DIURETICS
For more information, see Chapter 28 for use of diuretics in hypertension and Chapter 36, for mechanisms, adverse effects and pharmacokinetics.
Use in heart failure
Chronic heart failure: a diuretic is used to control symptomatic oedema and dyspnoea in patients with heart failure. A thiazide (see Chapters 28 and 36) may be adequate in very mild cases, but a loop diuretic (e.g. furosemide) is usually needed. Unlike several of the drugs described below, there has been no ran- domized controlled trial investigating the influence of loop diuretics on survival in heart failure, but the other treatments were added to a loop diuretic and this is usually the starting point of drug treatment. Spironolactoneimproves survival in patients with cardiac failure and counters diuretic-induced hypokalaemia. Diuretic-induced hypokalaemia increases the toxicity of digoxin. Conversely, spironolactoneand other K-retaining diuretics (e.g. amiloride,triamterene) can cause severe hyperkalaemia, especially if given with ACEI or sartans (see below) to patients with renal impairment. It is therefore important to monitor plasma Kduring treatment with all diuretic therapy.
Acute heart failure: acute pulmonary oedema is treated by sit- ting the patient upright, administering oxygen (FiO2, 28–40%) and intravenous furosemidewhich is often effective within a matter of minutes. Intravenous morphine(Chapter 25) is also useful. A slow intravenous infusion of furosemideby syringe pump may be useful in resistant cases. Once the acute situation
has resolved the situation is re-assessed and drugs used for chronic heart failure (see below), including oral diuretics, are usually indicated.
ANGIOTENSIN-CONVERTING ENZYME INHIBITORS For the mechanism of action and other aspects of angiotensin- converting enzyme inhibitors, see Chapter 28.
Use in heart failure
The first approach shown to reduce mortality in heart failure was combined hydralazineandnitratetherapy (see below).
Soon after, an angiotensin-converting enzyme inhibitor (ACEI) (captopril) was shown to do better. Other ACEI were also shown to improve survival and ACEI treatment for heart fail- ure was rapidly adopted. When symptoms are mild, diuretics can be temporarily discontinued a day or two before starting an ACEI, reducing the likelihood of first-dose hypotension.
In these circumstances, treatment with an ACE inhibitor can be started as an out-patient, as for hypertension (see Chapter 28).
A small starting dose is used and the first dose is taken last thing before retiring at night, with advice to sit on the side of the bed before standing if the patient needs to get up in the night. The dose is gradually increased to one that improves symptoms (and survival) with careful monitoring of blood pressure. Serum potassium and creatinine are checked after one to two weeks. Hypotension is more of a problem when starting treatment in heart failure patients than when treating hypertension, especially with short-acting drugs (e.g. capto- pril). Not only is the blood pressure lower to start with, but concentrations of circulating renin are high and increased fur- ther by diuretics. ACEI cause ‘first-dose’ hypotension most severely in patients with the greatest activation of the renin–angiotensin system. These are consequently those most likely to benefit from an ACEI in the long term. Long-acting drugs (e.g. ramipril, trandolapril) cause less first-dose hypotension and can be given once daily. ACEI are usually well tolerated during chronic treatment, although dry cough is common and occasionally unacceptable (see Chapter 28 for other adverse effects). Important drug–drug interactions can occur with NSAIDs (Chapter 26), which may cause renal failure and severe hyperkalaemia, especially in heart failure patients treated with ACEI.
ANGIOTENSIC RECEPTOR ANTAGONISTS, SARTANS See Chapter 28 for the mechanism of action.
Use in heart failure
As in hypertension, the pharmacodynamics of sartans are similar to those of ACEI apart from a lower incidence of some adverse effects, including, particularly, dry cough. Several of these drugs (e.g. candesartan,valsartan) have been shown to pro- long life in randomized controlled trials, the magnitude of the effect being similar to ACEI. It is possible that they have some additive effect when combined with ACEI, but this is hard to prove at doses that are not supramaximal. Because of the greater experience with ACEI and the lower cost, many physi- cians prefer to use an ACEI, unless this is not tolerated.
DRUGS FORHEARTFAILURE 213
Precautions in terms of first-dose hypotension and monitoring creatinine and electrolytes are similar to those for ACEI.
