulation on bone
mineral homeostasis is minor. However, in pharmacologic amounts, a number of
these hormones have actions on the bone mineral homeostatic mechanisms that can
be exploited therapeutically.
The principal effects of calcitonin are to lower serum calcium and
phosphate by actions on bone and kidney. Calcitonin
inhibits osteoclastic bone resorption.
Although bone formation is not impaired at first after calcitonin administration,
with time both formation and resorption of bone are
reduced.
Thus, the
early hope that calcitonin would prove useful in restoring bone mass has not
been realized. In the kidney, calcitonin reduces both calcium and phosphate
reabsorption as well as reabsorption of other ions, including sodium,
potassium, and magnesium. Tissues other than bone and kidney are also affected
by calcitonin. Calcitonin in pharmacologic amounts decreases gastrin secretion
and reduces gastric acid output while increasing secretion of sodium,
potassium, chloride, and water in the gut. Pentagastrin
is a potent stimulator of calcitonin secretion (as is hypercalcemia),
suggesting a possible physiologic relationship between gastrin and calcitonin.
In the adult human, no readily demonstrable problem develops in cases of
calcitonin deficiency (thyroidectomy) or excess (medullary carcinoma of the
thyroid). However, the ability of calcitonin to block bone resorption
and lower serum calcium makes it a useful drug for the treatment of Paget's
disease, hypercalcemia, and osteoporosis.
Clinical Pharmacology
Disorders of
bone mineral homeostasis generally present with abnormalities in serum or urine
calcium levels (or both), often accompanied by abnormal serum phosphate levels.
These abnormal mineral concentrations may themselves cause symptoms requiring
immediate treatment (eg, coma in malignant hypercalcemia, tetany in hypocalcemia). More commonly, they serve as clues to an
underlying disorder in hormonal regulators (eg,
primary hyperparathyroidism), target tissue response (eg,
chronic renal failure), or drug misuse (eg, vitamin D
intoxication). In such cases, treatment of the underlying disorder is of prime
importance.
Since bone
and kidney play central roles in bone mineral homeostasis, conditions that
alter bone mineral homeostasis usually affect either or both of these tissues
secondarily. Effects on bone can result in osteoporosis (abnormal loss of bone;
remaining bone histologically normal), osteomalacia
(abnormal bone formation due to inadequate mineralization), or osteitis fibrosa (excessive bone resorption with fibrotic replacement of resorption
cavities). Biochemical markers of skeletal involvement include changes in serum
levels of the skeletal isoenzyme of alkaline
phosphatase and
osteocalcin
(reflecting osteoblastic activity) and urine levels
of hydroxyproline and pyridinoline
cross-links (reflecting osteoclastic activity). The
kidney becomes involved when the calcium-timesphosphate
product in serum exceeds the point at which ectopic calcification occurs (nephrocalcinosis) or when the calcium-times-oxalate (or
phosphate) product in urine exceeds saturation, leading to nephrolithiasis.
Subtle early indicators of such renal involvement include polyuria, nocturia, and hyposthenuria.
Radiologic evidence of nephrocalcinosis and stones is
not generally observed until later. The degree of the ensuing renal failure is
best followed by monitoring the decline in creatinine
clearance.
Abnormal Serum Calcium & Phosphate Levels
Hypercalcemia
Hypercalcemia causes
central nervous system depression, including coma, and is potentially lethal.
Its major causes (other than thiazide therapy) are hyperparathyroidism and
cancer with or without bone metastases. Less common causes are hypervitaminosis D, sarcoidosis,
thyrotoxicosis, milkalkali syndrome, adrenal
insufficiency, and immobilization. With the possible exception of hypervitaminosis D, these latter disorders seldom require
emergency lowering of serum calcium. A number of approaches are used to manage
the hypercalcemic crisis.
When rapidity
of action is required, 1,25(OH)2D3 (calcitriol), 0.25–1 g daily, is the vitamin D metabolite of
choice, since it is capable of raising serum calcium within 24–48 hours. Calcitriol also raises serum phosphate, though this action
is usually not observed early in treatment. The combined effects of calcitriol and all other vitamin D metabolites and analogs
on both calcium and phosphate make careful monitoring of these mineral levels
especially important to avoid ectopic calcification secondary to an abnormally
high serum calcium x phosphate product. Since the choice of the levels of
high-energy organic
Vitamin D
deficiency, once thought to be rare in this country, is being recognized more
often, especially in the pediatric and geriatric populations on vegetarian
diets and with reduced sunlight exposure. This problem can be avoided by daily
intake of 400–800 units of vitamin D and treated by higher dosages (4000 units
per day). No other metabolite is indicated. The diet should also
contain
adequate amounts of calcium and phosphate.
Use of Vitamin D Preparations
The choice of
vitamin D preparation to be used in the setting of chronic renal failure in the
dialysis patient depends on the type and extent of bone disease and
hyperparathyroidism. No consensus has been reached regarding the advisability
of using any vitamin D metabolite in the predialysis
patient. 1,25(OH)2D3 (calcitriol)
will rapidly correct hypocalcemia and at least
partially reverse the secondary hyperparathyroidism and osteitis
fibrosa. Many patients with muscle weakness and bone
pain gain an improved sense of well-being.
