2 Cardiovascular system
2.6 Nitrates, calcium-channel blockers, and other antianginal drugs
2.6.2 Calcium-channel blockers
Calcium-channel blockers (less correctly called ‘calcium-antagonists’) interfere with the inward displacement of calcium ions through the slow channels of active cell membranes. They influence the myocardial cells, the cells within the specia-lised conducting system of the heart, and the cells of vascular smooth muscle.
Thus, myocardial contractility may be reduced, the formation and propagation of electrical impulses within the heart may be depressed, and coronary or systemic vascular tone may be diminished.
Calcium-channel blockers differ in their predilection for the various possible sites of action and, therefore, their therapeutic effects are disparate, with much greater variation than those of beta-blockers. There are important differences between verapamil, diltiazem, and the dihydropyridine calcium-channel blockers (amlo-dipine, nicar(amlo-dipine, nife(amlo-dipine, and nimodipine). Verapamil and diltiazem should usually beavoided in heart failure because they may further depress cardiac function and cause clinically significant deterioration.
Verapamil is used for the treatment of hypertension (section 2.5) and arrhythmias (section 2.3.2). However, it is no longer first-line treatment for arrhythmias in children because it has been associated with fatal collapse especially in infants under 1 year; adenosine is now recommended for first-line use.
Verapamil is a highly negatively inotropic calcium channel-blocker and it reduces cardiac output, slows the heart rate, and may impair atrioventricular conduction.
It may precipitate heart failure, exacerbate conduction disorders, and cause hypotension at high doses and should not be used with beta-blockers (see p. 140). Constipation is the most common side-effect.
Nifedipine relaxes vascular smooth muscle and dilates coronary and peripheral arteries. It has more influence on vessels and less on the myocardium than does verapamil, and unlike verapamil has no anti-arrhythmic activity. It rarely pre-cipitates heart failure because any negative inotropic effect is offset by a reduction in left ventricular work. Short-acting formulations of nifedipine are not recom-mended for long-term management of hypertension; their use may be associated with large variations in blood pressure and reflex tachycardia. However, they may be used if a modified-release preparation delivering the appropriate dose is not available or if a child is unable to swallow (a liquid preparation may be prepared using capsules). Nifedipine may also be used for the management of angina due to coronary artery disease in Kawasaki disease or progeria and in the management of Raynaud’s syndrome.
Nicardipine has similar effects to those of nifedipine and may produce less reduction of myocardial contractility; it is used to treat hypertensive crisis.
Amlodipine also resembles nifedipine and nicardipine in its effects and does not reduce myocardial contractility or produce clinical deterioration in heart failure. It has a longer duration of action and can be given once daily. Nifedipine and amlodipine are used for the treatment of hypertension. Side-effects associated with vasodilatation such as flushing and headache (which become less obtrusive after a few days), and ankle swelling (which may respond only partially to diuretics) are common.
Nimodipine is related to nifedipine but the smooth muscle relaxant effect preferentially acts on cerebral arteries. Its use is confined to prevention and treatment of vascular spasm following aneurysmal subarachnoid haemorrhage.
Diltiazem is a peripheral vasodilator and also has mild depressor effects on the myocardium. It is used in the treatment of Raynaud’s syndrome.
Withdrawal There is some evidence that sudden withdrawal of calcium-channel blockers may be associated with an exacerbation of myocardial ischaemia.
