ACE Inhibitors Pharmacology!

ACE Inhibitors Pharmacology

ACE inhibitors are among the most widely prescribed cardiovascular medicines.

ACE inhibitors are readily identified as they all contain the suffix –pril. Examples of ACE inhibitors include:

• Ramipril
• Lisinopril
• Perindopril
• Enalapril
• Captopril
• Fosinopril
• Benazepril
• Trandolapril

Captopril belongs to the sulfhydryl-containing class. Fosinopril belongs to the phosphonate-containing class. All others listed belong to the dicarboxylate-containing class.

ACE inhibitors are used in the treatment of conditions such as:

• Hypertension – ACE inhibitors reduce the risk of serious cardiovascular events, such as heart attack and stroke. They may be used first or second-line, usually in combination with another drug.
• Ischemic heart disease – as with hypertension, the purpose of ACE inhibitors is to reduce the risk of heart attack and stroke.
• Chronic heart failure – used for the symptomatic treatment of heart failure, improving overall prognosis.
• Diabetic nephropathy – ACE inhibitors can be used to prevent nephropathy from progressing in diabetic patients. They may also be used for chronic kidney disease (with proteinuria) to reduce proteinuria levels.

Mechanism of Action

How do ACE inhibitors work?

The mechanism of ACE inhibitors involves blocking the effects of ACE – “angiotensin-converting enzyme”. The ACE enzyme is predominantly found on the surface of pulmonary and renal epithelia.

This enzyme is responsible for converting angiotensin I (ATI) to angiotensin II (ATII). Angiotensin I is itself produced from angiotensinogen, a globular protein released from the liver in response to renin release from the kidney.

To summarize:

• Renin is released from the juxtaglomerular apparatus of the kidney in response to electrolyte and/or water imbalances in the body:

– Low sodium levels
– Low blood pressure
– Decreased blood volume

• Renin cleaves angiotensinogen into ATI.
• Angiotensin-converting enzyme turns ATI into ATII

Why is reducing angiotensin II levels important?

• ATII stimulates the release of aldosterone from the adrenal gland cortex.
• In turn, aldosterone promotes reabsorption of sodium and chloride ions, increasing water retention. During this process, potassium is also excreted.
• Vasoconstriction; increasing blood pressure.
• ADH secretion from the posterior lobe of the pituitary gland, promoting water retention from the collecting duct.

ACE inhibitors, by preventing production of ATII, has the following four effects:

• Prevent aldosterone release from the adrenal cortex.
• Elimination of sodium ions (and increased water loss) from the kidneys.
• Potassium ions are retained.
• Consequent reduction in blood volume and blood pressure.

ACE inhibitors pharmacology is dependent upon the cessation in production of ATII to reduce blood volume, blood pressure and halt diabetic nephropathy.

Side effects

Side effects of ACE inhibitors include:

• Hypotension – a notable consequence of its mechanism of action. Patients typically experience worsened hypotension during the first dose, the effect tapering off thereafter.
• Persistent, dry cough – attributable to the accumulation of kinins in the lung. If the cough becomes too troublesome, the patient may be switched to an angiotensin-receptor blocker (ARB) instead – examples include losartan and candesartan.
• Hyperkalemia – as we learned from their mechanism, ACE inhibitors promote retention of potassium ions. Patient potassium levels should be monitored.

Other side effects include headache, dizziness, fatigue, nausea, and angioedema.

Captopril has a thiol moiety and so is associated with a metallic taste.

Clinical Pharmacology

When we talk about the clinical pharmacology of ACE inhibitors, we must consider the following factors:

• ACE inhibitors should be avoided in patients with bilateral renal artery stenosis and used with caution in renal impairment generally.
• For chronic kidney disease, lower doses should be used and their effects monitored closely.
• ACE inhibitors are classified as pregnancy category D, meaning there is positive evidence of risk and must be avoided. Antihypertensive drugs safe in pregnancy include labetalol, methyldopa, hydralazine, and nifedipine.
• Caution is warranted when prescribing ACE inhibitors with other medicines that increase potassium levels – including potassium supplements; potassium-sparing diuretics such as amiloride, spironolactone, eplerenone, and triamterene; trimethoprim; and pentamidine.
• Patients should be counseled about the risk of first-dose hypotension. ACE inhibitors should not be co-prescribed with other hypotensive-producing agents, such as nitrates. To reduce any risks from first-dose hypotension, patients are counseled to take the first dose before bed.
• The risk of renal failure increases when ACE inhibitors are taken with NSAIDs and a diuretic; what is referred to as the “triple whammy effect“.
• Captopril was the first ACE inhibitor and has a much shorter duration of action compared to later ACE inhibitors. Multiple doses per day are required which reduces adherence, and the risk of adverse effects is also higher with captopril. Captopril is also the only ACE inhibitor that can cross the blood-brain barrier.

That concludes our review of ACE inhibitors pharmacology. Check back to our pharmacy blog soon for more exclusive content to help you master the science of drugs and medicines!