Dihydrotachysterol,
an analog of 1,25(OH)2D, is also available for
clinical use, though it is used much less frequently than calcitriol.
Dihydrotachysterol appears to be as effective as calcitriol, differing principally in its time course of
action; calcitriol increases serum calcium in 1–2
days, whereas dihydrotachysterol requires 1–2 weeks. For an equipotent dose (0.2 mg dihydrotachy-sterol
versus
Calcifediol
(25[OH]D3) may also be used to advantage. Calcifediol is less effective than calcitriol
in stimulating intestinal calcium transport, so that hypercalcemia
is less of a problem with calcifediol.
Like dihydrotachysterol, calcifediol
requires several weeks to restore normocalcemia in hypocalcemic individuals with chronic renal failure.
Presumably because of the reduced ability of the diseased kidney to metabolize calcifediol to more active metabolites, high doses (50–100
g daily) must be given to achieve the supraphysiologic
serum levels required for therapeutic effectiveness.
Vitamin D has been used in treating renal osteodystrophy. However, patients with a substantial degree
of renal failure who are thus unable to convert vitamin D to its active
metabolites usually are refractory to vitamin D. Its use is decreasing as more
effective alternatives become available.
Two analogs
of calcitriol, doxercalciferol
and paricalcitol, are approved for the treatment of
secondary hyperparathyroidism of chronic renal failure. Their principal
advantage is that they are less likely than calcitriol
to induce hypercalcemia. Their biggest impact will be
in patients in whom the use of calcitriol may lead to
unacceptably high serum calcium levels.
Regardless of
the drug employed, careful attention to serum calcium and phosphate levels is
required. Calcium supplements (dietary and in the dialysate) and phosphate
restriction (dietary and with oral ingestion of phosphate binders) should be
employed along with the use of vitamin D metabolites. Monitoring serum PTH and
alkaline phosphatase levels is useful in determining whether therapy is
correcting or preventing secondary hyperparathyroidism.
Although not
generally available, percutaneous bone biopsies for quantitative histomorphometry may help in choosing appropriate therapy
and following the effectiveness of such therapy. Unlike the rapid changes in
serum values, changes in bone morphology require months to years. Monitoring
serum levels of the vitamin D metabolites is useful to determine compliance,
absorption, and metabolism.
The common
features that appear to be important in this group of diseases are malabsorption of calcium and vitamin D. Liver disease may,
in addition, reduce the production of 25(OH)D from
vitamin D, though the importance of this in all but patients with terminal
liver failure remains in dispute. The malabsorption
of vitamin D is probably not limited to exogenous vitamin D. The liver secretes
into bile a substantial number of vitamin D metabolites and conjugates that are
reabsorbed in (presumably) the distal jejunum and ileum. Interference with this
process could deplete the body of endogenous vitamin D metabolites as well as
limit absorption of dietary vitamin D.
In mild forms of malabsorption,
vitamin D (25,000–50,000 units three times per week) should suffice to raise
serum levels of 25(OH)D into the normal range. Many
patients with severe disease do not respond to vitamin D. Clinical experience
with
Vitamin D is
a secosteroid produced in the skin from
7-dehydrocholesterol under the influence of ultraviolet irradiation. Vitamin D
is also found in certain foods and is used to supplement dairy products. Both
the natural form (vitamin D3, cholecalciferol) and
the plant-derived form (vitamin D2, ergocalciferol)
are present in the diet. These forms differ in that ergocalciferol
contains a double bond (C22–23) and an additional methyl group in the side
chain (Figure 42–2).
Vitamin D is
a prohormone that serves as precursor to a number of
biologically active metabolites (Figure 42–2). Vitamin D is first hydroxylated in the liver to form 25-hydroxyvitamin D
(25[OH]D). This metabolite is further converted in the
kidney to a number of other forms, the beststudied of
which are 1,25-dihydroxyvitamin D (1,25[OH]2D) and
24,25-dihydroxyvitamin D (24,25[OH]2D). Of the natural metabolites, only
vitamin D, 25(OH)D (as calcifediol), and 1,25(OH)2D
(as calcitriol)
are available for clinical use (see Table 42–1). Moreover, a number of analogs
of 1,25(OH)2 are being synthesized in an effort to
extend the usefulness of this metabolite to a variety of nonclassic
conditions. Calcipotriene (calcipotriol),
for example, is currently being used to treat psoriasis, a hyperproliferative
skin disorder. Doxercalciferol and paricalcitol have recently been approved for the
treatment of secondary hyperparathyroidism in patients with renal failure.
Other analogs are being investigated for the treatment of various malignancies.
The regulation of vitamin D metabolism is complex, involving calcium,
phosphate, and a variety of hormones, the most important of which is PTH, which
stimulates the production of 1,25(OH)2D by
the
kidney. mechanism of action of the vitamin D
metabolites remains under active investigation. However, calcitriol
is well established as the most potent agent with respect to stimulation of
intestinal calcium and phosphate transport and bone resorption.
Calcitriol appears to act on the intestine both by
induction of new protein synthesis (eg,
calcium-binding protein) and by modulation of calcium flux across the brush
border and basolateral membranes by a means does not
require new protein synthesis. The molecular action of calcitriol
on bone has received less attention. However, like PTH, calcitriol
can induce RANK ligand in osteoblasts and proteins such as osteocalcin,
which may regulate the mineralization process. The metabolites 25(OH)D and 24,25(OH)2D are far less potent stimulators of
intestinal calcium and phosphate transport or bone resorption.
