Abstract
Renin (half-life 80 minutes) splits the decapeptide angiotensin I from the circulating plasma protein angiotensinogen, which is synthesised in the liver and is present in the α2-globulin fraction of plasma proteins. Angiotensin-converting enzyme (ACE) converts angiotensin I to the active octapeptide angiotensin II, and also inactivates bradykinin. Angiotensin II is broken down in the kidney and liver to inactive metabolites and angiotensin III, which retains some activity (Figure 17.1).
Renin–Angiotensin–Aldosterone System
Physiology
The juxtaglomerular apparatus within the kidney consists of three distinct cell types:
Juxtaglomerular cells form part of the afferent arteriole as it enters the glomerulus and are supplied by sympathetic nerves. They contain prorenin, which is converted to the acid protease renin before systemic release.
The macula densa is a region of cells at the start of the distal convoluted tubule, which lie adjacent to the juxtaglomerular cells of the same nephron.
Agranular lacis cells, which lie between the afferent and efferent arterioles adjacent to the glomerulus.
Under the following conditions the juxtaglomerular apparatus will cause the release of renin into the circulation:
Reduced renal perfusion
Reduced Na+ at the macula densa
Stimulation of the renal sympathetic fibres via β1-adrenoceptors.
Renin (half-life 80 minutes) splits the decapeptide angiotensin I from the circulating plasma protein angiotensinogen, which is synthesised in the liver and is present in the α2-globulin fraction of plasma proteins. Angiotensin-converting enzyme (ACE) converts angiotensin I to the active octapeptide angiotensin II, and also inactivates bradykinin. Angiotensin II is broken down in the kidney and liver to inactive metabolites and angiotensin III, which retains some activity (Figure 17.1).
, Enzyme action; 
, negative feedback.Angiotensin II
Mechanism of Action
Two subtypes of angiotensin II receptor exist, AT1 and AT2. Angiotensin has a greater affinity for AT1 receptors, which are G-protein-coupled.
Effects
Potent vasoconstriction (about five times as potent as noradrenaline), acting directly on arterioles and indirectly via central mechanisms.
Blockade of noradrenaline re-uptake (uptake 1) at sympathetic nerves and sympathetic nervous system activation.
Central effects – it increases thirst and the release of ADH and ACTH.
It stimulates the release of aldosterone from the adrenal cortex and inhibits the release of renin from the juxtaglomerular cells.
Reduced glomerular filtration rate.
ACE inhibitors and angiotensin II receptor antagonists are used widely in the treatment of hypertension. β-Blockers (see Chapter 14) reduce sympathetically mediated release of renin, which contributes to their antihypertensive effects.
Angiotensin-Converting Enzyme Inhibitors
Angiotensin-converting enzyme (ACE) inhibitors are used in all grades of heart failure and in patients with myocardial infarction with left ventricular dysfunction where it improves the prognosis. They are used in hypertension, especially in insulin-dependent diabetics with nephropathy. However, hypertension is relatively resistant to ACE inhibition in the black population where concurrent diuretic therapy may be required. While most drugs should be continued throughout the peri-operative period, ACE inhibitors and angiotensin II receptor antagonists are often omitted due to the increased frequency of peri-operative hypotension.
From a kinetic point of view ACE inhibitors may be divided into three groups:
Group 1. Captopril – an active drug that is metabolised to active metabolites.
Group 2. Enalapril, ramipril – prodrugs, which only become active following hepatic metabolism to the diacid moiety.
Group 3. Lisinopril – an active drug that is not metabolised and is excreted unchanged in the urine.
In other respects the effects of ACE inhibitors are similar and are discussed under Ramipril.
Ramipril
Presentation
Ramipril is available as 1.25–10 mg tablets. The initial dose is 1.25 mg which is then titrated up depending on its indication.
Mechanism of Action
Ramipril is converted by liver esterases to the active moiety ramiprilat, which is a competitive ACE inhibitor and therefore prevents the formation of angiotensin II and its effects. Afterload is reduced to a greater degree than preload.
Effects
Cardiovascular – ramipril reduces the systemic vascular resistance significantly, resulting in a fall in blood pressure. The fall in afterload may increase the cardiac output, particularly in those with heart failure. Heart rate is usually unaffected but may increase. Baroreceptor reflexes are also unaffected. Transient hypotension may occur at the start of treatment which may be started under specialist supervision.
Renal – the normal function of angiotensin II to maintain efferent arteriolar pressure (by vasoconstriction) at the glomerulus in the presence of poor renal perfusion is forfeit. Therefore renal perfusion pressure falls and renal failure may follow. As a result bilateral renal artery stenosis or unilateral renal artery stenosis to a single functioning kidney is considered a contraindication. Where normal renal perfusion is preserved, renal vasodilatation may occur leading to a natriuresis.
Metabolic – reduced aldosterone release impairs the negative feedback to renin production so that renin levels become elevated. It may also lead to hyperkalaemia and raised urea and creatinine, especially in those with even mildly impaired renal function.
Interactions – ramipril reduces aldosterone release, which may result in hyperkalaemia, so it should not be used with potassium-sparing diuretics. It has been associated with unexplained hypoglycaemia in type I and II diabetes. These effects usually decrease with continued treatment. Non-steroidal anti-inflammatory drugs reduce ramipril’s antihypertensive effects and may precipitate renal failure.
Cough – a persistent dry cough may be the result of increased levels of bradykinin, which are normally broken down by ACE.
Miscellaneous – rare but serious effects may complicate its use and include angioedema (0.2%), agranulocytosis and thrombocytopenia. Less serious side effects are more common and include loss of taste, rash, pruritus, fever and aphthous ulceration. These are more common with higher doses and in patients with impaired renal function.
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