GLYCERYL TRINITRATE (continued)
136
2.6.2 Calcium-channel blockers BNFC 20092Cardiovascularsystem
AMLODIPINE
Cautions interactions: Appendix 1 (calcium-channel blockers)
Hepatic impairment half-life prolonged—may need dose reduction
Pregnancy no information available—manufac-turer advises avoid, but risk to fetus should be balanced against risk of uncontrolled maternal hypertension
Breast-feeding no information available—manu-facturer advises avoid
Contra-indications cardiogenic shock, significant aortic stenosis, acute porphyria (section 9.8.2) Side-effects abdominal pain, nausea; palpitation,
flushing, oedema; headache, dizziness, sleep dis-turbances, fatigue; less commonly gastro-intestinal disturbances, dry mouth, taste disturbances, hypotension, syncope, chest pain, dyspnoea, rhinitis, mood changes, asthenia, tremor, paraes-thesia, urinary disturbances, impotence, gynae-comastia, weight changes, myalgia, muscle cramps, back pain, arthralgia, visual disturbances, tinnitus, pruritus, rashes (including isolated reports of erythema multiforme), sweating, alo-pecia, purpura, and skin discolouration; very rarely gastritis, pancreatitis, hepatitis, jaundice, cholestasis, gingival hyperplasia, myocardial infarction, arrhythmias, tachycardia, vasculitis, coughing, peripheral neuropathy, hyperglyc-aemia, thrombocytopenia, angioedema, and urticaria
Licensed use not licensed for use in children Indication and dose
Hypertension . By mouth
Child 1 month–12 yearsinitially 100–200 micr-ograms/kg once daily; if necessary increase at intervals of 1–2 weeks up to 400 micrograms/kg once daily; max. 10 mg once daily
Child 12–18 yearsinitially 5 mg once daily; if necessary increase at intervals of 1–2 weeks to max. 10 mg once daily
Administration Tablets may be dispersed in water NoteTablets from various suppliers may contain different salts (e.g. amlodipine besilate, amlodipine maleate, and amlodipine mesilate) but the strength is expressed in terms of amlodipine (base); tablets containing different salts are considered interchangeable
Amlodipine(Non-proprietary)A
Tablets, amlodipine (as maleate or as mesilate) 5 mg, net price 28-tab pack = £1.12; 10 mg, 28-tab pack = £1.29
Brands include Amlostinc
Istinc(Pfizer)A
Tablets, amlodipine (as besilate) 5 mg, net price 28-tab pack = £13.04; 10 mg, 28-28-tab pack = £19.47 Extemporaneous formulations available see Extemporaneous Preparations, p. 8
DILTIAZEM HYDROCHLORIDE
Cautions heart failure or significantly impaired left ventricular function, bradycardia (avoid if severe), first degree AV block, or prolonged PR interval;interactions: Appendix 1 (calcium-channel blockers)
Hepatic impairment reduce dose Renal impairment start with smaller dose Breast-feeding significant amount present in milk—no evidence of harm but avoid unless no safer alternative
Contra-indications severe bradycardia, left ventricular failure with pulmonary congestion, second- or third-degree AV block (unless pace-maker fitted), sick sinus syndrome, acute por-phyria (but see section 9.8.2)
Pregnancy avoid
Side-effects bradycardia, sino-atrial block, AV block, palpitation, dizziness, hypotension, malaise, asthenia, headache, hot flushes, gastro-intestinal disturbances, oedema (notably of ankles); rarely rashes (including erythema multi-forme and exfoliative dermatitis), photosensit-ivity; hepatitis, gynaecomastia, gum hyperplasia, extrapyramidal symptoms, depression reported
Licensed use not licensed for use in children Indication and dose
Raynaud’s syndrome . By mouth
Child 12–18 years30–60 mg 2–3 times daily
Standard formulations
NoteThese formulations are licensed as generics and there is no requirement for brand name dispensing. Although their means of formulation has called for the strict designation
‘modified-release’ their duration of action corresponds to that of tablets requiring administration more frequently
Diltiazem(Non-proprietary)A
Tablets, m/r (but see note above), diltiazem hydrochloride 60 mg, net price 84 = £3.34.