However, 25(OH)D appears to be more potent than
1,25(OH)2D in stimulating renal reabsorption of calcium and phosphate and may
be the major metabolite regulating calcium flux and contractility in muscle.
Specific receptors for 1,25(OH)2D exist in target The
issues. However, the role and even the existence of receptors for 25(OH)D and 24,25(OH)2D remain controversial.
A summary of
the principal actions of PTH and vitamin D on the three main target tissues—
intestine, kidney, and bone—is presented in Table 42–2. The net effect of PTH
is to raise serum calcium and reduce serum phosphate; the net effect of vitamin
D is to raise both. Regulation of calcium and phosphate homeostasis is achieved
through a variety of feedback loops. Calcium is the principal regulator of PTH
secretion. It binds to a novel ion recognition site that is part of a Gq protein–coupled receptor and
links changes in intracellular free calcium concentration to changes in
extracellular
calcium. As serum calcium levels rise and bind to this receptor, intracellular
calcium levels increase and inhibit PTH secretion. Phosphate regulates PTH
secretion indirectly by forming complexes with calcium in the serum. Since it
is the ionized concentration of calcium that is detected by the parathyroid
gland, increases in serum phosphate levels reduce the ionized calcium and lead
to enhanced PTH secretion. Such feedback regulation is appropriate to the net
effect of PTH to raise serum calcium and reduce serum phosphate levels.
Likewise, both calcium and phosphate at high levels reduce the amount of 1,25(OH)2D produced by the kidney and increase the amount of
24,25(OH)2D produced. Since 1,25(OH)2D raises serum
calcium and phosphate, whereas 24,25(OH)2D has less effect, such feedback
regulation is again appropriate. 1,25(OH)2D itself
directly inhibits PTH secretion (independently of its effect on serum calcium)
by a direct action on PTH gene transcription. This provides yet another
negative feedback loop, because PTH is a major stimulus for 1,25(OH)2D
production. This ability of 1,25(OH)2D to inhibit PTH
secretion directly is being exploited using calcitriol
analogs that have less effect on serum calcium.
Such drugs
are proving useful in the management of secondary hyperparathyroidism
accompanying renal failure and may be useful in selected cases of primary
hyperparathyroidism.
A number of hormones modulate the actions of PTH
and vitamin D in regulating bone mineral homeostasis. Compared with that of PTH
and vitamin D, the physiologic impact of such secondary regulation on bone
mineral homeostasis is minor. However, in pharmacologic amounts, a number of
these hormones have actions on the bone mineral homeostatic mechanisms that can
be exploited therapeutically.
Calcitonin
The
calcitonin secreted by the parafollicular cells of
the mammalian thyroid is a single-chain peptide hormone with 32 amino acids and
a molecular weight of
British Medical Research Council (MRC) and
expressed as MRC units. Human calcitonin monomer has a half-life of about 10
minutes with a metabolic clearance of 8–9 mL/kg/min. Salmon calcitonin has a
longer half-life and a reduced metabolic clearance (3 mL/kg/min), making it
more attractive as a therapeutic agent. Much of the clearance occurs in the
kidney, although little intact calcitonin appears in the urine.
The principal
effects of calcitonin are to lower serum calcium and phosphate by actions on
bone and kidney. Calcitonin inhibits osteoclastic
bone resorption. Although bone formation is not
impaired at first after calcitonin administration, with time both formation and
resorption of bone are reduced.
Thus, the early
hope that calcitonin would prove useful in restoring bone mass has not been
realized. In the kidney, calcitonin reduces both calcium and phosphate
reabsorption as well as reabsorption of other ions, including sodium,
potassium, and magnesium. Tissues other than bone and kidney are also affected
by calcitonin. Calcitonin in pharmacologic amounts decreases gastrin secretion
and reduces gastric acid output while increasing secretion of sodium,
potassium, chloride, and water in the gut. Pentagastrin
is a potent stimulator of calcitonin secretion (as is hypercalcemia),
suggesting a possible physiologic relationship between gastrin and calcitonin.
In the adult human, no readily demonstrable problem develops in cases of
calcitonin deficiency (thyroidectomy) or excess (medullary carcinoma of the
thyroid). However, the ability of calcitonin to block bone resorption
and lower serum calcium makes it a useful drug for the treatment of Paget's
disease, hypercalcemia, and osteoporosis.
Clinical Pharmacology
Disorders of
bone mineral homeostasis generally present with abnormalities in serum or urine
calcium levels (or both), often accompanied by abnormal serum phosphate levels.
These abnormal mineral concentrations may themselves cause symptoms requiring
immediate treatment (eg, coma in malignant hypercalcemia, tetany in hypocalcemia). More commonly, they serve as clues to an
underlying disorder in hormonal regulators (eg,
primary hyperparathyroidism), target tissue response (eg,
chronic renal failure), or drug misuse (eg, vitamin D
intoxication). In such cases, treatment of the underlying disorder is of prime
importance.
