Drug treatment of cardiovascular disorders

Chapter 12 Drug treatment of cardiovascular disorders





INTRODUCTION


Diseases of the heart and circulatory system are the main cause of death in the UK and accounted for just over 216 000 deaths in 2004 (British Heart Foundation 2006). More than one in three people (37%) die from cardiovascular disease (CVD). The main forms of CVD are coronary heart disease (CHD) and stroke. About half (49%) of all deaths from CVD are from CHD, and more than a quarter (28%) are from stroke. Around one in five men and one in six women die from CHD. Death rates from CVD have been falling in the UK since the early 1970s. For people under 75 years, they have fallen by 38% in the past 10 years. Just under one in three of all deaths under 65 years resulting from social class inequalities is due to CHD. Death rates from CHD are highest in Scotland and the North of England, lowest in the South of England, and intermediate in Wales and Northern Ireland. The premature death rate for men living in Scotland is 57% higher than in the South West of England, and 103% higher for women.


The incidence of myocardial infarction (MI) varies around the UK, but on average the incidence rate for men aged between 30 and 69 is about 600 per 100 000 and for women is about 200 per 100 000. Using data from Morbidity Statistics from General Practice, the British Heart Foundation estimates that there are about 183 000 new cases of angina in all men living in the UK and about 161 000 in women. Studies of the incidence of heart failure are scarce, and different studies use different methods, particularly for diagnosing the condition. The Hillingdon Heart Failure Study found a crude incidence rate of 140 per 100 000 for men and 120 per 100 000 for women. Data from the 2003 Health Survey for England suggest that the prevalence of CHD in England is 7.4% in men and 4.5% in women. Prevalence rates increase with age, with around one in four men and one in five women aged 75 years and above living with CHD. It is estimated that there are just over 1.5 million men living in the UK who have had CVD (either angina or heart attack) and about 1.1 million women, giving a total of around 2.6 million.



ANATOMY AND PHYSIOLOGY



THE HEART


The heart lies between the lungs, behind the lower sternum, in front of the oesophagus and above the diaphragm, on which it rests. It is roughly conical in shape, with a base and an apex. It consists of four chambers: the right and left atria above, and the right and left ventricles below. The atria and ventricles are separated by, on the right side, the tricuspid valve and, on the left side, the mitral valve. The walls of the heart have three layers: outermost, a fibrous envelope called the pericardium; in the middle, a thick muscle known as the myocardium; and the innermost layer, a smooth lining called the endocardium (Fig. 12.1).



Venous blood returns from various parts of the body to the heart. It enters the right atrium via the superior and inferior venae cavae and passes through the tricuspid valve to the right ventricle. The right ventricle pumps the blood to the lungs via the pulmonary artery. In the lungs, the blood is oxygenated and carbon dioxide is removed. The blood then returns via the four pulmonary veins into the left atrium, from where it passes through the mitral valve into the left ventricle. The left ventricle pumps the oxygenated blood through the aortic valve into the aorta and out into the body.


The heart derives its own blood supply from the two main coronary arteries that originate from the aorta just above the aortic valve.


The activity of the heart is rhythmical, consisting of contraction (systole) and relaxation (diastole). The impulse to contract is generated by a microscopic area of specialised cardiac muscle known as the sinoatrial (SA) node, situated at the junction of the superior vena cava and the right atrium. The wave of excitation spreads throughout the muscle layer of both atria, causing them to contract, forcing blood into the ventricles. The impulse is picked up by another small mass of specialised cardiac muscle called the atrioventricular (AV) node, situated in the septal walls of the right atrium. It is relayed by the fibres of Purkinje down the bundle of His and along the right and left branches, causing the ventricles to contract and drive blood into the pulmonary artery and the aorta. The heart then relaxes, refills with venous blood, and awaits the next stimulus for contraction. Although the heart initiates its own impulse to contract, the fine adjustments to its activity required to meet the body’s constantly changing needs derive from the autonomic nervous system (see Ch. 9). Sympathetic innervation increases the heart rate, and parasympathetic innervation slows the heart rate.


The SA node is normally the pacemaker for the heart, because of its rapid firing rate of 60–100 electrical discharges per min. Although the specialised cells at the AV node and at the bundle of His are also capable of spontaneously producing an electrical discharge and taking over control of the rhythm, they are normally required to do so only if the SA node fails or becomes unduly slow. The cells of the AV node emit discharges at 50 per min, and those of the ventricles at 40 or fewer per min.


Every time the heart beats, approximately 70 mL of blood is pumped out of each ventricle. The heart rate is normally around 70 beats/min. These two figures multiplied together are termed the cardiac output.




POSITIVE INOTROPIC DRUGS




DIGOXIN


Digoxin is used in the management of atrial flutter and fibrillation, as it reduces conduction through the AV node and the bundle of His, allowing fewer of the excitatory transmissions from the atria to pass and hence slowing ventricular rate and restoring rhythm. In chronic congestive cardiac failure, digoxin is given to increase the force of myocardial contraction, hence increasing cardiac output for any given filling pressure.











DIURETICS


There are a number of different diuretics that produce the same end result but through a different mode of action (Fig. 12.3). In order to understand their differing modes of action, it is necessary to have a basic understanding of the physiology of the kidney.





