2 Cardiovascular system
2.5 Hypertension
2.5.5 Drugs affecting the renin-angiotensin system
2.5.5.1 Angiotensin-converting enzyme inhibitors 2.5.5.2 Angiotensin-II receptor antagonists
2.5.5.1 Angiotensin-converting enzyme inhibitors
Angiotensin-converting enzyme inhibitors (ACE inhibitors) inhibit the conversion of angiotensin I to angiotensin II. The main indications of ACE inhibitors in children are shown below. In infants and young children, captopril is often considered first.
Initiation under specialist supervision Treatment with ACE inhibitors should be initiated under specialist supervision and with careful clinical monitoring in children.
Heart failure ACE inhibitors have a valuable role in all grades of heart failure, usually combined with a loop diuretic (section 2.2). Potassium supplements and potassium-sparing diuretics should be discontinued before introducing an ACE inhibitor because of the risk of hyperkalaemia. In adults, a low dose of spirono-lactone may be beneficial in severe heart failure and can be used with an ACE inhibitor provided serum potassium is monitored carefully. Profound first-dose hypotension can occur when ACE inhibitors are introduced to children with heart failure who are already taking a high dose of a loop diuretic (see Cautions below).
Temporary withdrawal of the loop diuretic reduces the risk, but can cause severe rebound pulmonary oedema.
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Hypertension ACE inhibitors may be considered for hypertension when thi-azides and beta-blockers are contra-indicated, not tolerated, or fail to control blood pressure; they may be considered for hypertension in children with type 1 diabetes with nephropathy (see also section 6.1.5). ACE inhibitors can reduce blood pressure very rapidly in some patients particularly in those receiving diuretic therapy (see Cautions, below); the first dose should preferably be given at bedtime.
Diabetic nephropathy For comment on the role of ACE inhibitors in the management of diabetic nephropathy, see section 6.1.5.
Renal effects Renal function and electrolytes should be checked before starting ACE inhibitors (or increasing the dose) and monitored during treatment (more frequently if features mentioned below are present). Hyperkalaemia and other side-effects of ACE inhibitors are more common in children with impaired renal function and the dose may need to be reduced (see under individual drugs).
Concomitant treatment with NSAIDs increases the risk of renal damage, and potassium-sparing diuretics (or potassium-containing salt substitutes) increase the risk of hyperkalaemia.
In children with severe bilateral renal artery stenosis (or severe stenosis of the artery supplying a single functioning kidney), ACE inhibitors reduce or abolish glomerular filtration and are likely to cause severe and progressive renal failure.
They are therefore contra-indicated in children known to have these forms of critical renovascular disease.
ACE inhibitor treatment is unlikely to have an adverse effect on overall renal function in children with severe unilateral renal artery stenosis and a normal contralateral kidney, but glomerular filtration is likely to be reduced (or even abolished) in the affected kidney and the long-term consequences are unknown.
ACE inhibitors are therefore best avoided in those with known or suspected renovascular disease, unless the blood pressure cannot be controlled by other drugs. If they are used in these circumstances renal function needs to be monitored.
ACE inhibitors should also be used with particular caution in children who may have undiagnosed and clinically silent renovascular disease. ACE inhibitors are useful for the management of hypertension and proteinuria in children with nephritis. They are thought to have a beneficial effect by reducing intra-glom-erular hypertension and protecting the glomintra-glom-erular capillaries and membrane.
Cautions ACE inhibitors need to be initiated with care in children receiving diuretics (important: see Concomitant diuretics, below); first doses can cause hypotension especially in children taking high doses of diuretics, on a low-sodium diet, on dialysis, dehydrated or with heart failure (see above). Discontinue if marked elevation of hepatic enzymes or jaundice (risk of hepatic necrosis). Renal function should be monitored before and during treatment, and the dose reduced in renal impairment (see also above and under individual drugs). For use in known renovascular disease, see Renal Effects above. The risk of agranulocytosis is possibly increased in collagen vascular disease (blood counts recommended).
ACE inhibitors should be used with care in children with severe or symptomatic aortic stenosis (risk of hypotension) and in hypertrophic cardiomyopathy. They should be used with care (or avoided) in those with a history of idiopathic or hereditary angioedema. Children with primary aldosteronism and Afro-Caribbean children may respond less well to ACE inhibitors.Interactions: Appendix 1 (ACE inhibitors).