Since bone
and kidney play central roles in bone mineral homeostasis, conditions that
alter bone mineral homeostasis usually affect either or both of these tissues
secondarily. Effects on bone can result in osteoporosis (abnormal loss of bone;
remaining bone histologically normal), osteomalacia
(abnormal bone formation due to inadequate mineralization), or osteitis fibrosa (excessive bone resorption with fibrotic replacement of resorption
cavities). Biochemical markers of skeletal involvement include changes in serum
levels of the skeletal isoenzyme of alkaline
phosphatase and
osteocalcin
(reflecting osteoblastic activity) and urine levels
of hydroxyproline and pyridinoline
cross-links (reflecting osteoclastic activity). The
kidney becomes involved when the calcium-timesphosphate
product in serum exceeds the point at which ectopic calcification occurs (nephrocalcinosis) or when the calcium-times-oxalate (or
phosphate) product in urine exceeds saturation, leading to nephrolithiasis.
Subtle early indicators of such renal involvement include polyuria, nocturia, and hyposthenuria.
Radiologic evidence of nephrocalcinosis and stones is
not generally observed until later. The degree of the ensuing renal failure is
best followed by monitoring the decline in creatinine
clearance.
Abnormal Serum Calcium & Phosphate Levels
Hypercalcemia
Hypercalcemia
causes central nervous system depression, including coma, and is potentially
lethal. Its major causes (other than thiazide therapy) are hyperparathyroidism
and cancer with or without bone metastases. Less common causes are hypervitaminosis D, sarcoidosis,
thyrotoxicosis, milkalkali syndrome, adrenal
insufficiency, and immobilization. With the possible exception of hypervitaminosis D, these latter disorders seldom require
emergency lowering of serum calcium. A number of approaches are used to manage
the hypercalcemic crisis.
Calcitonin
Calcitonin
has proved useful as ancillary treatment in a large number of patients.
Calcitonin by itself seldom restores serum calcium to normal, and
refractoriness frequently develops. However, its lack of toxicity permits
frequent administration at high doses (200 MRC units or more). An effect on
serum calcium is observed within 4–6 hours and lasts for 6–10 hours. Calcimar (salmon calcitonin) is available for parenteral
and nasal administration.
Calcium
A number of
calcium preparations are available for intravenous, intramuscular, and oral
use.
Calcium gluceptate (0.9
meq calcium/mL), calcium gluconate
(0.45 meq calcium/mL), and calcium chloride
(0.68–1.36 meq calcium/mL) are available for
intravenous therapy. Calcium gluconate is the preferred
form because it is less irritating to veins. Oral preparations include calcium
carbonate (40% calcium), calcium lactate (13% calcium), calcium phosphate (25%
calcium), and calcium citrate (21% calcium). Calcium carbonate is often the
preparation of choice because of its high percentage of calcium, ready
availability (eg, Tums), low cost, and antacid
properties. In achlorhydric patients, calcium
carbonate should be given with meals to increase absorption or the patient
switched to calcium citrate, which is somewhat better absorbed. Combinations of
vitamin D and calcium are available, but treatment must be tailored to the
individual patient and individual disease, a flexibility lost by fixed-dosage
combinations. Treatment of severe symptomatic hypocalcemia
can be accomplished with slow infusion of 5–20 mL of 10% calcium gluconate.
Rapid
infusion can lead to cardiac arrhythmias. Less severe hypocalcemia
is best treated with oral forms sufficient to provide approximately 400–800 mg
of elemental calcium (1–2 g calcium carbonate) per day. Dosage must be adjusted
to avoid hypercalcemia and hypercalciuria.
When rapidity
of action is required, 1,25(OH)2D3 (calcitriol), 0.25–1 g daily, is the vitamin D metabolite of
choice, since it is capable of raising serum calcium within 24–48 hours. Calcitriol also raises serum phosphate, though this action
is usually not observed early in treatment. The combined effects of calcitriol and all other vitamin D metabolites and analogs
on both calcium and phosphate make careful monitoring of these mineral levels
especially important to avoid ectopic calcification secondary to an abnormally
high serum calcium x phosphate product. Since the choice of the
levels
of high-energy organic
Vitamin D
deficiency, once thought to be rare in this country, is being recognized more
often, especially in the pediatric and geriatric populations on vegetarian
diets and with reduced sunlight exposure. This problem can be avoided by daily
intake of 400–800 units of vitamin D and treated by higher dosages (4000 units
per day). No other metabolite is indicated. The diet should also
contain
adequate amounts of calcium and phosphate.
Use of Vitamin D Preparations
The
choice of vitamin D preparation to be used in the setting of chronic renal
failure in the dialysis patient depends on the type and extent of bone disease
and hyperparathyroidism. No consensus has been reached regarding the
advisability of using any vitamin D metabolite in the predialysis
patient. 1,25(OH)2D3 (calcitriol)
will rapidly correct hypocalcemia and at least
partially reverse the secondary hyperparathyroidism and osteitis
fibrosa. Many patients with muscle weakness and bone
pain gain an improved sense of well-being.
Dihydrotachysterol,
an analog of 1,25(OH)2D, is also available for clinical
use, though it is used much less frequently than calcitriol.