Label: 25 Brands include Optilc
Tildiemc(Sanofi-Synthelabo)A
Tablets, m/r (but see note above), off-white, dilti-azem hydrochloride 60 mg, net price 90-tab pack =
£8.28. Label: 25
NICARDIPINE HYDROCHLORIDE
Cautions congestive heart failure or significantly impaired left ventricular function; avoid grape-fruit juice (may affect metabolism);interactions:
Appendix 1 (calcium-channel blockers)
Hepatic impairment reduce dose Renal impairment start with smaller dose Pregnancy may inhibit labour; toxicity in animal studies; manufacturer advises avoid, but risk to
BNFC 2009 2.6.2 Calcium-channel blockers
137
2Cardiovascularsystem
fetus should be balanced against risk of uncon-trolled maternal hypertension
Contra-indications cardiogenic shock; advanced aortic stenosis; acute porphyria (section 9.8.2) Breast-feeding no information available—manu-facturer advises avoid
Side-effects dizziness, headache, peripheral oedema, flushing, palpitation, nausea; also gas-tro-intestinal disturbances, drowsiness, insomnia, tinnitus, hypotension, rashes, dyspnoea, paraes-thesia, frequency of micturition; thrombocytope-nia, depression and impotence reported Licensed use not licensed for use in children Indication and dose
Hypertensive crisis
. By continuous intravenous infusion Neonateinitially 500 nanograms/kg/minute, adjusted according to response; usual mainte-nance of 1–4 micrograms/kg/minute
Child 1 month–18 yearsinitially 500 nan-ograms/kg/minute, adjusted according to response; usual maintenance of 1–4 micr-ograms/kg/minute (max. 250 micrograms/
minute)
Administration for intravenous infusion, dilute to a concentration of 100 micrograms/mL with Glu-cose 5% or Sodium Chloride 0.9%; to minimise peripheral venous irritation, change site of infu-sion every 12 hours
Cardene IVcA
Injection, nicardipine 2.5 mg/mL (10-mL ampoule) Available from ‘special-order’ manufacturers or specialist importing companies, see p. 943
NIFEDIPINE
Cautions see notes above; also poor cardiac reserve; heart failure or significantly impaired left ventricular function (heart failure deterioration observed); severe hypotension; diabetes mellitus;
avoid grapefruit juice (may affect metabolism);
interactions: Appendix 1 (calcium-channel blockers)
Hepatic impairment dose reduction may be required in severe liver disease
Pregnancy may inhibit labour; manufacturer advises avoid before week 20, but risk to fetus should be balanced against risk of uncontrolled maternal hypertension; use only if other treatment options are not indicated or have failed Breast-feeding amount too small to be harmful but manufacturer advises avoid
Contra-indications cardiogenic shock; advanced aortic stenosis; acute porphyria (section 9.8.2) Side-effects gastro-intestinal disturbance;
hypo-tension, oedema, vasodilatation, palpitation;
headache, dizziness, lethargy, asthenia; less com-monly tachycardia, hypotension, syncope, chills, nasal congestion, dyspnoea, anxiety, sleep dis-turbance, vertigo, migraine, paraesthesia, tremor, polyuria, dysuria, nocturia, erectile dysfunction, epistaxis, myalgia, joint swelling, visual distur-bance, sweating, and hypersensitivity reactions (including angioedema, jaundice, pruritus, urti-caria, and rash); rarely anorexia, gum hyperplasia, mood disturbances, hyperglycaemia, male infertility, purpura, and photosensitivity reac-tions; also reported dysphagia, intestinal obstruction, intestinal ulcer, bezoar formation, gynaecomastia, agranulocytosis, and anaphylaxis Licensed use not licensed for use in children Indication and dose
Hypertensive crisis, acute angina in Kawasaki disease or progeria
. By mouth (see Administration, below) Child 1 month–18 years250–500 micrograms/
kg as a single dose
Hypertension, angina in Kawasaki disease or progeria
. By mouth
Child 1 month–12 years200–300 micrograms/
kg 3 times daily; max. 3 mg/kg daily or 90 mg daily
Child 12–18 years5–20 mg 3 times daily; max.
90 mg daily
NoteDose frequency depends on preparation used
Raynaud’s syndrome . By mouth
Child 2–18 years2.5–10 mg 2–4 times daily;
start with low doses at night and increase gra-dually to avoid postural hypotension NoteDose frequency depends on preparation used
Persistent hyperinsulinaemic hypoglycaemia see also section 6.1.4
. By mouth
Neonates100–200 micrograms/kg (max.
600 micrograms/kg) 4 times daily Administration for rapid effect in hypertensive
crisis or acute angina, use capsules or use liquid if 5- or 10-mg dose inappropriate; if liquid unavail-able, extract contents of capsule via a syringe and use immediately—cover syringe with foil to pro-tect contents from light; capsule contents may be diluted with water if necessary.