β-ADRENOCEPTOR ANTAGONISTS
For more information, see Chapter 28 for use in hypertension, Chapter 29 for use in ischaemic heart disease and Chapter 32 for use as antidysrhythmic drugs.
Classification of β-adrenoceptor antagonists
Adrenoceptors are classified as αorβ, with a further subdivision of the latter into β1, mainly in the heart, β2which are present in, for example, bronchioles and β3, which mediate metabolic effects in brown fat.
Cardioselective beta-blockers (e.g. atenolol, metoprolol) inhibitβ1-receptors relatively selectively, but are nonetheless hazardous for patients with asthma.
Some beta-blockers (e.g. oxprenolol) are partial agonists and possess intrinsic sympathomimetic activity. This is seldom important in practice.
Vasodilating beta-blockers include drugs (e.g. labetolol, carvedilol) with additional α-blocking activity. Celiprololhas additional agonist activity at β2-receptors. Nebivololreleases endothelium-derived nitric oxide, as well as being a highly selectiveβ1-adrenoceptor blocker.
Use in heart failure
Beta-blockers are negative inotropes and so intuitively would be expected to worsen heart failure. There is, however, a rationale for their use in terms of antagonizing counter- regulatory sympathetic activation and several randomized controlled trials have demonstrated improved survival when aβ-adrenoceptor antagonist is added to other drugs, includ- ing an ACEI. Several β-adrenoceptor antagonists have been shown to be of benefit including bisoprolol,metoprololand carvedilol.Bisoprolol andmetoprololare cardioselective β1
antagonists, whereas carvedilolis non-selective and has addi- tionalαantagonist properties. Carvedilolmay be more effec- tive than bisoprololin heart failure, but is less well tolerated because of postural hypotension. Treatment is started with a low dose when the patient is stable and the patient reviewed regularly at short intervals (e.g. every two weeks or more fre- quently if needed), often by a heart failure nurse, with dose titration as tolerated.
Adverse effects
• IntoleranceFatigue and cold extremities are common and dose related. Erectile dysfunction occurs, but is less common than with thiazide diuretics. Central nervous system (CNS) effects (e.g. vivid dreams) can occur.
• Airways obstructionβ-adrenoceptor antagonists
predispose to severe airways obstruction in patients with pre-existing obstructive airways disease, especially asthma.
• Peripheral vascular disease and vasospasmβ-adrenoceptor antagonists worsen claudication in patients with symptomatic atheromatous peripheral vascular disease and worsen Raynaud’s phenomenon.
• Hypoglycaemiaβ-adrenoceptor antagonists mask symptoms of hypoglycaemia, and slow the rate of recovery from it, because adrenaline stimulates gluconeogenesis via β2-adrenoceptors.
• Heart block.
ALDOSTERONE ANTAGONISTS For more information, see Chapter 36.
Spironolactone(or the newer expensive agent, eplerenone), when added to conventional therapy with loop diuretic, ACEI and β-adrenoceptor antagonist, further improves survival.
Concerns regarding hyperkalaemia in such patients may have been overstated, at least provided patients with appreciably impaired renal function are excluded from such treatment.
COMBINED HYDRALAZINE WITH ORGANIC NITRATE THERAPY
There is renewed interest in combined therapy with hydralazine(Chapter 28) and a long-acting nitrate(Chapter 29).
The pharmacologic basis for investigating this was that hydralazine reduced afterload and the nitrate reduced pre- load. As mentioned above, this improved survival in one ran- domized controlled trial, but performed less well overall in a direct comparison with an ACEI. However, a subgroup analy- sis suggested that African-American patients did better with the hydralazine/nitrate combination, whereas Caucasians did better with ACEI. This observation led to a further study in African-Americans which confirmed the efficacy of hydralazine–nitratetreatment. It is now often used for patients of African origin. Hopefully, genetic testing will further improve the targeting of appropriate therapy (‘personalized medicine’) in future.
DIGOXIN
For more information on the use of digoxin, refer to Chapter 32.
William Withering described an extract of foxglove as a
‘cure’ for ‘dropsy’ (congestive cardiac failure) in 1785. Digoxin remains useful for symptoms.