Dihydrotachysterol appears to be as effective as calcitriol, differing principally in its time course of
action; calcitriol increases serum calcium in 1–2
days, whereas dihydrotachysterol requires 1–2 weeks. For an equipotent dose (0.2 mg dihydrotachy-sterol
versus
Calcifediol
(25[OH]D3) may also be used to advantage. Calcifediol is less effective than calcitriol
in stimulating intestinal calcium transport, so that hypercalcemia
is less of a problem with calcifediol.
Like dihydrotachysterol, calcifediol
requires several weeks to restore normocalcemia in hypocalcemic individuals with chronic renal failure.
Presumably because of the reduced ability of the diseased kidney to metabolize calcifediol to more active metabolites, high doses (50–100
g daily) must be given to achieve the supraphysiologic
serum levels required for therapeutic effectiveness.
Vitamin D has
been used in treating renal osteodystrophy. However,
patients with a substantial degree of renal failure who are thus unable to
convert vitamin D to its active metabolites usually are refractory to vitamin
D. Its use is decreasing as more effective alternatives become available.
Two
analogs of calcitriol, doxercalciferol
and paricalcitol, are approved for the treatment of
secondary hyperparathyroidism of chronic renal failure. Their principal
advantage is that they are less likely than calcitriol
to induce hypercalcemia. Their biggest impact will be
in patients in whom the use of calcitriol may lead to
unacceptably high serum calcium levels.
Regardless of
the drug employed, careful attention to serum calcium and phosphate levels is
required. Calcium supplements (dietary and in the dialysate) and phosphate
restriction (dietary and with oral ingestion of phosphate binders) should be
employed along with the use of vitamin D metabolites. Monitoring serum PTH and
alkaline phosphatase levels is useful in determining whether therapy is
correcting or preventing secondary hyperparathyroidism.
Although not
generally available, percutaneous bone biopsies for quantitative histomorphometry may help in choosing appropriate therapy
and following the effectiveness of such therapy. Unlike the rapid changes in
serum values, changes in bone morphology require months to years. Monitoring
serum levels of the vitamin D metabolites is useful to determine compliance,
absorption, and metabolism.
The common
features that appear to be important in this group of diseases are malabsorption of calcium and vitamin D. Liver disease may,
in addition, reduce the production of 25(OH)D from
vitamin D, though the importance of this in all but patients with terminal
liver failure remains in dispute. The malabsorption
of vitamin D is probably not limited to exogenous vitamin D. The liver secretes
into bile a substantial number of vitamin D metabolites and conjugates that are
reabsorbed in (presumably) the distal jejunum and ileum. Interference with this
process could deplete the body of endogenous vitamin D metabolites as well as
limit absorption of dietary vitamin D.
In mild forms
of malabsorption, vitamin D (25,000–50,000 units
three times per week) should suffice to raise serum levels of 25(OH)D into the normal range. Many patients with severe disease
do not respond to vitamin D. Clinical experience with the other metabolites is
limited, but both calcitriol and calcifediol
have been used successfully in doses similar to those recommended for treatment
of renal osteodystrophy. Theoretically, calcifediol should be the drug of choice under these
conditions, since no impairment of the renal metabolism of 25(OH)D to 1,25(OH)2D and 24,25(OH)2D exists in these patients.
Both calcitriol and 24,25(OH)2D
may be of importance in reversing the bone disease. As in the other diseases
discussed, treatment of intestinal osteodystrophy
with vitamin D and its metabolites should be accompanied by appropriate dietary
calcium supplementation and monitoring of serum calcium and phosphate levels.
This protein
carboxylation is physiologically coupled with the oxidative deactivation of
vitamin K. The anticoagulant prevents reductive metabolism of the inactive
vitamin K epoxide back to its active hydroquinone form (Figure 34–6).
Mutational change of the responsible enzyme, vitamin K epoxide reductase, can give rise to genetic resistance to warfarin
in humans and especially in rats.
There is an
8- to 12-hour delay in the action of warfarin. Its anticoagulant effect results
from a balance between partially inhibited synthesis and unaltered degradation
of the four vitamin Kdependent clotting factors. The
resulting inhibition of coagulation is dependent on their degradation rate in
the circulation. These half-lives are 6, 24, 40, and 60 hours for factors VII,
IX, X, and II, respectively. Larger initial doses of warfarin—up to about 0.75
mg/kg—hasten the onset of the anticoagulant effect. Beyond this dosage, the
speed of onset is independent of the dose size. The only effect of a larger
loading dose is to prolong the time that the plasma concentration of drug
remains above that required for suppression of clotting factor synthesis. The
only difference among oral anticoagulants in producing and maintaining hypoprothrombinemia is the half-life of each drug.
Figure 34–6.
Toxicity
Warfarin
crosses the placenta readily and can cause a hemorrhagic disorder in the fetus.
Furthermore, fetal proteins with -carboxyglutamate
residues found in bone and blood may be affected by warfarin; the drug can
cause a serious birth defect characterized by abnormal bone formation. Thus,
warfarin should never be administered during pregnancy. Cutaneous necrosis with
reduced activity of protein C sometimes occurs during the first weeks of
therapy. Rarely, the same process causes frank infarction of breast, fatty
tissues, intestine, and extremities. The pathologic lesion associated with the
hemorrhagic infarction is venous thrombosis, suggesting that it is caused by
warfarin-induced depression of protein C synthesis.
