Give an account of how drugs may be used to lower the blood pressure. Compare and contrast the pharmacological properties of enalapril and hydrochlorothiazide.

Outline:

·        Hypertension in Singapore.

·        Need for treatment.

·        Goals of treatment.

·        Principles of drug treatment.

·        Choice of antihypertensives.

Suggested Answer:

Hypertension is a major etiology of coronary heart disease, cardiac failure, stroke and renal failure. It is estimated that of the 600 million people worldwide with hypertension, 3 million of them will die annually as a result of hypertension.

The 1998 Singapore National Health Survey showed that the crude prevalence of hypertension among Singapore residents rose from 22.2% in 1992 to 27.3% in 1998. With the aging of our population and the increase in predisposing factors to hypertension, such as high salt intake and obesity, the prevalence of hypertension is expected to increase.

Definitions and classifications of BP levels for adults aged 18 and above:

Hypertension is associated with increased risks of myocardial infarction, strokes, renal failure and heart failure. The primary treatment goal of a patient with hypertension is to reduce the risk of coronary vascular disease. The more immediate aim of treatment is to reduce the blood pressure to as near to normal as possible in the erect posture.

The targets of BP treatment are:

·        BP < 130 / < 85 mmHg in young, middle-aged or diabetic patients.

·        BP < 140 / < 90 mmHg in elderly patients.

Lifestyle modifications and non-pharmacological measures should be instituted whenever appropriate in all hypertensive patients, including those who require drug treatment. These modifications include: smoking cessation, weight reduction, moderation of alcohol consumption, reduction of salt intake and increased physical activity.

Principals of drug treatment in hypertension:

1.         Use low doses of drugs to initiate therapy, beginning with the lowest available dose of a particular drug to reduce adverse effects. If there is a good response to a low dose of a single drug but the BP is still short of adequate control, it is reasonable to increase the dose of the same drug, provided that this is well tolerated.

2.         Use appropriate drug combinations to achieve target BP levels if this cannot be achieved by one single hypertensive drug. It is often preferable to add a small dose of a second drug rather than to increase the dose of the original drug. This allows both the first and second drugs to be used in the low dose range that is more likely to be free from side effects.

3.         Change to different drug class altogether if there is very little response or poor tolerability to the first drug used in adequate dose.

4.         Use long-acting drugs providing 24-hour efficacy on a once daily basis. The advantages of such drugs include improvement in adherence to therapy and minimization of BP variability as a consequence of smoother and more consistent BP control.

The choice of antihypertensive is based on compelling indications, possible contraindications and cost:

It is difficult to predict the best drug for individual patients, though younger patients are more likely to respond to a beta-blocker or ACE inhibitor, and older patients to diuretic or calcium channel blocker. Since each drug acts on only one or two of the blood pressure control mechanisms, the factors that are uninfluenced by monotherapy are liable to adapt (homeostatic mechanism), to oppose the useful effect and to restore the previous state.

There are two principal mechanisms of such adaptation or tolerance:

1.            Increase in blood volume occurs with any drug that reduces peripheral vascular resistance or cardiac output due to activation of the renin-angiotensin-aldosterone system. The result is that cardiac output and blood pressure rises. This compensatory effect can be prevented by using a diuretic in combination with the other drug.

2.            Baroreceptor reflexes: a fall in blood pressure evokes reflex activity of the sympathetic system, causing increased peripheral resistance and cardiac activity.

Therefore, whenever high blood pressure is difficult to control and whenever a number of hypotensive drugs are used in combination, the drugs chosen should between them act on blood pressure, peripheral resistance and the heart to maximize antihypertensive efficacy, minimizing the opposing homeostatic effects and minimizing side effects of each drug.

A graded well-tried and conventional regimen is as follows:

1.         Start with a single morning dose of either a beta-blocker, e.g. atenolol, or a diuretic, e.g. bendrofluazide. Efficacy will begin to be seen within 2 – 3 days and most of it will have developed within 14 days.

2.         If the pressure is not controlled in 2 – 3 weeks, either change to a single drug of a different group or add the second drug.

3.         If blood pressure control is still inadequate, the patient should be given a trial of either an ACE inhibitor (younger patients) or calcium channel blocker (older patients).

Effective drug combinations to treat hypertension are:

·        Diuretic and beta-blocker.

·        Diuretic and ACE inhibitor or Angiotension II receptor antagonist.

·        Diuretic and calcium channel blocker.

·        Calcium channel blocker and beta-blocker.

·        Calcium channel blocker and ACE inhibitor.

·        Alpha-blocker and beta-blocker.

The randomized trials conducted to date have shown clear evidence of lower incidence of major coronary vascular disease events after high blood pressure was treated with antihypertensives.

Both enalapril and hydrochlorothiazide are drugs used in the treatment of hypertension. They act principally on the renal system though at different sites via different mechanisms of action to reduce blood pressure.

Enalapril is an ACE inhibitor. Enalapril is the prodrug of enalaprilat and has little pharmacologic activity until hydrolyzed in vivo to enalaprilat. The drugs appear to reduce blood pressure in normotensive individuals and hypertensive patients to produce beneficial hemodynamic effects mainly by suppressing the renin-angiotensin-aldosterone system. Enalapril prevents the conversion of angiotensin I to angiotensin II through inhibition of ACE. The drug competes with physiologic substrate for the active site of ACE. Inhibition of ACE results initially in decreased plasma angiotensin II concentrations and consequently, blood pressure may be reduced in part through decreased vasoconstriction and increased amounts of bradykinin, a vasodilator broken down by ACE. On the other hand, hydrochlorothiazide is a thiazide diuretic. It acts principally at the cortical diluting segment of the ascending limb of Loop of Henle, preventing sodium reabsorption by inhibiting a sodium-chloride co-transported. This causes 5 – 10% of the sodium load to be excreted. This lowers the blood pressure due to reduction in intravascular volume and peripheral vascular resistance. In chronic use, hydrochlorothiazide diminish the responsiveness of vascular smooth muscle to noradrenaline but may also have a direct action on vascular smooth muscle membranes through an ion channel.

Enalapril is well absorbed following oral administration with a bioavailability of 55 – 75%. Enalapril undergoes first-pass metabolism in the liver, being hydrolyzed to enalaprilat. Enalapril does not appear to distribute into any tissue and cross the blood-brain barrier poorly. The drug crosses into the placenta and is distributed in breast milk. The half-life of unchanged enalapril is less than 2 hours in the healthy individual. It is excreted in urine and faeces. Hydrochlorothiazide is well absorbed orally with a half-life of 5 – 14 hours. It crosses the placenta but not the blood brain barrier and is distributed into breast milk. It is not metabolized and is excreted unchanged in the urine.

Adverse effects of enalapril include bone marrow suppression, neutropenia, deterioration of renal function, blood disorders, persistent dry cough, angioneurotic edema and loss of taste while those of hydrochlorothiazide are electrolyte imbalance, hypokalaemia, rashes, thrombocytopenia, agranulocytosis, anorexia, decreased sexual function, cholecystitis, gout, jaundice, and pancreatitis.

Enalapril and hydrochlorothiazide have been used in combined formulations in the management of hypertension.