EFFECT OF THE ANTIHYPERTENSIVE DRUGS (ALPHA-METHYLDOPA, MODURETIC AND HYDRALAZINE) ON BLOOD PRESSURE AND CONCENTRATIONS OF SODIUM, POTASSIUM AND CALCIUM, IONS IN BLOOD AND URINE OF HYPERTENSIVE PATIENTS FOLLOWING SUBACUTE
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CHAPTER ONE: INTRODUCTION
1.1 Background to the study
Blood pressure is the force exerted by the blood against any area of the vessel wall (Guyton, 1981). The blood pressure (usually measured in millimetres of mercury, mmHg) in the body needs to be maintained within the normal range so that blood will adequately perfuse the tissues and organs of the body supply them with enough nutrients. The systolic blood pressure of a normal young adult (70kg) is about 120 mmHg while the average diasto0lic blood pressure is 80 mmHg (Guyton 1981) that is mean arterial blood pressure of 93 mmHg (diastolic pressure plus 1/3 (systolic pressure minus diastolic pressure)).
When the blood pressure is higher than the normal for a given young adult, the individual is said to have high blood pressure or hypertension. In hypertension, the diastolic blood pressure has been sued as an index of the severity of hypertensive state because it is the major blood pressure in the blood vessel walls when the heart is at rest. Further, it is the major blood pressure that maintains a steady blood flow in the vessels and causes the tissues and organs to be well perfused with blood.
Hypertension may be mild (90-105mmHg diastolic blood pressure), moderate (105-130mmHg diastolic blood pressure, severe (130-140mmHg diastolic blood pressure) or hypertensive crises (diastolic blood pressure > 140mmHg). Based on aetiology, hypertension may be essential or primary (absence of causal factors) or secondary (presence of causal factors) (Swales 1979), Guyton, 1981; Katzung 1982; Keel and Neil, 1971). Essential hypertension may be benign (210/110 blood pressure) or Malignant (210/110 – 260/150 blood pressure) (keel and Neil, 1971). Secondary hypertension may be caused by
- Sodium and water retention
- Excess vasoconstrictor (angiotensin II) secretion.
- Goldblatt hypertension (renal ischaemia) (4) excessive aldosterone secretion (5) nervous disorders or stress (6) toxaemia of pregnancy (7) monomine oxidase inhibitors (orams, 1971) and (8) alcohol (Saunders, et al 1981; Mitchell et al, 1980).
Hypertension can result in compensatory hypertrophy of arteries and arterioles (Folklow et al, 1973), left ventricular hypertrophy, coronary arteriosclerosis, cerebral or renal vessels haemorrhage (Guyton, 1981), optic disc oedema, optic nerve lesions (leading to blindness), arteriolar spasm, arteriolar necrosis, papilloedema, heart failure leading to death (kneel and Neil, 1971).
Anti-hypertensive agents include diuretics (such as hydrochlorothiazide), alpha-methyl noradrenalin in central adrenergic neurons. The alpha-methyl noradrenalin exerts agonistic action at alpha (1 & 2) receptors in the central nervous system (Vasomotor center) and thus inhibits sympathetic outflow which results in reduction of blood pressure via reduction of peripheral vascular resistance and relaxation of the arterial vasulature (Katzung 1982; Swales, 1979). Alpha-methyldopa has also been found to lower plasmarenin. Most cardiovascular reflexes remained intact after administration of alpha-methyldopa and blood pressure reduction was not markedly dependent upon maintenance of upright posture. it reduced blood pressure and peripheral resistance while cardiac output and renal blood flow were maintained (Safar et al 1979); but Katzung (1982) reported that there was little change in heart rate and cardiac output.
Owing to extensive first-pass metabolism (primarily o-sulphate conjugation by the gastrointestinal mucosa), the bio availability of alpha-methyldopa was low, averaging 25% (Kwan et al 1976; Saavedra et al 1975; Katzung, 1982). Orally, its maximum effect lasted up to 24 hours. About 2/3 of the drug that reached the plasma was cleared by renal excretion. It had a t1/2 for 2 hour (kwan et al 1976; Barnett et al 1977; Katzung, 1982). Impaired renal function resulted in reduced drug clearance (Myhre et al 1972; Katzung 1982).
Side and toxic effects of alpha-methyldopa include salt and water retention (Schild, 1980). Dry mouth, nasal stuffiness, drowsiness, impotence in some males (Glontz et al, 1968).