Use in heart failure
Rapid atrial fibrillation can worsen heart failure and digoxin can be used to control the ventricular response, which it does by stimulating vagal efferents to the heart (Chapter 32). Its positive inotropic action is an added benefit. Heart failure patients in sinus rhythm who remain symptomatic despite optimal treatment with life-prolonging medications also ben- efit. Addition of digoxinto diuretics and ACEI reduces hospi- talization and improves symptoms, without prolonging life. It is usually given orally, but can be given i.v. if a rapid effect is required. Since the half-life is approximately 30–48 hours, repeated administration of a once-daily maintenance dose results in a plateau concentration in about five to ten days. The dose may be adjusted based on plasma concentration determinations once steady state has been reached (Chapter 8). Such determi- nations are also useful if toxicity is suspected (e.g. because of nausea, bradycardia or ECG changes). In urgent situations, a 214 HEART FAILURE
therapeutic plasma concentration can be obtained more rap- idly by administering a loading dose (Chapter 3).
Mechanism of action
Digoxin inhibits Na/K adenosine triphosphatase (Na/K ATPase). This causes accumulation of intracellular Na and increased intracellular [Ca2] concentrations via reduced Na/Ca2exchange. The rise in availability of intracellular Ca2 accounts for the positive inotropic effect of digoxin. Excessive inhibition of Na/KATPase causes numerous non-cardiac as well as cardiac (dysrhythmogenic) toxic effects. Ventricular slowing results from increased vagal activity on the AV node.
Slowing of ventricular rate improves cardiac output in patients with atrial fibrillation by improving ventricular filling during diastole. Clinical progress is assessed by measuring heart rate (at the apex): apical rates of 70–80 per minute can be achieved at rest. Unfortunately, since vagal activity is suppressed during exercise (when heart rate is controlled by sympathetic acti- vation), control of rate during exercise is not usually achievable.
Pharmacokinetics
Approximately 80% is excreted unchanged in the urine in patients with normal renal function with a half-life of 30–48 hours. It is eliminated mainly by glomerular filtration, although small amounts are secreted and reabsorbed. A small amount (5–10%) undergoes metabolism to inactive products or excretion via the bile and elimination in faeces. The proportion eliminated by these non-renal clearance mechanisms increases in patients with renal impairment, being 100% in anephric patients, in whom the half-life is approximately 4.5 days.
Blood for digoxinconcentration determination should be sampled more than six hours after an oral dose or immedi- ately before the next dose is due (trough level) to allow its tis- sue distribution to be complete. The usual therapeutic range is 1–2 ng/mL, although toxicity can occur at concentrations of less than 1.5 ng/mL in some individuals.
Drug interactions
Digoxinhas a steep dose–response curve and a narrow thera- peutic range, and clinically important interactions are com- mon (see Chapters 13 and 32). Pharmacokinetic interactions withdigoxininclude combined pharmacokinetic effects involv- ing displacement from tissue-binding sites and reduced renal elimination (e.g. digoxintoxicity due to concurrent treatment withamiodaroneorquinidine).
Pharmacodynamic interactions are also important. In particular, drugs that cause hypokalaemia (e.g. diuretics, β-agonists, glucocorticoids) predispose to digoxintoxicity by increasing its binding to (and effect on) Na/KATPase.
OTHER POSITIVE INOTROPES
Positive inotropes for intravenous infusion (e.g. adrenaline) have a place in treating acute shock, but not for chronic heart failure. Orally active positive inotropes other than digoxin include phosphodiesterase inhibitors, e.g. milrinone. These increase cardiac output and may bring some symptomatic benefit, but they worsen survival.
DRUGS FORHEARTFAILURE 215
Key points
Heart failure: pathophysiology and principles of therapeutics
• Heart failure has diverse aetiologies; ischaemic and idiopathic cardiomyopathy are especially important.
• Neurohumoral activation (e.g. of sympathetic and renin–angiotensin systems) may have adverse consequences.
• Treatment is sometimes specific (e.g. valve replacement), but is also directed generally at:
– reducing preload (diuretics, nitrates, ACE inhibitors and sartans);
– reducing afterload (ACE inhibitors and hydralazine);
– increasing contractility (digoxin);
– reducing heart rate (rapid rates do not permit optimal filling; rapid atrial fibrillation is slowed by digoxin).
Treatment of chronic heart failure
• Dietary salt should be restricted.