The most serious interactions with warfarin are
those that increase the anticoagulant effect and the risk of bleeding. The most
dangerous of these interactions are the pharmacokinetic interactions with the pyrazolones phenylbutazone and sulfinpyrazone.
The
mechanisms for their hypoprothrombinemic interaction
are a stereoselective inhibition of oxidative
metabolic transformation of S-warfarin (the more potent isomer) and
displacement of albumin-bound warfarin, increasing the free fraction. For this
and other reasons, neither phenylbutazone nor sulfinpyrazone is in common use in the
Barbiturates
and rifampin cause a marked decrease of the anticoagulant effect by
induction of the hepatic enzymes that transform racemic warfarin. Cholestyramine binds warfarin in the intestine and reduces
its absorption and bioavailability.
Pharmacodynamic
reductions of anticoagulant effect occur with vitamin K (increased synthesis of
clotting factors), the diuretics chlorthalidone and
spironolactone (clotting factor concentration), hereditary resistance (mutation
of vitamin K reactivation cycle molecules), and hypothyroidism (decreased
turnover rate of clotting factors).
Enzymes drugs
The
immune response occurs when immunologically competent cells are activated in
response to foreign organisms or antigenic substances liberated during the
acute or chronic inflammatory response. The outcome of the immune response for
the host may be beneficial, as when it causes invading organisms to be phagocytosed or neutralized. On the other hand, the outcome
may be deleterious if it leads to chronic inflammation without resolution of
the underlying injurious process. Chronic inflammation involves the release of
a number of mediators that are not prominent in the acute response. One of the
most important conditions involving these mediators is rheumatoid arthritis, in
which chronic inflammation results in pain and destruction of bone and
cartilage that can lead to severe disability and in which systemic changes
occur that can result in shortening of life.
Purine
Nucleoside Kinase
Exogenous
adenosine is the precursor of the entire purine nucleotide pool in T vaginalis through its partial conversion to inosine and the action of purine nucleoside kinase, a
unique enzyme in the organism, which converts adenosine and inosine
to the corresponding nucleotides. It performs a critical role in T vaginalis purine salvage and has a
unique substrate specificity suitable as a target of chemotherapy.
Background On Enzymes
Trypanothione
Synthase, Reductase, & Peroxidase
Protozoa with
kinetoplasts are unusual in that a considerable
proportion of their intracellular spermidine and glutathione
is found in the unique conjugate N1-N8-(glutathionyl)spermidine, which has been
assigned the name trypanothione.
Trypanothione
synthase, reductase, and peroxidase
activities
have been detected in these parasites. A knockout of the gene encoding trypanothione reductase from the
African trypanosome Trypanosoma brucei resulted in apparent cessation of growth of the
organism. Nifurtimox, a nitrofuran
derivative effective in treating Chagas' disease
(caused by Trypanosoma cruzi),
has been found to be a potent inhibitor of trypanothione
reductase, and other inhibitors are under study. No
extensive studies of trypanothione synthetase or peroxidase have been performed. The antitrypanosomal trivalent arsenicals are taken up by the
African trypanosome Trypanosoma brucei and complex with trypanothione,
forming a product that is also an effective inhibitor of trypanothione
reductase.
Glycolipid
Synthetic Enzymes
The variant
surface glycoprotein on the plasma membranes of bloodstream African
trypanosomes provides the organisms with the means of evading host immune
responses. The glycoprotein is anchored to the cell surface by a glycosyl phosphatidylinositol that contains myristate as its only fatty acid component. Thus, the
introduction of a subversive substrate to replace myristate
from the glycolipid anchor could result in loss of the variant surface
glycoprotein, which might suppress development of trypanosomes in mammalian
blood. A myristate analog, 10-(propoxy)
decanoic acid, was found incorporated into the
glycolipid and also active against T brucei in
vitro tests.
However,
further validation of this approach to antitrypanosomal
chemotherapy must await results of in vivo tests.
Shikimate
Pathway Enzymes
The
availability of P falciparum genome database led to the identification
of shikimate pathway enzymes in this organism. The
pathway is known to exist in bacteria, fungi, algae, and plants but not in
mammals. A herbicide, glyphosate, known to inhibit the
enzyme 5'-enolpyruvylshikimate 3- phosphate synthase, was found to inhibit
growth of P falciparum. However, it is not known if the in vitro
antimalarial action of glyphosate is by inhibiting this enzyme. Furthermore,
the shikimate pathway leads to biosynthesis of
aromatic amino acids. Since P falciparum grows on digested
hemoglobin,
it is not clear if biosynthesis of aromatic amino acids plays an essential role
in this organism.
Isoretinoid
Biosynthetic Enzymes
A mevalonate-independent isoprenoid
biosynthetic pathway occurring only among bacteria, algae, and plants was also
identified in P falciparum and T gondii. Fosmidomycin, known to inhibit
1-deoxy-D-xylulose-5-phosphate isomerase in this
pathway, was found to also inhibit in vitro growth of P falciparum and
to cure P vinckei infection in mice. However, the
same questions about whether the pathway plays an indispensable role in this
parasitic organism and whether fosmidomycin inhibits
the parasites by inhibiting the particular enzyme remain to be answered.