Modified-release tablets may be crushed—this may alter the release profile; crushed tablets should be administered within 30–60 seconds to avoid significant loss of potency of drug Nifedipine(Non-proprietary)A
Capsules, nifedipine 5 mg, net price 84-cap pack =
£2.84; 10 mg, 84-cap pack = £3.94 Dose
Give 3 times daily
NICARDIPINE HYDROCHLORIDE (continued)
138
2.6.2 Calcium-channel blockers BNFC 20092Cardiovascularsystem
Oral liquid, available from ‘special-order’ manu-facturers or specialist importing companies, see p. 943
Adalatc(Bayer)A
Capsules, orange, nifedipine 5 mg, net price 90-cap pack = £6.08; 10 mg, 90-cap pack = £7.74 Dose
Give 3 times daily
Modified release
NoteDifferent versions of modified-release preparations may not have the same clinical effect. To avoid confusion between these different formulations of nifedipine, prescri-bers should specify the brand to be dispensed. Modified-release formulations may not be suitable for dose titration in hepatic disease
AdalatcLA(Bayer)A
LA 20 tablets, m/r, f/c, pink, nifedipine 20 mg, net price 28-tab pack = £5.27. Label: 25
LA 30 tablets, m/r, f/c, pink, nifedipine 30 mg, net price 28-tab pack = £7.59. Label: 25
LA 60 tablets, m/r, f/c, pink, nifedipine 60 mg, net price 28-tab pack = £9.69. Label: 25
CounsellingTablet membrane may pass through gastro-intestinal tract unchanged, but being porous has no effect on efficacy
Cautionsdose form not appropriate for use in hepatic impairment or where there is a history of oesophageal or gastro-intestinal obstruction, decreased lumen diameter of the gastro-intestinal tract, or inflammatory bowel dis-ease (including Crohn’s disdis-ease)
Dose
Give once daily
AdalatcRetard(Bayer)A
Retard 10 tablets, m/r, f/c, grey-pink, nifedipine 10 mg, net price 56-tab pack = £8.50. Label: 25 Retard 20 tablets, m/r, f/c, grey-pink, nifedipine 20 mg, net price 56-tab pack = £10.20. Label: 25 Dose
Give twice daily
AdipinecMR(Chiesi)A
Tablets, m/r, nifedipine 10 mg (apricot), net price 56-tab pack = £5.96; 20 mg (pink), 56-tab pack =
£7.43. Label: 21, 25 Dose
Give twice daily
AdipinecXL(Chiesi)A
Tablets, m/r, red, nifedipine 30 mg, net price 28-tab pack = £5.89. Label: 25
Dose
Give once daily
Coracten SRc(UCB Pharma)A
Capsules, m/r, nifedipine 10 mg (grey/pink, enclosing yellow pellets), net price 60-cap pack =
£4.70; 20 mg (pink/brown, enclosing yellow pel-lets), 60-cap pack = £6.52. Label: 25
Dose
Give twice daily
Coracten XLc(UCB Pharma)A
Capsules, m/r, nifedipine 30 mg (brown), net price 28-cap pack = £5.89; 60 mg (orange), 28-cap pack
= £8.84. Label: 25 Dose
Give once daily
Fortipine LA 40c(Goldshield)A
Tablets, m/r, red, nifedipine 40 mg, net price 30-tab pack = £9.60. Label: 21, 25
Dose
Give 1–2 times daily
HypolarcRetard 20(Sandoz)A
Tablets, m/r, red, f/c, nifedipine 20 mg, net price 56-tab pack = £5.75. Label: 25
Dose
Give twice daily
NifedipresscMR(Dexcel)A
Tablets, m/r, pink, nifedipine 10 mg, net price 56-tab pack = £9.23; 20 mg, 56–56-tab pack = £10.06.
Label: 25 Dose
Give twice daily
NoteAlso available as CalchancMR
Tensipine MRc(Genus)A
Tablets, m/r, pink-grey, nifedipine 10 mg, net price 56-tab pack = £4.30; 20 mg, 56-tab pack = £5.49.
