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Adverse effects
Adverse effects
Persistent dry cough
Persistent dry cough
How can ACE inhibitors cause a dry cough?
How can ACE inhibitors cause a dry cough?
Bradykinins are pro-inflammatory mediators that are normally metabolised by angiotensin-converting enzyme.
ACE inhibitors cause accumulation of bradykinins by inhibiting their metabolism.
Bradykinins accumulate in the upper respiratory tract leading to irritation and a dry cough.
ACE inhibitors cause the accumulation of bradykinins in the respiratory tract
How common is this side-effect?
How common is this side-effect?
Occurs in ~10% of patients who start ACE inhibitors. For an unknown reason, it is more common in women.
When does it present?
When does it present?
It usually starts 1-2 weeks after starting therapy (can be up to 6 months). If the patient presents with cough after 6 months, it is very unlikely to be due to the ACE inhibitor.
Bradykinins cause inflammation and an irritating dry cough
How should it be managed?
How should it be managed?
This side-effect is not dose-dependent and therefore lowering the dose will not be effective. The ACE inhibitor should be stopped and the cough should settle after 4-7 days.
An ARB can be trialled in replacement, as ARBs do not promote bradykinin build-up, so patients are far less likely to develop a cough (incidence only ~3%).
Acute kidney injury (AKI)
Acute kidney injury (AKI)
How can ACE inhibitors cause AKI?
How can ACE inhibitors cause AKI?
The RAAS is one mechanism which helps maintain renal perfusion.
ACE inhibitors and ARBs can cause AKI by 2 main mechanisms:
1. By reducing arterial blood pressure this reduces the intraglomerular pressure which drives ultrafiltration, leading to a decline in glomerular filtration rate (GFR) and AKI.
2. Angiotensin-II causes vasoconstriction of the efferent arteriole. When ACE inhibitors/ARBs prevent this action of angiotensin-II, it causes dilation of the efferent arteriole. This, too, reduces the intraglomerular pressure which drives ultrafiltration, leading to a decline in glomerular filtration rate (GFR) and AKI.
Both of these mechanisms are pre-renal causes of AKI.
Postural hypotension
Postural hypotension
How can ACE inhibitors cause postural hypotension?
How can ACE inhibitors cause postural hypotension?
When a person stands up from a sitting/lying position the baroreceptors in the carotid sinus and the aortic arch detect a fall in mean arterial BP and quickly send signals to the medulla oblongata to increase sympathetic drive (and inhibit parasympathetic drive) in to order to cause vasoconstriction and tachycardia which increases arterial BP.
ACE inhibitors/ARBs lower blood pressure and reduce sympathetic activity, therefore the baroreceptor reflex may be reduced in patients who take these drugs.
The effect is that patients may experience a fall in blood pressure when they stand up (postural hypotension), so there will be a significant difference in their lying and standing BP.
Hypotension is more common with ARBs than with ACE inhibitors.
Features of postural hypotension
Angioedema
Angioedema
What is angioedema?
What is angioedema?
Angioedema describes swelling caused by fluid accumulation in the deep layers under the skin. Its caused by leaky capillaries, probably due to the effects of histamine and bradykinin. It typically affects under the eyes, lips and the throat where it may cause life-threatening airway obstruction.
How can ACE inhibitors cause angioedema?
How can ACE inhibitors cause angioedema?
Bradykinins are pro-inflammatory mediators that are normally metabolised by ACE. ACE inhibitors cause an accumulation of bradykinins by inhibiting their metabolism. These bradykinins (and prostaglandins) cause vessels to become leaky, leading to fluid accumulation in the deep cutaneous layers.
When does it present?
When does it present?
It typically occurs episodically in patients taking ACE inhibitors.
It comes on suddenly, remaining typically for 2-5 days, before resolving over 1-3 days.
How common is this side-effect?
How common is this side-effect?
With ACE inhibitors, angioedema occurs in 2 in 1000 and is 2-4 x more common in patients of Afro-Caribbean descent than Caucasian.
How should it be managed?
How should it be managed?
Airway monitoring and discontinuation of the ACE inhibitor. It may be appropriate to try an ARB in replacement as the risk of angioedema is much less but this should be counselled with the patient.
Characteristic lip swelling in angioedema
ACE inhibitors cause the accumulation of bradykinins in the respiratory tract
Hyperkalaemia
Hyperkalaemia
How can ACE inhibitors cause hyperkalaemia?
How can ACE inhibitors cause hyperkalaemia?
The reduced secretion of aldosterone leads to decreased renal secretion of K+ in the distal convoluted tubule. This leads to retention of K+ and hyperkalaemia.
How common is this side-effect?
How common is this side-effect?
Hyperkalaemia occurs in ~3% of patients on an ACEi or an ARB.
Risk factors for developing hyperkalaemia include:
- renal impairment (esp. patients on haemodialysis)
- diabetes
- concurrent use of a drug promoting potassium retention such as a potassium-sparing diuretic or an NSAID.
Mechanism of hyperkalaemia with ACE inhibitor therapy
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