Antihypertensive drugs are used in the treatment of high blood pressure. Hypertension is not an insignificant diagnosis. It is linked to a substantially increased risk of heart attack and stroke. Studies show, though, that even a modest reduction in blood pressure can slash those risks by as much as a third.
That’s where antihypertensive drugs come in.
Though drugs are not the ideal nor total solution, they play an increasingly important role. Cardiovascular disease remains the leading cause of death worldwide.
Before we review the pharmacology of antihypertensive drugs, let’s briefly take a moment to consider the extent of hypertension throughout the United States.
According to the American Heart Association, there are more than 100 million Americans living with high blood pressure.
That is almost half of all adult Americans.
In November 2017, the criteria for diagnosing a patient as hypertensive was redefined. Previously, a patient had to read 140/80 on a sphygmomanometer. Now, it has been reduced to 130/80 – meaning many more people now find themselves cast within the diagnostic net.
The statistics surrounding cardiovascular disease, and its wider implications, are sobering:
- 23 million Americans have type 2 diabetes
- Over 350,000 cardiac arrests that occur outside the home each year
- As of 2014, almost 40 percent of Americans are considered obese
- Almost 800,000 people will suffer from a stroke this year
- Over 16 million people, aged 20 or older, are living with coronary artery disease
And perhaps most astonishingly…
- Between 2005 and 2015, there has been a 38 percent increase in the number of hypertension-related deaths.
Antihypertensive drugs have, then, never been more important. Along with diet and exercise, they remain one of the most effective methods to reduce high blood pressure.
Antihypertensive Drug Classes
When we talk about the pharmacology of antihypertensive drugs, we’re talking about a very large and diverse family of medicines (see below).
Some of the medicines reviewed below are no longer used as the first or second-line treatment option for hypertension. That being said, those drugs do have significant antihypertensive effects, and, for that reason, they are included in this guide for the sake of completion.
The antihypertensive drug classes we will review include:
- ACE inhibitors
- Angiotensin II receptor antagonists
- Calcium channel blockers
- Beta blockers
- Alpha blockers
- Alpha-2 agonists
- Renin inhibitors
For each drug class, we offer examples, their mechanism of action, side effect and drug interaction profiles, and any other relevant clinical features.
Let’s begin, then, with ACE inhibitors.
ACE inhibitors are among the most widely prescribed cardiovascular medicines.
Mechanism: ACE inhibitors work by inhibiting the enzyme, angiotensin-converting enzyme (ACE); an enzyme found on the surface of pulmonary and renal epithelia. By blocking ACE, these drugs prevent aldosterone release from the adrenal cortex and eliminate sodium ions (along with water) from the kidneys. These two cumulative effects serve to reduce blood volume and blood pressure.
- Hypotension – first-dose hypotension is prevalent with ACE inhibitors
- Persistent, dry cough – due to pulmonary kinin accumulation
- Hyperkalemia – ACE inhibitors promote potassium retention
- Other effects – fatigue, nausea, dizziness, headache
Take a few minutes to learn more about ACE inhibitors and their clinical considerations.
Angiotensin II receptor antagonists
Angiotensin II receptor antagonists are also known as ARBs, or angiotensin receptor blockers. They are sometimes used in place of ACE inhibitors, particularly where the persistent, dry cough has become unbearable for the patient.
Mechanism: Angiotensin-receptor blockers have a similar mechanism of action to ACE inhibitors. Whereas ACE inhibitors block the conversion of angiotensin I into angiotensin II, ARBs work by blocking the action of angiotensin II at the AT1 receptor. Because angiotensin II promotes aldosterone secretion and acts as a vasoconstrictor, its blockage reduces peripheral vascular resistance and, as a result, lowers blood pressure.
- Renal failure (as with ACE inhibitors)
- Cough – though less likely than with an ACE inhibitor
Due to the risk of hyperkalemia, other potassium-elevating drugs should not be prescribed. This includes potassium supplements, potassium-sparing diuretics.
As with ACE inhibitors, taking ARBs with NSAIDs increases the risk of renal failure.
Diuretics are drugs that promote diuresis, or water loss. There are many different diuretic classes, too many to review in detail here. However, we have examined many of the major diuretic drug classes elsewhere (see links below).
Diuretic drug classes:
- Loop diuretics – furosemide, bumetanide
- Thiazide and thiazide-like diuretics – bendroflumethiazide, hydrochlorothiazide, indapamide, metolazone
- Potassium-sparing diuretics – amiloride, spironolactone
The purpose of diuretics is to eliminate excess sodium and water from the body. Some diuretic classes also eliminate potassium, increasing the risk of hypokalemia.
Other drugs though, such as amiloride and spironolactone, retain potassium ions – increasing the risk of hyperkalemia. However, diuretic combinations are invariably used to balance and offset these risks.
Diuretics act at different points along the nephron. For example:
- Loop diuretics act at the thick ascending limb
- Thiazide diuretics act at the distal convoluted tubule
- Potassium-sparing diuretics act at the cortical collecting duct
- Osmotic diuretics, such as mannitol, act at the proximal tubule
- Carbonic anhydrase inhibitors, such as acetazolamide, also act at the proximal tubule
In general terms, the broad side effects associated with diuretics include:
- Loop diuretics – hypovolemia, hypokalemia, metabolic alkalosis, hyperuricemia.