Anaphylactoid reactionsTo prevent anaphylactoid reactions, ACE inhibitors should be avoided during dialysis with high-flux polyacrylonitrile membranes and during low-density lipoprotein apheresis with dextran sulphate; they should also be withheld before desensitisation with wasp or bee venom Concomitant diuretics ACE inhibitors can cause a very rapid fall in blood pressure in volume-depleted children; treatment should therefore be initiated with very low doses. In some children the diuretic dose may need to be reduced or the diuretic discontinued at least 24 hours beforehand (may not be possible in heart failure—
risk of pulmonary oedema). If high-dose diuretic therapy cannot be stopped, close observation is recommended after administration of the first dose of ACE inhibitor, for at least 2 hours or until the blood pressure has stabilised.
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Contra-indications ACE inhibitors are contra-indicated in children with hyper-sensitivity to ACE inhibitors (including angioedema) and in bilateral renovascular disease (see also above). ACE inhibitors should not be used in pregnancy unless essential—they may adversely affect fetal and neonatal blood pressure control and renal function, and possibly cause skull defects and oligohydramnios; toxicity in animal studies has been reported.
Side-effects ACE inhibitors can cause profound hypotension (see Cautions), renal impairment (see Renal effects above), and a persistent dry cough. They can also cause angioedema (onset may be delayed; higher incidence reported in Afro-Caribbean patients), rash (which may be associated with pruritus and urticaria), pancreatitis, and upper respiratory-tract symptoms such as sinusitis, rhinitis, and sore throat. Gastro-intestinal effects reported with ACE inhibitors include nausea, vomiting, dyspepsia, diarrhoea, constipation, and abdominal pain. Altered liver function tests, cholestatic jaundice, hepatitis, fulminant hepatic necrosis, and hepatic failure have been reported—discontinue if marked elevation of hepatic enzymes or jaundice. Hyperkalaemia, hypoglycaemia and blood disorders includ-ing thrombocytopenia, leucopenia, neutropenia, and haemolytic anaemia have also been reported. Other reported side-effects include headache, dizziness, fatigue, malaise, taste disturbance, paraesthesia, bronchospasm, fever, serositis, vasculitis, myalgia, arthralgia, positive antinuclear antibody, raised erythrocyte sedimentation rate, eosinophilia, leucocytosis, and photosensitivity.
Neonates The neonatal response to treatment with ACE inhibitors is very variable, and some neonates develop profound hypotension with even small doses; a test-dose should be used initially and increased cautiously. Adverse effects such as apnoea, seizures, renal failure, and severe unpredictable hypo-tension are very common in the first month of life and it is therefore recom-mended that ACE inhibitors are avoided whenever possible, particularly in preterm neonates.
CAPTOPRIL
Cautions see notes above; acute porphyria (sec-tion 9.8.2)
Renal impairment see notes above; start with low dose and adjust according to response Breast-feeding avoid in first few weeks after delivery—risk of profound neonatal hypotension;
can be used in older infant if essential but monitor infant’s blood pressure
Contra-indications see notes above Pregnancy avoid unless essential (see notes above)
Side-effects see notes above; tachycardia, serum sickness, weight loss, stomatitis, maculopapular rash, photosensitivity, flushing and acidosis Licensed use not licensed for use in children
under 18 years Indication and dose
Hypertension, heart failure, proteinuria in nephritis(under specialist supervision) . By mouth
Neonate(caution, see neonatal information above) test dose, 10–50 micrograms/kg (10 micrograms/kg in neonate less than 37 weeks post-menstrual age), monitor blood pressure carefully for 1–2 hours; if tolerated give 10–50 micrograms/kg 2–3 times daily increased as necessary to max. 2 mg/kg daily in divided doses (max. 300 micrograms/kg daily in divided doses in neonate less than 37 weeks post-men-strual age)
Child 1 month–12 yearstest dose, 100 micr-ograms/kg (max. 6.25 mg), monitor blood
pressure carefully for 1–2 hours; if tolerated give 100–300 micrograms/kg 2–3 times a day, increased as necessary to max. 6 mg/kg daily in divided doses (max. 4 mg/kg daily in divided doses for child 1 month–1 year)
Child 12–18 yearstest dose, 100 micrograms/
kg or 6.25 mg, monitor blood pressure carefully for 1–2 hours; if tolerated give 12.5–25 mg 2–3 times a day, increased as necessary to max.
150 mg daily in divided doses
Diabetic nephropathy(under specialist supervi-sion)
. By mouth
Child 12–18 yearstest dose, 100 micrograms/
kg or 6.25 mg, monitor blood pressure carefully for 1–2 hours; if tolerated, give 12.5–25 mg 2–3 times a day, increased as necessary to max.