Enzymes
Indispensable Only in Parasites
Because of
the many metabolic deficiencies among parasites resulting from the unique
environments in which parasites live in their hosts, there are enzymes whose
functions may be essential for the survival of the parasites, but the same
enzymes are not indispensable to the host— ie, the
host may be able to survive the complete loss of these enzyme functions by
achieving the same result through alternative pathways. This discrepancy opens
up opportunities for antiparasitic chemotherapy,
though insufficiently selective inhibition of parasite enzymes remains an
important safety concern.
Lanosterol
C-14 Demethylase
T cruzi and leishmania
contain ergosterol as the principal sterol in plasma
membranes. The azole antifungal agents (eg,
ketoconazole, miconazole, itraconazole),
which are known to act by inhibiting the cytochrome P450-dependent C-14 demethylation of lanosterol in
the ergosterol biosynthetic pathway, also inhibit
growth of T cruzi and leishmania
by blocking C-14 demethylation of lanosterol
in these parasites. Recently, an antifungal bistriazole,
D0870, demonstrated encouraging in vivo anti-T cruzi
activity in mouse infection models. It is thus likely that lanosterol C-14 demethylase plays
an essential role in ergosterol synthesis and
therefore qualifies as a target for chemotherapy against T cruzi and leishmania.
The same C-14
demethylation of lanosterol
is also required for cholesterol synthesis in mammals. As rather nonselective
inhibitors of lanosterol C-14 demethylases,
the azoles may exert a variety of endocrine side effects by inhibiting this
enzyme in the adrenal glands and gonads while remaining acceptable as systemic
antifungal agents. Because of its excessive toxicity, D0870 was not developed
as an antifungal or antiparasitic agent. However,
since human and yeast lanosterol C- 14 demethylases share only 38–42% sequence identities, there
may be a good chance of designing inhibitors that are more selective against
the fungal or parasitic enzymes.
DNA helps create enzymes, ...
Purine Phosphoribosyl
Transferases
The absence
of de novo purine nucleotide synthesis in protozoal
parasites as well as in the trematode Schistosoma mansoni is
reflected in the relative importance of purine phosphoribosyl
transferases in many parasite species. G lamblia has an exceedingly simple scheme of purine
salvage. It possesses only two pivotal enzymes: the adenine and guanine phosphoribosyl transferases,
which convert exogenous adenine and guanine to the corresponding nucleotides.
There is no salvage of hypoxanthine, xanthine, or any purine nucleosides and no
interconversion between adenine and guanine
nucleotides in the parasite.
Functions of
the two phosphoribosyl transferases
are thus both essential for the survival and development of G lamblia (Figure 52–1). The guanine phosphoribosyl
transferase is an interesting enzyme because it does
not recognize hypoxanthine, xanthine, or adenine as substrate. This substrate
specificity distinguishes the giardia enzyme from the mammalian enzyme, which
uses hypoxanthine, and the bacterial one, which uses xanthine as substrate.
Design of a highly specific inhibitor of this enzyme is thus possible. The
crystal structures of both guanine and adenine phosphoribosyltransferases
from G lamblia have been solved recently,
which should provide good opportunities for specific inhibitor design.
Dihydrofolate Reductase-Thymidylate Synthase Bifunctional
Enzyme
Dihydrofolate reductase (DHFR), a classic target in antimicrobial and
anticancer chemotherapy, has been shown to be a useful therapeutic target in
plasmodium, toxoplasma, and eimeria species.
Pyrimethamine is
the prototypical DHFR inhibitor, exerting inhibitory effects in all three
groups.
However, pyrimethamine resistance in P falciparum has become
widespread in recent years. This is largely attributable to specific point
mutations in P falciparum DHFR that have rendered the enzyme less
susceptible to the inhibitor.
A highly
unusual feature of DHFR in Apicomplexa and Kinetoplastida is its association with thymidylate
synthase in the same protein. DHFR activity is always located at the amino
terminal portion, while the thymidylate synthase
activity resides in the carboxyl terminal. The two enzyme functions do not
appear to be interdependent; eg, the DHFR portion of
the P falciparum enzyme molecule was found to function normally in the
absence of the thymidylate synthase portion. It is
likely that since the protozoan parasites do not perform de novo synthesis of
purine nucleotides, the primary function of the tetrahydrofolate
produced by DHFR is to provide 5,10- methylenetetrahydrofolate only for the thymidylate
synthase-catalyzed reaction. Physical association of the two enzymes may
improve efficiency of TMP synthesis. If an effective means of disrupting the
coordination between the two activities can be developed, this bifunctional protein may qualify as a target for antiparasitic therapy.
Thiamin
Transporter
Carbohydrate
metabolism provides the main energy source in coccidia.
Diets deficient in thiamin, riboflavin, or nicotinic acid—all cofactors in
carbohydrate metabolism—result in suppression of parasitic infestation of
chickens by E tenella and E acervulina. A thiamin analog, amprolium—1-
[(4-amino-2-propyl-5-pyrimidinyl)-methyl]-2-picolinium chloride—has long been
used as an effective anticoccidial agent in chickens
and cattle with relatively low host toxicity. The antiparasitic
activity of amprolium is reversible by thiamin and is
recognized to involve inhibition of thiamin transport in the parasite.
Unfortunately, amprolium has a rather narrow spectrum
of antiparasitic activity; it has poor activity
against toxoplasmosis, a closely related parasitic infection.
