Flucortisone Against Blackouts Bradycardia

Secondary diseases: Heart failure

Coronary atherosclerosis angina pectoris, myocardial infarction, arrhythmia Atherosclerosis of cerebral vessels cerebral infarction stroke

Cerebral hemorrhage Atherosclerosis of renal vessels renal failure

Decreased life expectancy

Antihypertensive therapy

Secondary Hypertension Classification

A. Arterial hypertension and pharmacotherapeutic approaches

Beets Adverse Side Effects

Decreased life expectancy

Hypotension

The venous side of the circulation, excluding the pulmonary circulation, accommodates ~ 60% of the total blood volume; because of the low venous pressure (mean -15 mmHg) it is part of the low-pressure system. The arterial vascular beds, representing the high-pressure system (mean pressure, -100 mmHg), contain - 15%. The arterial pressure generates the driving force for perfusion of tissues and organs. Blood draining from the latter collects in the low-pressure system and is pumped back by the heart into the high-pressure system.

The arterial blood pressure (ABP) depends on: (1) the volume of blood per unit of time that is forced by the heart into the high-pressure system—cardiac output corresponding to the product of stroke volume and heart rate (beats/ min), stroke volume being determined inter alia by venous filling pressure; (2) the counterforce opposing the flow of blood, i.e., peripheral resistance, which is a function of arteriolar caliber.

Chronic hypotension (systolic BP <105 mmHg). Primary idiopathic hypotension generally has no clinical importance. If symptoms such as lassitude and dizziness occur, a program of physical exercise instead of drugs is advisable.

Secondary hypotension is a sign of an underlying disease that should be treated first. If stroke volume is too low, as in heart failure, a cardiac glycoside can be given to increase myocardial contractility and stroke volume. When stroke volume is decreased due to insufficient blood volume, plasma substitutes will be helpful in treating blood loss, whereas aldosterone deficiency requires administration of a mineralocor-ticoid (e.g., fludrocortisone). The latter is the drug of choice for orthostatic hypotension due to autonomic failure. A parasympatholytic (or electrical pacemaker) can restore cardiac rate in bradycardia.

Acute hypotension. Failure of orthostatic regulation. A change from the recumbent to the erect position (ortho-stasis) will cause blood within the low-pressure system to sink towards the feet because the veins in body parts below the heart will be distended, despite a reflex venoconstriction, by the weight of the column of blood in the blood vessels. The fall in stroke volume is partly compensated by a rise in heart rate. The remaining reduction of cardiac output can be countered by elevating the peripheral resistance, enabling blood pressure and organ perfusion to be maintained. An orthostatic malfunction is present when counter-regulation fails and cerebral blood flow falls, with resultant symptoms, such as dizziness, "black-out," or even loss of consciousness. In the sympathotonicform, sympathetically mediated circulatory reflexes are intensified (more pronounced tachycardia and rise in peripheral resistance, i.e., diastolic pressure); however, there is failure to compensate for the reduction in venous return. Prophylactic treatment with sympathomimetics therefore would hold little promise. Instead, cardiovascular fitness training would appear more important. An increase in venous return may be achieved in two ways. Increasing NaCl intake augments salt and fluid reserves and, hence, blood volume (contraindications: hypertension, heart failure). Constriction of venous capacitance vessels might be produced by dihydroer-gotamine. Whether this effect could also be achieved by an a-sympathomi-metic remains debatable. In the very rare asympathotonic form, use of sympa-thomimetics would certainly be reasonable.

In patients with hypotension due to high thoracic spinal cord transections (resulting in an essentially complete sympathetic denervation), loss of sympathetic vasomotor control can be compensated by administration of sympa-thomimetics.

Sympathetic Vasomotor

Gout

Gout is an inherited metabolic disease that results from hyperuricemia, an elevation in the blood of uric acid, the end-product of purine degradation. The typical gout attack consists of a highly painful inflammation of the first meta-tarsophalangeal joint ("podagra"). Gout attacks are triggered by precipitation of sodium urate crystals in the synovial fluid of joints.

During the early stage of inflammation, urate crystals are phagocytosed by polymorphonuclear leukocytes (1) that engulf the crystals by their ameboid cytoplasmic movements (2). The phagocytic vacuole fuses with a lysosome (3). The lysosomal enzymes are, however, unable to degrade the sodium urate. Further ameboid movement dislodges the crystals and causes rupture of the phagolysosome. Lysosomal enzymes are liberated into the granulocyte, resulting in its destruction by self-digestion and damage to the adjacent tissue. Inflammatory mediators, such as pros-taglandins and chemotactic factors, are released (4). More granulocytes are attracted and suffer similar destruction; the inflammation intensifies—the gout attack flares up.

Treatment of the gout attack aims to interrupt the inflammatory response. The drug of choice is colchicine, an alkaloid from the autumn crocus (Colchicum autumnale). It is known as a "spindle poison" because it arrests mitosis at metaphase by inhibiting contractile spindle proteins. Its antigout activity is due to inhibition of contractile proteins in the neutrophils, whereby ameboid mobility and phagocytotic activity are prevented. The most common adverse effects of colchicine are abdominal pain, vomiting, and diarrhea, probably due to inhibition of mitoses in the rapidly dividing gastrointestinal epithelial cells. Colchicine is usually given orally (e.g., 0.5 mg hourly until pain subsides or gastrointestinal disturbances occur; maximal daily dose, 10 mg).