Drowsiness, vertigo, overt sedation, psychic depression, extra-pyramidal sings, nightmares, lactation associated with increased prolactin secretion, jaundice (Elkington et al, 1969; Katzung, 1982).
Hydrallazine: Hydrallazine acts directly on the arterioles to cause relaxation and decrease of blood pressure. The vascular relaxation and decreased blood pressure elicited compensatory responses mediated by baroreceptors and sympathetic nervous system, as well as renin, angiotensin and aldosterone (Swales, 1969, Katzung 1982; Schild 1980).
Hydralazine is well-absorbed orally and rapidly metabolized by the liver during the first pass, mainly by acetylation (Reidemberg et al, 1979). The bioavailability was low (averaging 25%) and variable among individuals. Simultaneous ingestion of food and hydralazine increased the bio availability of the frung (Melander et al 1977).
Side-effects include headache, nausea, anorexia, palpilations, weating, flushing, salt (Na+) and water retention, nasal congestion, iacrimation, paraesthesia, oedema, tremor, muscle cramps and urticarial (Swales, 1969; Katzung, 1982)
Hydrochlorothiazide exerts its diuretic effect largely by inhibiting tabular reabsorption of sodium and water at the early segments of distal convoluted tubule of the kidney nepron (Tsaifan, 1981; Katzung, 1982). Friedman et al (1960) also observed that hydrochlorothiazide exerted its anti-hypertensive effect by reducing vascular muscular tone resulting from reduced intracellular sodium content. Hydrochlorothiazide caused secretin of potassium in exchange for sodium, resulting in increased potassium excretion at distal tubule (Giebisch, 1976; shild, 1980). It was reported also that hydrochlorothiazide reduced renal excretion of calcium (Edwards et al, 1973; Katzung 1982). However, Tsaifran (1981) has observed that it induced calciuresis by inhibiting calcium reabsorption, calcuresis was reduced by increased renal tabular calcium reabsorption.
Hydrochlorothiazide also inhibited tabular secretin of uric acid because it competed with it for secretion (Katzung, 1982).
When given orally, hydrochlorothiazide is absorbed from the gastrointestinal tract. The drug was shown to have a high degree extent by the renal tabules. Hydrochlorothiazide underwent active secretion in the proximal tabule and was excreted within 3 to 6 hours.
Toxic effects include weakness, paresthesias, potassium depletion and metabolic alkalosis, impaired carbohydrate tolerance, hyperuricemia and hyperlipidemia, hyponatremia and allergic reactions (christensson et al 1977; Dolley 1973; Katzung, 1982; steele et al 1977; Linderman et al, 1976).
Amiloride, one of the potassium- sparring diutics increases sodium loss and reduces potassium loss by a direct action on ion transport in the renal distal tubule. Gatzy (1971) has shown that amiloride inhibited secretion of potassium and thus indicated that it could cause potassium retention.
About 15-26% of the drug is absorbed in the gastrointestinal tract. After oral administration, its action on the kidney reached a peak within about 6 hours and ceased within 24 hours (Mudge, 1980; Laurence, 1980).
Its toxic effects include hyperkalaemia, muscle weakness, adominal pain, stiffness, paraesthesia in the extremities, cardiac arrest and increased secretion of Uvic acid (Bowman and Rand, 1980).
1.2 Statement of the problem
Hypertension represents a major public health problem affecting more than one billion individuals worldwide. Hypertension is the most important risk factor for CVD and prevalence continues to rise and expected to affect 1.5billion people worldwide. Prevalence in Nigeria is about 30 –45%. The advent of antihypertensive therapy has substantially reduced the occurrence of cardiovascular events. However, antihypertensive therapy failed to achieve blood pressure control in all patients, with hypertension control rates remaining in general disappointingly low. Blood pressure goals are not attained in some patients despite the simultaneous use of several antihypertensive medications. Several terms have been used to define this condition: “refractory hypertension”, “difficult-to-treat hypertension”, “difficult-to-control hypertension”; however, the term “resistant hypertension” seems to prevail.
However, anti-hypertensive agents under discussion have been reported to alter the con-centration of important electrolytes such as sodium (Na+), potassium (k+), and calcium (ca2+) tisaitan, 1981; Katzung 1982; Schild, 1980; Giebisch, 1976; Gatzy, 1971). Moreover, skraball et al (1981) had reported that a high potassium intake promoted sodium loss, prevented rise in plasma catecholamines, increased baroreflex sensitivity and then reduced diastolic blood pressure.