150 mg daily in divided doses
Administration Administer under close supervi-sion, see notes above. Give test dose whilst child supine. Tablets can be dispersed in water Captopril(Non-proprietary)A
Tablets, captopril 12.5 mg, net price 56-tab pack =
£1.59; 25 mg, 56-tab pack = £1.70; 50 mg, 56-tab pack = £2.22
Brands include Ecopacec, Kaplonc, Tensoprilc Liquid, various strengths available from ‘special-order’ manufacturers or specialist importing com-panies, see p. 943
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Capotenc(Squibb)A
Tablets, captopril 12.5 mg (scored), net price 56-tab pack = £9.82; 25 mg, 56-tab pack = £11.19, 50 mg (scored), 56-tab pack = £19.07 (also available as Aceprilc)
Extemporaneous formulations available see Extemporaneous Preparations, p. 8
ENALAPRIL MALEATE
Cautions see notes above
Hepatic impairment monitor closely Renal impairment see notes above; start with low dose and adjust according to response Breast-feeding avoid in first few weeks after delivery—risk of profound neonatal hypotension;
can be used in older infant if essential but monitor infant’s blood pressure
Contra-indications see notes above Pregnancy avoid unless essential (see notes above)
Side-effects see notes above; also dyspnoea;
depression, asthenia; blurred vision; less com-monly dry mouth, peptic ulcer, anorexia, ileus;
arrhythmias, palpitation, flushing; confusion, nervousness, drowsiness, insomnia, vertigo;
impotence; muscle cramps; tinnitus; alopecia, sweating; hyponatraemia; rarely stomatitis, glos-sitis, Raynaud’s syndrome, pulmonary infiltrates, allergic alveolitis, abnormal dreams, gynaeco-mastia, Stevens-Johnson syndrome, toxic epi-dermal necrolysis, exfoliative dermatitis, pemphigus; very rarely gastro-intestinal angio-edema
Licensed use not licensed for use in children for congestive heart failure, proteinuria in nephritis or diabetic nephropathy; not licensed for use in children less than 20 kg for hypertension Indication and dose
Hypertension, congestive heart failure, protei-nuria in nephritis(under specialist supervision) . By mouth
Neonate(limited information) initially 10 micr-ograms/kg once daily, monitor blood pressure carefully for 1–2 hours, increased as necessary up to 500 micrograms/kg daily in 1–3 divided doses
Child 1 month–12 yearsinitially 100 micr-ograms/kg once daily, monitor blood pressure carefully for 1–2 hours, increased as necessary up to max. 1 mg/kg daily in 1–2 divided doses Child 12–18 yearsinitially 2.5 mg once daily, monitor blood pressure carefully for 1–2 hours, usual maintenance dose 10–20 mg daily in 1–2 divided doses; max. 40 mg daily in 1–2 divided doses if body-weight over 50 kg
Diabetic nephropathy(under specialist supervi-sion)
. By mouth
Child 12–18 yearsinitially 2.5 mg once daily, monitor blood pressure carefully for 1–2 hours, usual maintenance dose 10–20 mg daily in 1–2 divided doses; max. 40 mg daily in 1–2 divided doses if body-weight over 50 kg
Administration Tablets may be crushed and sus-pended in water immediately before use Enalapril Maleate(Non-proprietary)A
Tablets, enalapril maleate 2.5 mg, net price 28-tab pack = £1.31; 5 mg, tab pack = £1.10; 10 mg, 28-tab pack = £1.12; 20 mg, 28-28-tab pack = £1.22 Brands include Ednytc
Liquid, various strengths available from ‘special-order’ manufacturers or specialist importing com-panies, see p. 943
Innovacec(MSD)A
Tablets, enalapril maleate 2.5 mg, net price 28-tab pack = £5.35; 5 mg (scored), 28-tab pack = £7.51;
10 mg (red), 28-tab pack = £10.53; 20 mg (peach), 28-tab pack = £12.51
LISINOPRIL
Cautions see notes above
Renal impairment see notes above; start with low dose and adjust according to response Breast-feeding avoid—no information available Contra-indications see notes above
Pregnancy avoid unless essential (see notes above)
Side-effects see notes above; also less commonly tachycardia, palpitation, cerebrovascular acci-dent, Raynaud’s syndrome, confusion, mood changes, vertigo, sleep disturbances, asthenia, impotence; rarely dry mouth, gynaecomastia, alopecia, psoriasis; very rarely allergic alveolitis, pulmonary infiltrates, profuse sweating,
pemphi-gus, Stevens-Johnson syndrome, and toxic epi-dermal necrolysis
Licensed use not licensed for use in children Indication and dose
Hypertension(under specialist supervision)
Child 6–12 yearsinitially 70 micrograms/kg (max.