Label: 21, 25 Dose
Give twice daily
Valni XLc(Winthrop)A
Tablets, m/r, red, nifedipine 30 mg, net price 28-tab pack = £9.89; 60 mg, 28-tab pack = £14.71.
Label: 25
Cautionsdose form not appropriate for use in hepatic impairment, or where there is a history of oesophageal or gastro-intestinal obstruction, decreased lumen diameter of the gastro-intestinal tract, inflammatory bowel disease, or ileostomy after proctocolectomy
Dose
Give once daily
NIFEDIPINE (continued)
BNFC 2009 2.6.2 Calcium-channel blockers
139
2Cardiovascularsystem
NIMODIPINE
Cautions cerebral oedema or severely raised intracranial pressure; hypotension; avoid conco-mitant administration of nimodipine tablets and infusion, other calcium-channel blockers, or beta-blockers; concomitant nephrotoxic drugs; avoid grapefruit juice (may affect metabolism); inter-actions: Appendix 1 (calcium-channel blockers, alcohol (infusion only))
Hepatic impairment elimination reduced in cirrhosis—monitor blood pressure; reduce oral dose by 50% in children with severe cirrhosis Renal impairment manufacturer advises monitor renal function closely
Pregnancy manufacturer advises use only if potential benefit outweighs risks
Contra-indications acute porphyria (section 9.8.2)
Side-effects hypotension, variation in heart-rate, flushing, headache, gastro-intestinal disorders, nausea, sweating and feeling of warmth; throm-bocytopenia and ileus reported
Licensed use not licensed for use in children Indication and dose
Treatment of vasospasm following subarach-noid haemorrhageunder specialist advice only . By intravenous infusion
Child 1 month–12 yearsinitially 15 micr-ograms/kg/hour (max. 500 micrograms/hour) or initially 7.5 micrograms/kg/hour if blood pressure unstable; increase after 2 hours to 30 micrograms/kg/hour (max. 2 mg/hour) if no severe decrease in blood pressure; continue for at least 5 days (max. 14 days)
Child 12–18 yearsinitially 500 micrograms/
hour (up to 1 mg/hour if body-weight over 70 kg and blood pressure stable), increase after 2 hours to 1–2 mg/hour if no severe fall in blood pressure; continue for at least 5 days (max. 14 days)
Prevention of vasospasm following subarach-noid haemorrhage
. By mouth
Child 1 month–18 years0.9–1.2 mg/kg (max.
60 mg) 6 times daily, starting within 4 days of haemorrhage and continued for 21 days Administration for continuous intravenous infusion,
administer undiluted via a Y-piece on a central venous catheter connected to a running infusion of Glucose 5%, Sodium Chloride 0.9%, or Com-pound Sodium Lactate; not to be added to an infusion container; incompatible with polyvinyl chloride giving sets or containers; protect infu-sion from light.
For administration by mouth, tablets may be crushed or halved but are light sensitive—
administer immediately
Nimotopc(Bayer)A
Tablets, yellow, f/c, nimodipine 30 mg, net price 100-tab pack = £38.85
Intravenous infusion, nimodipine 200 micrograms/
mL; also contains ethanol 20% and macrogol ‘400’
17%. Net price 50-mL vial (with polyethylene infusion catheter) = £13.24
NotePolyethylene, polypropylene, or glass apparatus should be used; PVC should be avoided
VERAPAMIL HYDROCHLORIDE
Cautions first-degree AV block; patients taking beta-blockers (important: see below); avoid grapefruit juice (may affect metabolism); inter-actions: Appendix 1 (calcium-channel blockers) Verapamil and beta-blockersVerapamil injection should not be given to patients recently treated with beta-blockers because of the risk of hypotension and asystole.
The suggestion that when verapamil injection has been given first, an interval of 30 minutes before giving a beta-blocker is sufficient has not been confirmed.
It may also be hazardous to give verapamil and a beta-blocker together by mouth (should only be contemplated if myocardial function well preserved).