Mitochondrial
Electron Transporter
Mitochondria
of E tenella appear to lack cytochrome c and
to contain cytochrome o—a cytochrome oxidase commonly found in the bacterial
respiratory chain—as the terminal oxidase. Certain 4- hydroxyquinoline
derivatives such as buquinolate, decoquinate,
and methyl benzoquate that have long been known to be
relatively nontoxic and effective anticoccidial
agents have been found to act on the parasites by inhibiting mitochondrial
respiration. Direct investigation on isolated intact E tenella
mitochondria indicated that the 4-hydroxyquinolines have no effect on NADH
oxidase or succinoxidase activity but that they are
extremely potent inhibitors of NADH- or succinate-induced mitochondrial respiration.
On the other hand, the ascorbate-induced E tenella mitochondrial respiration was totally
insusceptible to these 4-hydroxyquinolines. The block by the anticoccidial agents thus may be located between the
oxidases and cytochrome b in the electron transport chain.
Team
of Enzymes Working ...
A certain
component at this location must be essential for mediating the electron transport
and would appear to be highly sensitive to the 4-hydroxyquinolines. This
component must be a very specific chemotherapeutic target in eimeria species, since the 4-hydroxyquinolines have no
effect on chicken liver and mammalian mitochondrial respiration and no activity
against any parasites other than eimeria.
Many 2-hydroxynaphthoquinones have demonstrated
therapeutic activities against Apicomplexa.
Parvaquinone and
buparvaquinone have been developed for
the treatment of theileriosis in cattle and other domestic
animals. Atovaquone is an antimalarial
drug and is also used in the treatment of Pneumocystis jiroveci
and P carinii infections. The
2-hydroxynaphthoquinones are analogs of ubiquinone. The primary site of action
of atovaquone in Plasmodium is the cytochrome
bc1 complex, where an apparent drug-binding site is present in cytochrome b. In
plasmodium, ubiquinone also plays an important role as an electron acceptor for
dihydroorotate oxidase.
Consequently,
pyrimidine biosynthesis in plasmodium is also inhibited by atovaquone.
This chemical compound has also been found to be active against T gondii cysts in the brains of infected mice.
The
cell damage associated with inflammation acts on cell membranes to cause
leukocytes to release lysosomal enzymes; arachidonic acid is then liberated from precursor
compounds, and various eicosanoids are synthesized. Compounds, the
cyclooxygenase pathway of arachidonate metabolism
produces prostaglandins, which have a variety of effects on blood vessels, on
nerve endings, and on cells involved in inflammation. The discovery of
cyclooxygenase (COX) isoforms (COX-1 and COX-2) led to the concepts that the
constitutive COX-1 isoform tends to be homeostatic in function, while COX-2 is
induced during inflammation and tends to facilitate the inflammatory response. On this basis, highly selective COX-2 inhibitors have been
developed and marketed on the assumption that such selective inhibitors would
be safer than nonselective COX-1 inhibitors but without loss of efficacy.
The lipoxygenase pathway of arachidonate
metabolism yields leukotrienes, which have a powerful
chemotactic effect on eosinophils, neutrophils, and
macrophages and promote bronchoconstriction and alterations in vascular
permeability. Kinins, neuropeptides, and histamine
are also released at the site of tissue injury, as are complement components,
cytokines, and other products of leukocytes and platelets. Stimulation of the
neutrophil membranes produces oxygen-derived free radicals.
Superoxide
anion is formed by the reduction of molecular oxygen, which may stimulate the
production of other reactive molecules such as hydrogen peroxide and hydroxyl
radicals. The interaction of these substances with arachidonic
acid results in the generation of chemotactic substances, thus perpetuating the
inflammatory process.
Reduction
of inflammation with nonsteroidal anti-inflammatory drugs (NSAIDs) often
results in relief of pain for significant periods. Furthermore, most of the nonopioid analgesics (aspirin, etc)
also have anti-inflammatory effects, so they are appropriate for the treatment
of both acute and chronic inflammatory conditions.
Another
important group of agents are characterized as slow-acting antirheumatic drugs (SAARDs) or
disease-modifying antirheumatic
drugs (DMARDs). They may slow the bone damage associated with rheumatoid
arthritis and are thought to affect more basic inflammatory mechanisms than do
the NSAIDs. Unfortunately, they may also be more toxic than the nonsteroidal anti-inflammatory agents.
1. http://www.youtube.com/watch?v=dcw1m31zuTE&feature=fvsr
2. http://www.youtube.com/watch?v=D6EPGDb6kEo
3. http://www.youtube.com/watch?v=FMt_BOrswQc&feature=related
4. http://www.youtube.com/watch?v=xs20hZFmr84&feature=related
5. http://www.youtube.com/watch?v=cbZsXjgPDLQ&feature=related
6. http://www.youtube.com/watch?v=s4jEZ9Os6QM&NR=1
7. http://www.youtube.com/watch?v=1d11iODKoSk&feature=related
8. http://www.youtube.com/watch?v=AFbPHlhI13g&feature=related
9. http://www.youtube.com/watch?v=qDEVBMldiY8&feature=related
10.http://www.youtube.com/watch?v=E90D4BmaVJM&feature=related