1.1 Cardiac glycosides

72 2.1.1 Cardiac glycosides

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2.1.2 Phosphodiesterase inhibitors

Digoxin-specific antibody

nance therapy (not immediately after myocardial infarction); acute heart failure, including low output

Digoxin-specific antibody fragments are indicated for states following heart surgery the treatment of known or strongly suspected digoxin or

Cautions see under Enoximone; also correct hypo- digitoxin overdosage, in situations where measures

kalaemia; renal impairment (Appendix 3); pregnancy beyond the withdrawal of the cardiac glycoside and

(Appendix 4); breast-feeding (Appendix 5) correction of any electrolyte abnormalities are felt to

be necessary (see also notes above). Side-effects ectopic beats, ventricular tachycardia,

supraventricular arrhythmias (more likely in patients Digibind c (GSK) A with pre-existing arrhythmias), hypotension; head-

Injection , powder for preparation of infusion, digoxin- ache; less commonly ventricular fibrillation, chest pain, specific antibody fragments (F(ab)) 38 mg, net price

tremor, hypokalaemia, thrombocytopenia; very rarely per vial = £93.97 (hosp. and poisons centres only)

bronchospasm, anaphylaxis, and rash Dose consult product literature

Dose . By intravenous injection over 10 minutes, either

undiluted or diluted before use, 50 micrograms/kg followed by intravenous infusion at a rate of 375–

2.1.2 Phosphodiesterase

750 nanograms/kg/minute, usually for up to

inhibitors

12 hours following surgery or for 48–72 hours in congestive heart failure; max. daily dose 1.13 mg/kg

Primacor Enoximone and milrinone are selective phosphodi- c (Sanofi-Aventis) A esterase inhibitors which exert most of their effect on

Injection , milrinone (as lactate) 1 mg/mL, net price the myocardium. Sustained haemodynamic benefit has

10-mL amp = £16.61 been observed after administration, but there is no

evidence of any beneficial effect on survival.

2 ENOXIMONE

2.2 Diuretics

ardiov C

Indications congestive heart failure where cardiac

output reduced and filling pressures increased

2.2.1 Thiazides and related diuretics

Cautions heart failure associated with hypertrophic

2.2.2 Loop diuretics

ascular

cardiomyopathy, stenotic or obstructive valvular dis-

2.2.3 Potassium-sparing diuretics and

ease or other outlet obstruction; monitor blood pres-

aldosterone antagonists

sure, heart rate, ECG, central venous pressure, fluid and electrolyte status, renal function, platelet count,

2.2.4 Potassium-sparing diuretics with syst

hepatic enzymes; avoid extravasation; renal impair-

other diuretics

ment (Appendix 3); pregnancy (Appendix 4); breast-

2.2.5 Osmotic diuretics em

feeding (Appendix 5) Side-effects

2.2.6 Mercurial diuretics

ectopic beats; less frequently ventricular tachycardia or supraventricular arrhythmias (more

2.2.7 Carbonic anhydrase inhibitors

likely in patients with pre-existing arrhythmias);

2.2.8 Diuretics with potassium

hypotension; also headache, insomnia, nausea and vomiting, diarrhoea; occasionally, chills, oliguria,

Thiazides (section 2.2.1) are used to relieve oedema fever, urinary retention; upper and lower limb pain

due to chronic heart failure (section 2.5.5) and, in lower Dose

doses, to reduce blood pressure. . By slow intravenous injection (rate not exceeding

Loop diuretics (section 2.2.2) are used in pulmonary

12.5 mg/minute), diluted before use, initially 0.5– oedema due to left ventricular failure and in patients

1 mg/kg, then 500 micrograms/kg every 30 min- with chronic heart failure (section 2.5.5). utes until satisfactory response or total of 3 mg/kg

Combination diuretic therapy may be effective in given; maintenance, initial dose of up to 3 mg/kg

patients with oedema resistant to treatment with one may be repeated every 3–6 hours as required

diuretic. Vigorous diuresis, particularly with loop diur- . By intravenous infusion , initially 90 micrograms/

etics, may induce acute hypotension; rapid reduction of kg/minute over 10–30 minutes, followed by con-

plasma volume should be avoided. tinuous or intermittent infusion of 5–20 micr- ograms/kg/minute

Elderly Lower initial doses of diuretics should be used Total dose over 24 hours should not usually exceed

in the elderly because they are particularly susceptible

24 mg/kg to the side-effects. The dose should then be adjusted Perfan c (INCA-Pharm) A according to renal function. Diuretics should not be

Injection , enoximone 5 mg/mL. For dilution before used continuously on a long-term basis to treat simple use. Net price 20-mL amp = £15.02

gravitational oedema (which will usually respond to

Excipients include alcohol, propylene glycol

increased movement, raising the legs, and support Note Plastic apparatus should be used; crystal formation if

stockings).

glass used

Potassium loss Hypokalaemia may occur with both

MILRINONE

thiazide and loop diuretics. The risk of hypokalaemia depends on the duration of action as well as the potency

Indications short-term treatment of severe congestive and is thus greater with thiazides than with an equipo- heart failure unresponsive to conventional mainte-

tent dose of a loop diuretic.

