книги студ / Color Atlas of Pharmacology

Hypertension

Arterial hypertension (high blood pressure) generally does not impair the well-being of the affected individual; however, in the long term it leads to vascular damage and secondary complications (A). The aim of antihypertensive therapy is to prevent the latter and, thus, to prolong life expectancy.

Hypertension infrequently results from another disease, such as a cate- cholamine-secreting tumor (pheochromocytoma); in most cases the cause cannot be determined: essential (primary) hypertension. Antihypertensive drugs are indicated when blood pressure cannot be sufficiently controlled by means of weight reduction or a lowsalt diet. In principle, lowering of either cardiac output or peripheral resistance may decrease blood pressure (cf. p. 306, 314, blood pressure determinants). The available drugs influence one or both of these determinants. The therapeutic utility of antihypertensives is determined by their efficacy and tolerability. The choice of a specific drug is determined on the basis of a benefit:risk assessment of the relevant drugs, in keeping with the patient’s individual needs.

In instituting single-drug therapy

(monotherapy), the following considerations apply: β-blockers (p. 92) are of value in the treatment of juvenile hypertension with tachycardia and high cardiac output; however, in patients disposed to bronchospasm, even β1-se- lective blockers are contraindicated. Thiazide diuretics (p. 162) are potentially well suited in hypertension associated with congestive heart failure; however, they would be unsuitable in hypokalemic states. When hypertension is accompanied by angina pectoris, the preferred choice would be a β-blocker or calcium antagonist (p. 122) rather than a diuretic. As for the calcium antagonists, it should be noted that verapamil, unlike nifedipine, possesses cardiodepressant activity. α-Blockers may be of particular benefit in patients with benign prostatic hyperplasia and im-

paired micturition. At present, only β- blockers and diuretics have undergone large-scale clinical trials, which have shown that reduction in blood pressure is associated with decreased morbidity and mortality due to stroke and congestive heart failure.

In multidrug therapy, it is necessary to consider which agents rationally complement each other. A β-blocker (bradycardia, cardiodepression due to sympathetic blockade) can be effectively combined with nifedipine (reflex tachycardia), but obviously not with verapamil (bradycardia, cardiodepression). Monotherapy with ACE inhibitors (p. 124) produces an adequate reduction of blood pressure in 50% of patients; the response rate is increased to 90% by combination with a (thiazide) diuretic. When vasodilators such as dihydralazine or minoxidil (p. 118) are given, β-blockers would serve to prevent reflex tachycardia, and diuretics to counteract fluid retention.

Abrupt termination of continuous treatment can be followed by rebound hypertension (particularly with short

t1/2 β-blockers).

Drugs for the control of hypertensive crises include nifedipine (capsule, to be chewed and swallowed), nitroglycerin (sublingually), clonidine (p.o. or i.v., p. 96), dihydralazine (i.v.), diazoxide (i.v.), fenoldopam (by infusion, p. 114) and sodium nitroprusside (p. 120, by infusion). The nonselective α-blocker phentolamine (p. 90) is indicated only in pheochromocytoma.

Antihypertensives for hypertension in pregnancy are β1-selective adrenoceptor-blockers, methyldopa (p. 96), and dihydralazine (i.v. infusion) for eclampsia (massive rise in blood pressure with CNS symptoms).

Diuretics

- blockers β

If therapeutic result inadequate

change to drug from another group

In severe cases

α-blocker Reserpine e.g.,

prazosine

combine with drug from another group

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 highpressure 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 mineralocorticoid (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 (orthostasis) will cause blood within the lowpressure 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 sympathotonic form, sympa- thetically 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 dihydroergotamine. Whether this effect could also be achieved by an α-sympathomi- metic remains debatable. In the very rare asympathotonic form, use of sympathomimetics 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 sympathomimetics.

Brain

Lung

Venous return

Heart

Kidney

Intestines

Skeletal muscle

β-Sympathomimetics

Cardiac Parasymglycosides patholytics

Stroke vol. x rate = cardiac output

Blood pressure (BP)

Peripheral resistance

Arteriolar α-Sympatho- caliber mimetics

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 metatarsophalangeal 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-diges- tion and damage to the adjacent tissue. Inflammatory mediators, such as prostaglandins 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 phe- nylbutazone, 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 methylxanthine caffeine does not enter purine metabolism.

Uricostatics decrease urate production. Allopurinol, as well as its accumulating metabolite alloxanthine (oxypurinol), 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, pro- mote 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.

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 postmenopausal 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. Adminis- tered 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 compressive, 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 osteoclast 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 esophageal 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.

Promotion of bone formation

Inhibition of bone resorption

Rheumatoid Arthritis

Rheumatoid arthritis or chronic polyarthritis is a progressive inflammatory joint disease that intermittently attacks more and more joints, predominantly those of the fingers and toes. The probable cause of rheumatoid arthritis is a pathological reaction of the immune system. This malfunction can be promoted or triggered by various conditions, including genetic disposition, age–related wear and tear, hypothermia, and infection. An initial noxious stimulus elicits an inflammation of synovial membranes that, in turn, leads to release of antigens through which the inflammatory process is maintained. Inflammation of the synovial membrane is associated with liberation of inflammatory mediator substances that, among other actions, chemotactically stimulate migration (diapedesis) of phagocytic blood cells (granulocytes, macrophages) into the synovial tissue. The phagocytes produce destructive enzymes that promote tissue damage. Due to the production of prostaglandins and leukotrienes (p. 196) and other factors, the inflammation spreads to the entire joint. As a result, joint cartilage is damaged and the joint is ultimately immobilized or fused.

Pharmacotherapy. Acute relief of inflammatory symptoms can be achieved by prostaglandin synthase inhibitors; nonsteroidal anti-inflam- matory drugs, or NSAIDs, such as diclofenac, indomethacin, piroxicam, p. 200), and glucocorticoids (p. 248). The inevitably chronic use of NSAIDs is likely to cause adverse effects. Neither NSAIDs nor glucocorticoids can halt the progressive destruction of joints.

The use of disease-modifying agents may reduce the requirement for NSAIDs. The use of such agents does not mean that intervention in the basic pathogenetic mechanisms (albeit hoped for) is achievable. Rather, disease-modi- fying therapy permits acutely acting agents to be used as add-ons or as required. The common feature of disease-

modifiers is their delayed effect, which develops only after treatment for several weeks. Among possible mechanisms of action, inhibition of macrophage activity and inhibition of release or activity of lysosomal enzymes are being discussed. Included in this category are: sulfasalazine (an inhibitor of lipoxygenase and cyclooxygenase, p. 272), chloroquine (lysosomal binding), gold compounds (lysosomal binding; i.m.: aurothioglucose, aurothiomalate; p.o.: auranofin, less effective), as well as D-pen- icillamine (chelation of metal ions needed for enzyme activity, p. 302). Frequent adverse reactions are: damage to skin and mucous membranes, renal toxicity, and blood dyscrasias. In addition, use is made of cytostatics and immune suppressants such as methotrexate (low dose, once weekly) and leflumomid as well as of cytokin antibodies (infliximab) and soluble cytokin receptors (etanercept). Methotrexate exerts an anti-inflammatory effect, apart from its anti-autoimmune action and, next to sulfasalazine, is considered to have the most favorable risk:benefit ratio. In most severe cases cytostatics such as azathioprin and cyclophosphamide will have to be used.

Surgical removal of the inflamed synovial membrane (synovectomy) fre- quently provides long-term relief. If feasible, this approach is preferred because all pharmacotherapeutic measures entail significant adverse effects.