- Thiazides – associated with the side effects listed for loop diuretics, plus hypercalcemia and hyponatremia.
- Hyperkalemia – amiloride, triamterene, spironolactone.
Take a few minutes to consult the specific articles on loop diuretics and thiazides (above) for more detailed accounts on their side effect, drug interaction and clinical pharmacy profiles.
Calcium channel blockers
Not all calcium channel blockers are used for their antihypertensive effects. Nonetheless, the following drugs have a significant antihypertensive effect as part of their clinical action.
Amlodipine and nifedipine may be used for hypertension whereas diltiazem and verapamil are predominantly used to control heart rate / arrhythmias.
Mechanism: as their name suggests, calcium channel blockers reduce calcium entry into vascular and cardiac cells. This reduces intracellular calcium concentration which, in turn, causes relaxation and vasodilation in arterial smooth muscle. Calcium channel blockers also reduce myocardial contractility in the heart.
Because diltiazem and verapamil (the non-dihydropyridine CCBs) are used as class III antiarrhythmic drugs, the side effect profile below focusses on amlodipine and nifedipine.
- Ankle swelling
- Shortness of breath
Beta-blockers are not just used in the treatment of hypertension (though not generally given as initial therapy), they are also used in the treatment of ischemic heart disease, chronic heart failure, atrial fibrillation and supraventricular tachycardia.
Mechanism: beta-blockers act through a variety of means. For hypertension, they act to reduce renin secretion form the kidney – an effect ordinarily mediated by beta-1 receptors. Recall that beta-1 receptors are located mainly in the heart, whereas beta-2 receptors are mainly located in the smooth muscle of blood vessels and the airways.
- Cold extremities
- Vivid dreams
Vivid dreams / nightmares are more likely with lipophilic beta blockers, such as propranolol and metoprolol.
Take a few minutes to review some great beta blocker mnemonics.
Alpha blockers may be used to treat hypertension in resistant cases where other drugs – such as ACE inhibitors, calcium channel blockers and thiazide diuretics – have proven ineffective.
Mechanism: alpha-1 receptors are predominantly found in smooth muscle, such as blood vessels or the urinary tract. Stimulation produces contraction and inhibition causes relaxation. Alpha blockers are highly selective for the alpha-1 receptor, causing vasodilation and a reduction in blood pressure.
- Postural hypotension
These three effects are more pronounced after the first dose.
As with the alpha blockers, alpha-2 agonists are rarely used. They are typically only used when all other conventional options have been exhausted. When used, they are usually taken alongside a diuretic.
Mechanism: more specifically, alpha-2 agonists are classified as “centrally-acting alpha-2 agonists”. These receptors are activated in the brain which, once activated, open peripheral blood vessels around the body, reducing blood pressure.
- Dry nasal mucosa
- Dry mouth
- Rebound hypertension
- Postural hypotension
Renin is a protein and enzyme secreted by the kidneys.
It works by cleaving angiotensinogen (hepatic-produced) into angiotensin I. ACE then converts angiotensin I into angiotensin II and, in turn, angiotensin II causes increased secretion of aldosterone – increasing blood pressure. Renin inhibitors are, then, an effective way to block the effects of angiotensin II and reduce blood pressure.
Mechanism: See above.
Aliskiren should not be taken alongside an angiotensin-receptor blocker or ACE inhibitor in diabetic patients due to an increased risk of stroke, hyperkalemia and kidney complications.
Due to the above risks and side effect profile, many clinicians regard aliskiren as more harmful than beneficial.
There are two medicines to consider:
Sodium nitroprusside has been used in cases of hypertensive emergency. It is administered via the intravenous route and, for this reason, has a rapid onset of effect.
Sodium nitroprusside deploys nitric oxide for its antihypertensive effect. Nitric oxide works to reduce total peripheral resistance and venous return. This reduces both preload and afterload.
Side effects associated with sodium nitroprusside include:
- Cyanide poisoning
- Renal azotemia
Hydralazine is used to treat hypertension, though it is more often used to treat high blood pressure in pregnancy – gestational hypertension. Like sodium nitroprusside, it may also be used in hypertensive emergencies where symptoms from hypertension are present.
Side effects with hydralazine include:
- Aching / swelling joints
It works as a direct-acting smooth muscle relaxant, working as a vasodilator in resistance arterioles – decreasing total peripheral resistance and lowering blood pressure.
Studying the pharmacology of antihypertensive drugs doesn’t need to be difficult. Once the underlying physiological mechanisms are understood, the likely side effect and drug interaction profiles begin to fall into place and make more sense. With enough time and even more effort, you too can commit all antihypertensive drug classes to memory. For more facts and pharmacy quiz questions on antihypertensive drugs, register with PharmaFactz today. Check back to our pharmacy blog soon for even more great articles on the various antihypertensive drug classes.