ACE Inhibitors and ARBs

Indications for use

Generally ACE inhibitors and ARBs are interchangeable but not used in combination with one another*. If ACE inhibitors are not tolerated, an ARB is a suitable alternative. 

• Hypertension: ACE inhibitors and ARBs may be less effective in patients of Black African or African-Caribbean origin and those with primary aldosteronism. ACE inhibitors are less effective for those aged over 55 years. ACE inhibitors are particularly indicated for hypertension in patients with type 1 diabetes and nephropathy. 
• All grades of heart failure (*candesartan and valsartan can be used alongside ACE inhibitors under specialist supervision for heart failure)
• Diabetic nephropathy
• Prophylaxis of cardiovascular events

Mechanism of action

Both ACE inhibitors and ARBs reduce the action of the hormone angiotensin II. When blood pressure is low, renin is released by the kidneys which causes angiotensinogen to be converted to angiotensin I, which is then converted to angiotensin II by the ACE enzyme. 

• ACE inhibitors block the conversion of angiotensin I to angiotensin II through blockade of the ACE enzyme. 
• ARBs work by blocking the receptors (such as the AT1 receptor) that angiotensin II acts on. 

Angiotensin II is a vasoconstrictor of blood vessels via the following mechanisms

• Stimulates release of aldosterone which increases blood volume via retention of sodium and water. This also leads to excretion of potassium (via Na+/K+ pumps). Inhibition of angiotensin II can therefore cause hyperkaelamia.
• Directly acts on vascular smooth muscle cells via angiotensin II receptor type 1 (AT1) to increase blood pressure by vasoconstriction. 

The ACE enzyme also inactivates bradykinin by breaking it down, therefore inhibition of ACE leads to increased bradykinin levels (enhancing the hypotensive effect). However due to the inflammatory nature of bradykinin, increased levels can also lead to persistent dry cough (~10% of patients treated with ACE inhibitors). The cough usually begins within 1-2 weeks of starting an ACE inhibitor, but can take months or years to develop.

Cautions and contraindications

• Contraindications with ACE inhibitors and ARBs:
  • Pregnancy or planning pregnancy
  • People with diabetes mellitus, or with an estimated glomerular filtration rate (eGFR) less than 60 mL/minute/1.73 m2, who are also taking aliskiren.
• Cautions with ACE inhibitors and ARB use:
  • Renal impairment or diabetes (increased risk of hyperkalaemia)
  • Patients of Black African or African-Caribbean origin or with primary aldosteronism (ARBs and ACE inhibitors may be less effective)
• Cautions with ACE inhibitors only:
  • Severe or symptomatic aortic stenosis (increased risk of hypotension)
• Cautions with ARBs only:
  • Renal artery stenosis 
  • A history of angio-oedema 
  • Aortic or mitral valve stenosis 
  • Hepatic impairment

Adverse effects

Alongside hyperkaelamia, ACE inhibitors and ARBs may cause: 

• Renal impairment – ACE inhibitors and ARBs lower the pressure in the kidneys, giving the kidneys a chance to rest, which in turn reduces excretion of creatinine and leads to a worsening of eGFR/CrCl
• Angio-oedema – a non allergic drug reaction can occur which precipitates angio-oedema which is swelling of the mouth, tongue and or throat.
• Dizziness and headaches – common in hypovolaemia/hyponatraemia
• Dry cough can occur with ACE-Inhibitor use (ARB can be used as alternative therapy if this occurs) 

Interactions 

ACE inhibitors and ARB’s should be used cautiously with other medications that can cause similar effects. The following interactions apply to both ACE inhibitors and ARBs:

• Aliskiren (renin inhibitor), potassium sparing diuretics* (e.g. spironolactone, eplerenone) and NSAIDs: increased risk of hyperkalaemia, hypotension and renal impairment (*monitoring required)
• Loop/thiazide like diuretics – risk of hypotension and renal impairment (monitoring required)
• Lithium – increases in serum lithium concentrations reported with concomitant therapy with ACE inhibitors and ARBs (monitoring of lithium levels recommended)
• Other hyperkalaemia-causing drugs: e.g., Amiloride, ciclosporin, heparins, potassium salts, trimethoprim, tacrolimus