Clinical applications of ACE inhibition

ACE inhibitors are established in the treatment of hypertension; they decrease morbidity and mortality in congestive cardiac failure, and improve left ventricular dysfunction after myocardial infarction. They delay the progression of diabetic nephropathy and have a protective effect in non-diabetic chronic renal failure, although they are associated with proteinuria in approximately 1% of patients. ACE inhibitors improve vascular endothelial function by their effects on A-II and bradykinin; the clinical importance of this in patients with vascular disease is unknown.

ACE inhibitors have a common mechanism of action, differing in the chemical structure of their active moieties, in potency, bioavailability, plasma half-life, route of elimination, distribution and affinity for tissue-bound ACE (Table 7.10). However, the efficacy of most ACE inhibitors is similar. Most of the newer compounds are prodrugs, converted to an active metabolite by the liver, and have a prolonged duration of action. Most are excreted via the kidneys, and dosage should be reduced in the elderly and those with impaired renal or cardiac function. Enalapril is available as the active drug, enalaprilat, and may be administered intravenously (1.25 mg over 5 min) for the treatment of hypertensive emergencies.

ACE inhibitors are generally tolerated well, with no rebound hypertension after stopping therapy and few metabolic effects. Symptomatic first-dose hypotension may occur, particularly in hypo-volaemic or sodium-depleted patients with high plasma renin concentrations. Symptomatic hypotension was more common with the higher doses originally used. ACE inhibitors have a synergistic effect with diuretics (which increase the activity of the renin-angiotensin system), but are less effective in patients taking NSAIDs.

The adverse effects of ACE inhibitors may be classified into those that are class-specific (related to inhibition of ACE) and those that relate to specific drugs. Class-specific effects include hypotension, renal insufficiency, hyperkalaemia, cough (10%) and angioneurotic oedema (0.1-0.2%). ACE inhibitors may cause renal impairment, particularly if renal perfusion is decreased (e.g. because of renal artery stenosis, congestive cardiac failure or hypovolemia) or there is pre-existing renal disease. Renal impairment is also more likely in

Table 7.10 Pharmacology of ACE inhibitors

Captopril

Lisinopril

Enalapril

Perindopril

Quinapril

Trandolapril

Ramipril

Fosinopril

Zinc ligand

Sulphhydryl

Carboxvl

Carboxvl

Carboxvl

Carboxyl

Carboxyl

Carboxvl

Phosphinyl

Prodrug

No

No '

Yes

Yes

Yes

Yes

Yes

Yes

Bioavailability (%)

75

25

60

65

40

70

50

35

(ma (h)a

0.8

6-8

3-1

3-4

2

4-6

2-3

3-6

h/2 (h)»

2

12

11

2Sb

20-2 SLl

16-24t>

4—5 O1-1

12

Metabolism 1

Oxidation

Minimal

Minimal

Prodrug

Prodrug

Prodrug

Prodrug

Prodrug

(50%)

Elimination

Renal

Renal

Renal

Renal

Renal

Renal,

Renal

Renal,

hepatic

hepatic

aThc prodrugs arc metabolized in the gut mucosa and liver to active compounds. Pharmacokinetic data refer to the active compounds. These drugs have poiyphasic pharmacokinetics, with a dose-dependent prolonged terminal elimination phase from plasma of over 24 h.

aThc prodrugs arc metabolized in the gut mucosa and liver to active compounds. Pharmacokinetic data refer to the active compounds. These drugs have poiyphasic pharmacokinetics, with a dose-dependent prolonged terminal elimination phase from plasma of over 24 h.

the elderly or those receiving NSAIDs, and renal function should be checked before starting ACE inhibitor therapy, and monitored subsequently. Hyperkalaemia (plasma K+ concentration usually increases by 0.1-0.2 mmol L~1 because of decreased aldosterone concentrations) may be more marked in those with impaired renal function or in patients taking potassium supplements or potassium-sparing diuretics. The mechanism of cough is not known but is mediated by C fibres and may be related to bradykinin or substance P production. It is reversible on stopping the ACE inhibitor. Other adverse effects include upper respiratory congestion, rhinorrhoea, gastrointestinal disturbances, and increased insulin sensitivity and hyperglycaemia in diabetic patients.

Some adverse effects - skin rashes (1%), taste disturbances, proteinuria (1%) and neutropenia (0.05%) - are related to the presence of a sulphydryl group (e.g. captopril). ACE inhibitors may cause fetal abnormalities and are contraindicated in pregnancy.

Although anaesthesia per se has no direct effect on the RAS or ACE inhibitors, the RAS is activated by several stimuli which may occur during the perioperative period. These include blood or fluid losses and the stress response to surgical stimulation. Activation of the RAS contributes to the maintenance of arterial pressure after haemorrhage, or during anaesthesia. The incidence of hypotension during anaesthesia is increased in patients receiving long-term antihypertensive treatment with ACE inhibitors, and it has been argued that they should be stopped before surgery if significant blood loss or fluid shifts are likely. ACE inhibitors improve ventricular function in patients with cardiac failure or after myocardial infarction, but it is not known whether acute cessation before surgery is harmful. Conversely, they may have beneficial effects on regional blood flow and have been associated with improved renal function in patients undergoing aortic surgery. There is no consensus on the optimum perioperative management of patients receiving ACE inhibitors.

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