Hypokalaemia is dangerous in severe cardiovascular disease and in patients also being treated with cardiac glycosides. Often the use of potassium-sparing diuretics (section 2.2.3) avoids the need to take potassium sup- plements.

In hepatic failure, hypokalaemia caused by diuretics can precipitate encephalopathy, particularly in alcoholic cirrhosis; diuretics may also increase the risk of hypo- magnesaemia in alcoholic cirrhosis, leading to arrhyth- mias. Spironolactone, a potassium-sparing diuretic (sec- tion 2.2.3), is chosen for oedema arising from cirrhosis of the liver.

Potassium supplements or potassium-sparing diuretics are seldom necessary when thiazides are used in the routine treatment of hypertension (see also section 9.2.1.1).

2.2.1 Thiazides and related diuretics

Thiazides and related compounds are moderately potent diuretics; they inhibit sodium reabsorption at the beginning of the distal convoluted tubule. They act within 1 to 2 hours of oral administration and most have

a duration of action of 12 to 24 hours; they are usually administered early in the day so that the diuresis does not interfere with sleep.

In the management of hypertension a low dose of a thiazide, e.g. bendroflumethiazide (bendrofluazide)

2.5 mg daily, produces a maximal or near-maximal blood pressure lowering effect, with very little biochem- ical disturbance. Higher doses cause more marked changes in plasma potassium, sodium, uric acid, glu- cose, and lipids, with little advantage in blood pressure control. For reference to the use of thiazides in chronic heart failure see section 2.5.5.

Bendroflumethiazide (bendrofluazide) is widely used for mild or moderate heart failure and for hyper- tension—alone in the treatment of mild hypertension or with other drugs in more severe hypertension.

Chlortalidone (chlorthalidone), a thiazide-related com- pound, has a longer duration of action than the thiazides and may be given on alternate days to control oedema. It is also useful if acute retention is liable to be pre- cipitated by a more rapid diuresis or if patients dislike the altered pattern of micturition caused by other diur- etics.

Other thiazide diuretics (including benzthiazide, clop- amide, cyclopenthiazide, hydrochlorothiazide, and hydroflumethiazide) do not offer any significant advan- tage over bendroflumethiazide or chlortalidone.

Metolazone is particularly effective when combined with a loop diuretic (even in renal failure); profound diuresis can occur and the patient should therefore be monitored carefully.

Xipamide and indapamide are chemically related to chlortalidone. Indapamide is claimed to lower blood pressure with less metabolic disturbance, particularly less aggravation of diabetes mellitus.

Cautions See also section 2.2. Thiazides and related diuretics can exacerbate diabetes, gout, and systemic lupus erythematosus. Electrolytes should be monitored,

particularly with high doses, long-term use, or in renal impairment. Thiazides and related diuretics should also

be used with caution in nephrotic syndrome, hyperaldo- steronism, malnourishment, hepatic impairment (avoid if severe; Appendix 2), renal impairment (Appendix 3), pregnancy (Appendix 4), and breast-feeding (Appendix 5); interactions: Appendix 1 (diuretics)

Contra-indications Thiazides and related diuretics should be avoided in refractory hypokalaemia, hypo- natraemia and hypercalcaemia, symptomatic hyperuric- aemia, and Addison’s disease.

Side-effects Side-effects of thiazides and related diur- etics include mild gastro-intestinal disturbances, postur- al hypotension, altered plasma lipid concentrations, metabolic and electrolyte disturbances including hypo- kalaemia (see also notes above), hyponatraemia, hypo- magnesaemia, hypercalcaemia, hyperglycaemia, hypo- chloraemic alkalosis, hyperuricaemia, and gout. Less common side-effects include blood disorders such as agranulocytosis, leucopenia, and thrombocytopenia, and impotence. Pancreatitis, intrahepatic cholestasis, cardiac arrhythmias, headache, dizziness, paraesthesia, visual disturbances, and hypersensitivity reactions (including pneumonitis, pulmonary oedema, photo- sensitivity, and severe skin reactions) have also been reported.