• Drugs that improve survival usually reduce preload, afterload or heart rate by interrupting counter- regulatory hormonal mechanisms. They comprise:
– diuretics (e.g. furosemide);
– ACEI (e.g. captopril acutely, then ramipril, trolandopril);
– sartans (e.g. candesartan);
– β-adrenoceptor antagonists (e.g. bisoprolol, carvedilol);
– aldosterone antagonists (e.g. spironolactone);
– hydralazine plus an organic nitrate in African- American patients.
• Digoxin does not influence survival, but can improve symptoms.
• Other positive inotropes (e.g. phosphodiesterase inhibitors, milrinone) worsen survival.
Case history
A 62-year-old physician has developed symptoms of chronic congestive cardiac failure in the setting of treated essential hypertension. He had had an angioplasty to an isolated atheromatous lesion in the left anterior descending coron- ary artery two years previously, since when he had not had angina. He also has a past history of gout. He is taking ben- droflumethiazide for his hypertension and takes meclofena- mate regularly to prevent recurrences of his gout. He disregarded his cardiologist’s advice to take aspirin because he was already taking another cyclo-oxygenase inhibitor (in the form of the meclofenamate). On examination, he has a regular pulse of 88 beats/minute, blood pressure of 160/98 mmHg, a 4–5 cm raised jugular venous pressure, mild pretib- ial oedema and cardiomegaly. Routine biochemistry tests are unremarkable except for a serum urate level of 0.76 mmol/L, a total cholesterol concentration of 6.5 mmol/L, a trigly- ceride concentration of 5.2 mmol/L and γ-glutamyltranspep- tidase twice the upper limit of normal. An echocardiogram shows a diffusely poorly contracting myocardium.
Question
Decide whether each of the following would be appropri- ate as immediate measures.
(a) Digitalization
(b) Intravenous furosemide
(c) A detailed personal/social history
(d) Substitution of allopurinol for the meclofenamate (e) Hold the bendroflumethiazide temporarily and start
an ACE inhibitor (f) Start bezafibrate.
Answer
(a) False (b) False (c) True (d) False (e) True (f) False.
Comment
The aetiology of the heart failure in this case is uncertain.
Although ischaemia and hypertension may be playing a part, the diffusely poorly contracting myocardium suggests the possibility of diffuse cardiomyopathy, and the raised γ-glutamyltranspeptidase and triglyceride levels point to the possibility of alcohol excess. If this is the case, and if it is corrected, this could improve the blood pressure, dyslipi- daemia and gout, as well as cardiac function. In the long term, allopurinol should be substituted for the NSAID, but if done immediately this is likely to precipitate an acute attack. Aspirin should be taken (for its antiplatelet effect, which may not be shared by all other NSAIDs). Treatment with a fibrate would be useful for this pattern of dyslipi- daemia, but only after establishing that it was not alcohol- induced.
216 HEART FAILURE
FURTHER READING
Brater DC. Diuretic therapy. New England Journal of Medicine1998;339:
387–95.
Cohn JN. The management of chronic heart failure. New England Journal of Medicine1996;335: 490–8.
Frishman WH. Carvedilol. New England Journal of Medicine1998;339:
1759–65.
Jessup M, Brozena S. 2003 Medical progress: heart failure. New England Journal of Medicine2003;348: 2007–18.
McMurray JJV, Pfeffer MA. Heart failure. Lancet2005;365: 1877–89.
Nabel EG. Cardiovascular disease. New England Journal of Medicine 2003;349: 60–72.
Palmer BF. Managing hyperkalemia caused by inhibitors of the renin–angiotensin–aldosterone system. New England Journal of Medicine2004;351: 585–92.
Pfeffer MA, Stevenson LW. β-Adrenergic blockers and survival in heart failure. New England Journal of Medicine1996;334: 1396–7.
Schrier RW, Abraham WT. Mechanisms of disease – hormones and hemodynamics in heart failure. New England Journal of Medicine 1999;341: 577–85.
Weber KT. Mechanisms of disease – aldosterone in congestive heart failure. New England Journal of Medicine2001;345: 1689–97.
●Common dysrhythmias 217
●General principles of management 218
●Classification of anti-dysrhythmic drugs 218
●Cardiopulmonary resuscitation and cardiac arrest:
basic and advanced life support 218
●Treatment of other specific dysrhythmias 221
●Selected anti-dysrhythmic drugs 223
CHAPTER 32