5 mg) once daily, increased in intervals of 1–2 weeks to max. 600 micrograms/kg (or 40 mg) once daily
Child 12–18 yearsinitially 2.5 mg once daily;
usual maintenance dose 10–20 mg once daily;
max. 80 mg once daily CAPTOPRIL (continued)
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Heart failure (adjunct)(under specialist supervi-sion)
Child 12–18 yearsinitially 2.5 mg once daily;
increased in steps no greater than 10 mg at intervals of at least 2 weeks up to max. 35 mg once daily if tolerated
Lisinopril(Non-proprietary)A
Tablets,lisinopril (as dihydrate) 2.5 mg, net price 28-tab pack = 91p; 5 mg, 28-tab pack = £1.02;
10 mg, 28-tab pack = £1.10; 20 mg, 28-tab pack =
£1.37
Liquid, various strengths available from ‘special-order’ manufacturers or specialist importing com-panies, see p. 943
Caracec(Bristol-Myers Squibb)A
Tablets, lisinopril 5 mg (scored), net price 28-tab pack = £8.51; 10 mg (yellow, scored), 28-tab pack =
£10.51; 20 mg (orange, scored), 28-tab pack =
£11.89
Zestrilc(AstraZeneca)A
Tablets, lisinopril (as dihydrate) 2.5 mg, net price 28-tab pack = £6.26; 5 mg (pink), 28-tab pack =
£7.86; 10 mg (pink), 28-tab pack = £9.70; 20 mg (pink), 28-tab pack = £10.97
Extemporaneous formulations available see Extemporaneous Preparations, p. 8
2.5.5.2 Angiotensin-II receptor antagonists
Losartan is a specific angiotensin-II receptor antagonist with many properties similar to those of the ACE inhibitors. However, unlike ACE inhibitors, losartan does not inhibit the breakdown of bradykinin and other kinins, and therefore does not appear to cause the persistent dry cough which commonly complicates ACE inhibitor therapy. It is therefore an alternative for children who have to discon-tinue an ACE inhibitor because of persistent cough.
Losartan can be used as an alternative to an ACE inhibitor in the management of hypertension; however, evidence for its use in children is very limited.
LOSARTAN POTASSIUM
Cautions renal artery stenosis (see also Renal Effects under ACE inhibitors, section 2.5.5.1);
monitor plasma-potassium concentration (parti-cularly in children with renal impairment); aortic or mitral valve stenosis; hypertrophic cardio-myopathy; children with primary aldosteronism and Afro-Caribbean children, particularly those with left ventricular hypertrophy, may not benefit from losartan;interactions: Appendix 1 (angio-tensin-II receptor antagonists)
Hepatic impairment manufacturer advises avoid in children 6–16 years—no information available;
child 17–18 years consider dose reduction in mild to moderate impairment, avoid in severe impair-ment (no information available)
Renal impairment manufacturer advises avoid in children 6–16 years with estimated glomerular fil-tration rate less than 30 mL/minute/1.73m2—no information available
Contra-indications
Pregnancy avoid unless essential—may adversely affect fetal and neonatal blood pressure control and renal function; also possible skull defects and oligohydramnios; toxicity in animal studies
Breast-feeding avoid—no information available Side-effects diarrhoea, symptomatic hypotension
including dizziness (particularly in children with intravascular volume depletion e.g. those taking
high-dose diuretics); cough, asthenia, vertigo, migraine, hyperkalaemia; arthralgia, myalgia;
urticaria, pruritus, rash; rarely hepatitis, anaemia (in severe renal disease or following renal trans-plant), thrombocytopenia, vasculitis (including Henoch-Scho¨nlein purpura), anaphylaxis, and angioedema
Licensed use not licensed for use in children Indication and dose
Hypertension(under specialist supervision) . By mouth
Child 6–16 years
Body-weight 20–50 kginitially 25 mg once daily; adjusted according to response to max.
50 mg once daily
Body-weight 50 kg and overinitially 50 mg once daily adjusted according to response to max.
100 mg once daily
Child 16–18 yearsinitially 50 mg once daily (intravascular volume depletion, initially 25 mg once daily); if necessary increased after several weeks to 100 mg once daily
Cozaarc(MSD)A
Tablets, f/c, losartan potassium 25 mg, net price 28-tab pack = £16.18; 50 mg (scored), 28-tab pack
= £12.80; 100 mg, 28-tab pack = £16.18 LISINOPRIL (continued)
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