Drugs for Maintaining Calcium Homeostasis

At rest, the intracellular concentration of free calcium ions (Ca2+) is kept at 0.1 µm (see p.132 for mechanisms involved). During excitation, a transient rise of up to 10 µm elicits contraction in muscle cells (electromechanical coupling) and secretion in glandular cells (electrosecretory coupling). The cellular content of Ca2+ is in equilibrium with the extracellular Ca2+ concentration (~ 1000 µm), as is theplasmaprotein-boundfractionofcalcium inblood.Ca2+ maycrystallizewithphosphate to form hydroxyapatite, the mineral of bone. OsteoclastsarephagocytesthatmobilizeCa2+ by resorption of bone. Slight changes in extracellularCa2+ concentration can alterorgan function: thus, excitability of skeletal muscle increasesmarkedlyasCa2+ islowered(e.g.,in hyperventilationtetany).Threehormonesare available to the body for maintaining a constant extracellular Ca2+ concentration.

Vitamin D hormone is derived from vitamin D (cholecalciferol). Vitamin D can also be produced in the body; it is formed in the skin from dehydrocholesterol during irradiation with UV light. When there is lack of solar radiation, dietary intake becomes essential, codliveroilbeingarichsource.Metabolically active vitamin D hormone results from two successive hydroxylations: in the liver at position 25 (†calcifediol) and in the kidney at position 1 (†calcitriol = vitamin D hormone). 1-Hydroxylation depends on the level of calcium homeostasis and is stimulated by parathormone and a fall in plasma levels of Ca2+ andphosphate.VitaminDhormonepromotesenteralabsorptionandrenalreabsorption of Ca2+ and phosphate. As a result of the increased Ca2+ and phosphate concentration in blood, there is an increased tendency for theseionsto be deposited inboneintheform of hydroxyapatite crystals. In vitamin D deficiency, bone mineralization is inadequate (rickets, osteomalacia). Therapeutic use aims at replacement. Mostly,vitaminDisgiven; in liver disease, calcifediol may be indicated, in renal disease, calcitriol. Effective-

ness, as well as rate of onset and cessation of action increase in the order vitamin D < 25- OH-vitamin D < 1,25-di-OH vitamin D. Overdosage may induce hypercalcemia with deposits of calcium salts in tissues (particularly in kidney and blood vessels): calcinosis.

The polypeptide parathormone is released from the parathyroid glands when the plasma Ca2+ level falls. It stimulates osteoclasts to increase bone resorption; in the kidneys it promotes calcium reabsorption, while phosphate excretion is enhanced. As blood phosphate concentration diminishes, the tendency of Ca2+ to precipitate as bone mineral decreases. By stimulating the formation of vitamin D hormone, parathormone has an indirect effect on the enteral uptake of Ca2+ and phosphate. In parathormone deficiency, vitamin D can be used as a substitute that, unlike parathormone, is effective orally. Teriparatide is a recombinant shortened parathormone derivative containing the portion required for binding to the receptor. It can be used in the therapy of postmenopausal osteoporosis and promotes bone formation. While this effect seems paradoxical in comparison with hyperparathyroidism, it obviously arises from the special mode of administration: the once daily s.c. injection generates a quasi-pulsatile stimulation. Additionally, adequate intake of calcium and vitamin D must be ensured.

The polypeptide calcitonin is secreted by thyroid C-cells during imminent hypercalcemia. It lowers elevated plasma Ca2+ levels by inhibiting osteoclast activity. Its uses include hypercalcemia and osteoporosis. Remarkably, calcitonin injection may produce a sustained analgesic effect that alleviates pain associated with bone diseases (Paget disease, osteoporosis, neoplastic metastases) or Sudek syndrome.

Hypercalcemia can be treated by (1) administering 0.9% NaCl solution plus furosemide (if necessary) † renal excretion ⁄; (2) the osteoclast inhibitors calcitonin and clodronate (a biphosphonate) † bone Ca mobilizationø; (3) glucocorticoids.

Drugs for Treating Bacterial Infections

When bacteria overcome the cutaneous or mucosal barriers and penetrate into body tissues, a bacterial infection is present. Frequently the body succeeds in removing the invaders, without outward signs of disease, by mounting an immune response. However, certain pathogens have evolved a sophisticated counterstrategy. Although they are taken up into host cells via the regular phagocytotic pathway, they are able to forestall the subsequent fusion of the phagosome with a lysosome and in this manner can escape degradation. Since the wall of the sheltering vacuole is permeable to nutrients (amino acids, sugars), the germs are able to grow and multiply until the cell dies and the released pathogens can infect new host cells. This strategy is utilized, e.g., by Chlamydia and Salmonella species, Mycobacterium tuberculosis, Legionella pneumophila, Toxoplasma gondii, and Leishmania species. It is easy to see that targeted pharmacotherapy is especially dif cult in such cases because the drug cannot reach the pathogen until it has surmounted first the cell membrane and then the vacuolar membrane. If bacteria multiply faster than the body’s defenses can destroy them, infectious disease develops, with inflammatory signs, e.g., purulent wound infection or urinary tract infection. Appropriate treatment employs substances that injure bacteria and thereby prevent their further multiplication, without harming cells of the host organism (1).

Specific damage to bacteria is particularly feasible when a substance interferes with a metabolic process that occurs in bacterial but not in host cells. Clearly this applies to inhibitors of cell wall synthesis, since human or animal cells lack a cell wall. The points of attack of antibacterial agents are schematically illustrated in a grossly simplified bacterial cell, as depicted in (2).

In the following sections, plasmalemmadamaging polymyxins and tyrothricin are

not considered further. Because of their poor tolerability, they are suitable only for topical use.

The effect of antibacterial drugs can be observed in vitro (3). Bacteria multiply in a growth medium under controlled conditions. If the medium contains an antibacterial drug, two results can be discerned: (a) bacteria are killed—bactericidal effect; or

(b) bacteria survive, but do not multiply— bacteriostatic effect. Although variations may occur under therapeutic conditions, the different drugs can be classified according to their primary mode of action (color tone in 2 and 3).

When bacterial growth remains unaffected by an antibacterial drug, bacterial resistance is present. This may occur because of certain metabolic characteristics that confer a natural insensitivity to the drug on a particular strain of bacteria (natural resistance). Depending on whether a drug affects only few or numerous types of bacteria, the terms narrow-spectrum (e.g., penicillin G) or broad-spectrum (e.g., tetracyclines) antibiotic are applied. Naturally susceptible bacterial strains can be transformed under the influence of antibacterial drugs into resistant ones (acquired resistance), when a random genetic alteration (mutation) gives rise to a resistant bacterium. Under the influence of the drug, the susceptible bacteria die off, whereas the mutant multiplies unimpeded. The more frequently a given drug is applied, the more probable the emergence of resistant strains (e.g., hospital strains with multiple resistance)!

Resistance can alsobe acquired when DNA responsible for nonsusceptibility (so-called resistance plasmid) is passed on from other resistant bacteria by conjugation or transduction.