Hepatic impairment oral dose may need to be reduced
Pregnancy may reduce uterine blood flow with fetal hypoxia; manufacturer advises avoid during first trimester unless absolutely necessary; may inhibit labour
Breast-feeding amount too small to be harmful Contra-indications hypotension, bradycardia,
second- and third-degree AV block, sick sinus syndrome, cardiogenic shock, sino-atrial block;
history of heart failure or significantly impaired left ventricular function, even if controlled by therapy; atrial flutter or fibrillation complicating syndromes associated with accessory conducting pathways (e.g. Wolff-Parkinson-White syndrome); acute porphyria (section 9.8.2)
Side-effects constipation; less commonly nausea, vomiting, flushing, headache, dizziness, fatigue, ankle oedema; rarely allergic reactions (erythe-ma, pruritus, urticaria, angioede(erythe-ma, Stevens-Johnson syndrome); myalgia, arthralgia, paraes-thesia, erythromelalgia; increased prolactin con-centration; gynaecomastia and gingival hyper-plasia after long-term treatment; after intravenous administration or high doses, hypo-tension, heart failure, bradycardia, heart block, and asystole; hypersensitivity reactions involving reversibly raised liver function tests
Licensed use Modified release preparation not licensed for use in children
Indication and dose
Hypertension, prophylaxis of supraventricular arrhythmiasunder specialist advice only . By mouth
Child 1–2 years20 mg 2–3 times daily Child 2–18 years40–120 mg 2–3 times daily
140
2.6.2 Calcium-channel blockers BNFC 20092Cardiovascularsystem
Treatment of supraventricular arrhythmias . By intravenous injection over 2–3 minutes
(with ECG and blood-pressure monitoring and under specialist advice)
Child 1–18 years100–300 micrograms/kg (max. 5 mg) as a single dose, repeated after 30 minutes if necessary
Administration for intravenous injection, may be diluted with Glucose 5% or Sodium Chloride 0.9%; incompatible with solutions of pH greater than 6
Verapamil(Non-proprietary)A
Tablets, coated, verapamil hydrochloride 40 mg, net price 84-tab pack = £1.54; 80 mg, 84-tab pack =
£1.68; 120 mg, 28-tab pack = £1.41; 160 mg, 56-tab pack = £20.23
Oral solution, verapamil hydrochloride 40 mg/
5 mL, net price 150 mL = £36.90 Brands include Zolverac Cordiloxc(Dexcel)A
Tablets, yellow, f/c, verapamil hydrochloride 40 mg, net price 84-tab pack = £1.50; 80 mg, 84-tab pack = £2.05; 120 mg, 28-tab pack = £1.15; 160 mg, 56-tab pack = £2.80
Injection, verapamil hydrochloride 2.5 mg/mL, net price 2-mL amp = £1.11
Securonc(Abbott)A
Injection, verapamil hydrochloride 2.5 mg/mL, net price 2-mL amp = £1.08
Extemporaneous formulations available see Extemporaneous Preparations, p. 8
Modified release Half Securon SRc(Abbott)A
Tablets, m/r, f/c, verapamil hydrochloride 120 mg, net price 28-tab pack = £7.50. Label: 25 Dose
Give once daily (doses above 240 mg daily, give 2–3 times daily)
Securon SRc(Abbott)A
Tablets, m/r, pale green, f/c, scored, verapamil hydrochloride 240 mg, net price 28-tab pack =
£6.29. Label: 25 Dose
Give once daily (doses above 240 mg daily, give 2–3 times daily)
Univerc(Cephalon)A
Capsules, m/r, verapamil hydrochloride 120 mg (yellow/dark blue), net price 28-cap pack = £7.51;
180 mg (yellow), 56-cap pack = £18.15; 240 mg (yellow/dark blue), 28-cap pack = £12.24. Label: 25 Dose
Give once daily
Verapress MRc(Dexcel)A
Tablets, m/r, pale green, f/c, verapamil hydro-chloride 240 mg, net price 28-tab pack = £9.90.
Label: 25 Dose
Give 1–2 times daily
NoteAlso available as CordiloxcMR VertabcSR 240(Chiesi)A
Tablets, m/r, pale green, f/c, scored, verapamil hydrochloride 240 mg, net price 28-tab pack =
£8.63. Label: 25 Dose
Give 1–2 times daily