Antihypertensives in Review

Blood pressure control is paramount when it comes to managing health risks. Hypertension is known to be an important risk factor for cardiovascular diseases such as coronary artery disease, peripheral vascular disease, heart failure, atrial fibrillation, and stroke. It is also highly associated with the development of chronic kidney disease. Therefore, treating hypertension forms an integral part of the overall management of a patient’s cardiovascular risk. This article is a review of the basic classes of antihypertensives and is based on the latest guidelines from the National Heart Foundation of Australia.

Beta blockers (e.g. atenolol, metoprolol, nebivolol, oxprenolol)

• Reduce heart rate;
• Reduce blood pressure and cardiac contractility;
• Depress sinus node rate and slow conduction through the atrioventricular (AV) node; and
• Prolong atrial refractory periods.

Patients with hypertension and angina are often prescribed beta blockers, e.g. atenolol and metoprolol which are commonly used post-myocardial infarction. Beta blockers are also indicated for tachyarrhythmias, atrial fibrillation (AF), and in chronic systolic heart failure.

These medications should be used with caution in patients with diabetes as they may affect glucose metabolism and can also mask some of the early warning signs of hypoglycaemia. Beta-blockers can also diminish some of the signs of hyperthyroidism. Therefore, caution should be exercised in patients with thyroid dysfunction. Beta-blockers should not be used in patients with severe or poorly controlled asthma due to the risk of bronchospasm. If a beta-blocker is indicated in a patient with asthma, a cardioselective agent is preferred, although specialist advice is recommended. Cardioselective beta-blockers include atenolol, bisoprolol, and metoprolol.

Beta-blockers are contraindicated in bradycardia, AV block, and uncontrolled heart failure. Common adverse effects include bradycardia, hypotension, bronchospasm, cold extremities, fatigue, dizziness, and abnormal vision.

Calcium channel blockers (e.g. amlodipine, diltiazem, felodipine, lercanidipine, verapamil)

• Block the inward current of calcium into cells in vascular smooth muscle, myocardium, and cardiac conducting system;
• Reduce vascular resistance; and
• Reduce myocardial oxygen requirements (relieving angina).

Calcium channel blockers can be divided into two groups, dihydropyridines and non-dihydropyridines. Dihydropyridines include amlodipine, felodipine, lercanidipine, and nifedipine. These agents act mainly on arteriolar smooth muscle to reduce peripheral vascular resistance and blood pressure. Non-dihydropyridines include verapamil and diltiazem. These agents act on cardiac and arteriolar smooth muscle to reduce cardiac contractility, heart rate and conduction. Although both of these agents are contraindicated in heart failure, verapamil is more cardioselective than diltiazem and causes a greater depressant effect on heart rate and myocardial contractility.

Common adverse effects include peripheral oedema, headache, flushing, dizziness, and hypotension. The non-dihydropyridine calcium channel blockers, verapamil and diltiazem, cause less peripheral vasodilation than the dihydropyridine agents. Therefore, adverse effects such as peripheral oedema, headache, and flushing are less pronounced with these agents. However, these more cardioselective agents are more likely to cause bradycardia, constipation (particularly with verapamil), atrioventricular block, and heart failure.

ACE inhibitors (e.g. captopril, enalapril, perindopril, ramipril)

• Block the conversion of angiotensin I to angiotensin II and inhibit the breakdown of bradykinin.
• Reduced formation of angiotensin II leads to vasodilation, sodium release, and reduced aldosterone secretion.

ACE-Inhibitors are often used for hypertension, chronic heart failure, diabetic nephropathy, and for preventing the progression of renal failure in patients with persistent proteinuria. Common adverse effects include hypotension, headache, dizziness, cough, hyperkalaemia, fatigue, nausea, and renal impairment. These agents are contraindicated during pregnancy, and in patients with a history of hereditary or idiopathic angioedema, and bilateral renal artery stenosis.

Angiotensin II receptor blockers (e.g. candesartan, irbesartan, olmesartan)

• Competitively block the binding of angiotensin II to type1 angiotensin (AT₁) receptors.
• Reduced angiotensin II-induced vasoconstriction, sodium reabsorption, and aldosterone release.

Angiotensin II receptor blockers (ARBs) are indicated for the treatment of hypertension. Candesartan and valsartan are also approved for the treatment of chronic systolic heart failure, and valsartan may be used for left ventricular failure or dysfunction after a myocardial infarction (MI).

These agents are contraindicated during pregnancy. Although they may be used in patients with a history of ACE-inhibitor-induced angioedema, caution should be taken as there is a risk of recurrence. Patients with bilateral renal artery stenosis are at an increased risk of renal failure if an ARB is initiated.

Common adverse effects include dizziness, headache, and hyperkalaemia. Renal impairment may worsen, particularly in patients taking non-steroidal anti-inflammatory drugs (NSAIDs) or if hypovolaemia is present.

Comparative information: ACE-I vs ARBs

• ACE-I and ARBs have demonstrated equal efficacy in lowering blood pressure. However, there is currently more consistent data supporting a mortality benefit for ACE-Is in patients with a previous MI, coronary heart disease, or heart failure;
• ARBs may be useful for patients who cannot tolerate ACE-Is due to the development of a cough;
• ACE-Is in early diabetes have been demonstrated to help prevent the onset of nephropathy;
• ARBs help prevent kidney failure in advanced diabetic nephropathy; and
• Both classes of medication can cause retention of potassium. This effect is more likely to occur in patients with renal impairment and those taking other medications that can increase serum potassium. Such medications include spironolactone, eplerenone, amiloride, trimethoprim, ciclosporin, and potassium supplements.

Thiazide and Related Diuretics (e.g. hydrochlorothiazide, indapamide, chlortalidone)

• Inhibit the renal reabsorption of sodium and chloride and also increase potassium excretion.
• Thiazide diuretics also cause vasodilation which contributes to the blood pressure lowering effect.

These moderately potent diuretics are used in the treatment of hypertension, oedema (associated with heart failure or hepatic cirrhosis), and nephrogenic diabetes insipidus.

Common adverse effects include postural hypotension, dizziness, hypokalaemia, hyponatraemia, and hyperuricaemia. Hypokalaemia is less likely to occur when low doses of the thiazide are used and when administration occurs with an ACE-I, ARB, or a potassium-sparing diuretic. Gout may be aggravated by thiazide-induced increases in serum urate levels. A less common metabolic adverse effect is hyperglycaemia. Although this is often not clinically important at low doses, a dosage adjustment of antidiabetic agents may be required.

Management Recommendations

Combinations of drugs to avoid

Medications that can affect blood pressure
When patients are being treated for hypertension, it is important to consider other medications that may affect their blood pressure. The following list includes some medications known to increase blood pressure.

• NSAIDs (including COX-2-selective agents);
• Sympathomimetics (e.g. pseudoephedrine);
• Corticosteroids;
• Stimulants (e.g. methylphenidate, dexamphetamine);
• Serotonin-noradrenaline reuptake inhibitors (e.g. venlafaxine);
• Monoamine oxidase inhibitors (e.g. moclobemide, phenelzine, tranylcypromine);
• Hormone replacement therapy; and
• Oestrogen-containing oral contraceptives.

A number of complementary medications can also raise blood pressure as can lifestyle factors such as a high intake of salt, caffeine, and alcohol.

For patients diagnosed with hypertension, it is also important to consider non-pharmacological methods to manage blood pressure. These might include education and encouragement to quit smoking as well as the promotion of regular physical activity, healthy eating, and weight reduction for patients who are overweight.