Nonsteroidal anti-inflammatory drugs, such as indomethacin and phenylbutazone, are also effective. In severe cases, glucocorticoids may be indicated.

Effective prophylaxis of gout attacks requires urate blood levels to be lowered to less than 6 mg/100 mL.

Diet. Purine (cell nuclei)-rich foods should be avoided, e.g., organ meats. Milk, dairy products, and eggs are low in purines and are recommended. Coffee and tea are permitted since the meth-ylxanthine caffeine does not enter purine metabolism.

Uricostatics decrease urate production. Allopurinol, as well as its accumulating metabolite alloxanthine (oxy-purinol), inhibit xanthine oxidase, which catalyzes urate formation from hypoxanthine via xanthine. These precursors are readily eliminated via the urine. Allopurinol is given orally (300-800 mg/d). Except for infrequent allergic reactions, it is well tolerated and is the drug of choice for gout prophylaxis. At the start of therapy, gout attacks may occur, but they can be prevented by concurrent administration of colchicine (0.5-1.5 mg/d). Uricosurics, such as probenecid, benzbromarone (100 mg/d), or sulfinpyrazone, promote renal excretion of uric acid. They saturate the organic acid transport system in the proximal renal tubules, making it unavailable for urate reabsorption. When underdosed, they inhibit only the acid secretory system, which has a smaller transport capacity. Urate elimination is then inhibited and a gout attack is possible. In patients with urate stones in the urinary tract, uricosurics are contraindicated.

Uricosurics Mechanism

Osteoporosis

Osteoporosis is defined as a generalized decrease in bone mass (osteopenia) that affects bone matrix and mineral content equally, giving rise to fractures of vertebral bodies with bone pain, kyphosis, and shortening of the torso. Fractures of the hip and the distal radius are also common. The underlying process is a disequilibrium between bone formation by osteoblasts and bone resorption by osteoclasts.

Classification: Idiopathic osteoporosis type I, occurring in postmenopausal females; type II, occurring in senescent males and females (>70 y). Secondary osteoporosis: associated with primary disorders such as Cushing's disease, or induced by drugs, e.g., chronic therapy with glucocorticoids or heparin. In these forms, the cause can be eliminated.

Postmenopausal osteoporosis represents a period of accelerated loss of bone mass. The lower the preexisting bone mass, the earlier the clinical signs become manifest.

Risk factors are: premature menopause, physical inactivity, cigarette smoking, alcohol abuse, low body weight, and calcium-poor diet.

Prophylaxis: Administration of estrogen can protect against postmeno-pausal loss of bone mass. Frequently, conjugated estrogens are used (p. 254). Because estrogen monotherapy increases the risk of uterine cancer, a gestagen needs to be given concurrently (except after hysterectomy), as e.g., in an oral contraceptive preparation (p. 256). Under this therapy, menses will continue. The risk of thromboembolic disorders is increased and that of myocardial infarction probably lowered. Hormone treatment can be extended for 10 y or longer. Before menopause, daily calcium intake should be kept at 1 g (contained in 1 L of milk), and 1.5 g thereafter.

Therapy. Formation of new bone matrix is induced by fluoride. Administered as sodium fluoride, it stimulates osteoblasts. Fluoride is substituted for hydroxyl residues in hydroxyapatite to form fluorapatite, the latter being more resistant to resorption by osteoclasts. To safeguard adequate mineralization of new bone, calcium must be supplied in sufficient amounts. However, simultaneous administration would result in precipitation of nonabsorbable calcium fluoride in the intestines. With sodium monofluorophosphate this problem is circumvented. The new bone formed may have increased resistance to com-pressive, but not torsional, strain and paradoxically bone fragility may increase. Because the conditions under which bone fragility is decreased remain unclear, fluoride therapy is not in routine use.

Calcitonin (p. 264) inhibits osteo-clast activity, hence bone resorption. As a peptide it needs to be given by injection (or, alternatively, as a nasal spray). Salmonid is more potent than human calcitonin because of its slower elimination.

Bisphosphonates structurally mimic endogenous pyrophosphate, which inhibits precipitation and dissolution of bone minerals. They retard bone resorption by osteoclasts and, in part, also decrease bone mineralization. Indications include: tumor osteolysis, hypercalcemia, and Paget's disease. Clinical trials with etidronate, administered as an intermittent regimen, have yielded favorable results in osteoporosis. With the newer drugs clodronate, pamidronate, and alendronate, inhibition of osteoclasts predominates; a continuous regimen would thus appear to be feasible.

Bisphosphonates irritate esophage-al and gastric mucus membranes; tablets should be swallowed with a reasonable amount of water (250 mL) and the patient should keep in an upright position for 30 min following drug intake.

Bradycardia With Hypercalcemia
A. Bone: normal state and osteoporosis

Promotion of bone formation

Fluoride ions NaF:

Activation of osteoblasts, Formation of Fluorapatite

In postmenopause Estrogen (+ Gestagen)

Osteoblasts

Osteoblasts

Calcium-salts 1 - 1.5g Ca2+ per day

Inhibition of bone resorption

Calcitonin

Peptide consisting of 32 amino acids

Calcitonin

Peptide consisting of 32 amino acids

Physiological

Bisphosphonates

constituent:

(CH2I3

From PMS To PPD

From PMS To PPD

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