PHYSIOLOGY OF THE KIDNEY


Each kidney is made up of approximately 1 million nephrons, each nephron comprising a glomerulus and a proximal and distal tubule that are connected by the loop of Henle (see Ch. 18). The glomerulus consists of a group of capillaries, and as the blood passes through these it is filtered. A large amount of water and dissolved salts is filtered from the blood and passes on to the tubules. In the tubules, a selective reabsorption takes place. Glucose is normally completely reabsorbed. Water and electrolytes, including sodium, potassium, chloride and bicarbonate, are selectively reabsorbed and pass back into the circulation. Urea, excess water, salts and other unwanted substances are excreted as urine. The exact amount of each substance excreted in the urine is controlled in order to maintain the composition of the body fluids at normal levels. The urine is further concentrated and, depending on the electrolyte balance, more sodium is absorbed in exchange for potassium. In the distal tubule, antidiuretic hormone (ADH, vasopressin) excreted by the posterior pituitary gland is an important controlling factor. Increased ingestion of water results in an increased urine flow. When water is absorbed from the gastrointestinal tract, it causes the plasma to become more dilute, and this in turn decreases the release of ADH by the posterior lobe of the pituitary gland. Less ADH reaches the kidney, and this causes the tubules to reabsorb less water so that more is excreted as urine (see Ch. 8 for renal drug excretion).




THIAZIDE AND RELATED DIURETICS









LOOP DIURETICS










ALDOSTERONE ANTAGONIST: POTASSIUM-SPARING DIURETIC


Spironolactone and eplerenone are both aldosterone antagonists. Spironolactone is also used as a potassium-sparing diuretic.









ANTIARRHYTHMIC DRUGS



DISORDERS OF CONDUCTION


Under certain circumstances, the cycle of contraction and relaxation of the heart may be disturbed. These disturbances are known as cardiac arrhythmias. There are several types of arrhythmia for which antiarrhythmic drugs are used. An antiarrhythmic drug is a drug that is used to control or correct abnormal rhythms of cardiac action. These drugs may be used for several different types of cardiac arrhythmia, and it is essential that the specific type of arrhythmia is diagnosed by electrocardiogram prior to commencement of treatment.



SUPRAVENTRICULAR ARRHYTHMIAS


As their name implies, these involve arrhythmias arising from above the ventricles and are normally tachyarrhythmias (i.e. faster than normal). The most common of these are atrial flutter and atrial fibrillation, which are often a result of ischaemic heart disease.









THE CARDIAC ACTION POTENTIAL


Antiarrhythmic drugs are used to treat abnormal electrical activity of the heart. To understand the actions of these drugs, it is necessary first to examine the cardiac action potential (Fig. 12.4).











ANTIARRHYTHMIC DRUGS


These drugs limit cardiac electrical activity to normal conduction pathways and decrease abnormally fast heart rates. They may be classified in a number of ways:






A drug may show more than one of the classes of antiarrhythmic action. The main function of this classification is to define drugs with similar modes of action and to identify possible antiarrhythmic compounds by their effects on cardiac conduction. The clinical value of this classification is limited, and it excludes some antiarrhythmic agents such as the cardiac glycosides.




TREATMENT OF SUPRAVENTRICULAR AND VENTRICULAR ARRHYTHMIAS


Amiodarone should be initiated only under hospital or specialist supervision. It is used for treatment of other arrhythmias when previous treatments have failed (e.g. paroxysmal supraventricular, nodal and ventricular tachycardias; atrial fibrillation and flutter; and ventricular fibrillation). It may also be used to treat tachycardia associated with the Wolff–Parkinson–White syndrome (this is a congenital abnormality occurring in about 0.2% of the population and results from an additional conducting system between the atria and the ventricles). Amiodarone can be given orally or by intravenous infusion. It has a long half-life (30–45 days). Its onset of action may take 1–2 weeks, and effects can be seen months after the drug is withdrawn. Most patients on amiodarone develop corneal microdeposits, usually reversible on withdrawal of the drug. This may lead to drivers being dazzled by headlights at night. As it contains 37% iodine, it can affect thyroid hormone metabolism. Pulmonary toxicity may also be a problem and can result in pneumonitis and fibrosis.


The antiarrhythmic properties of beta-blockers are conferred mainly through their β1-blocking actions, which oppose the electrophysical effects of catecholamines and raise the threshold for ventricular fibrillation. The different beta-blockers have different selectivity for the two receptors β1 and β2. For example, atenolol, acebutolol and bisoprolol are relatively β1-selective when compared with propranolol, oxprenolol and sotolol, which have equal activity for β1 and β2. Beta-blockers are useful in pre-venting arrhythmias induced by exercise, emotion or anaesthesia, and for controlling the ventricular rate in atrial fibrillation. Intravenous esmolol gives rapid beta blockade of short duration (a few minutes) and is particularly useful for the rapid control, for instance, of perioperative tachyarrhythmias. Sotalol has specific antiarrhythmic properties. It may reverse or prevent recurrence of atrial fibrillation and paroxysmal junction tachycardia associated with the Wolff–Parkinson–White syndrome (see below) and may prevent recurrent life-threatening ventricular arrhythmias. However, sotalol may itself cause serious ventricular arrhythmia, including torsades de pointes, especially in patients with depressed left ventricular function, hypokalaemia, or if given with other drugs that prolong the QT interval. Sotalol should be reserved for patients with serious arrhythmias likely to benefit specifically from its antiarrhythmic actions.


Disopyramide is very effective against ventricu-lar extrasystoles and is also used for ventricular arrhythmias, especially where MI is suspected or has been proven. It suppresses the frequency of ectopic ventricular beats as well as the frequency and duration of self-limiting bursts of ventricular tachycardia. It can be given orally or by intravenous infusion. Too rapid an infusion rate can lead to hypotension and cardiac failure. It has anticholinergic side effects, including dry mouth and blurred vision.


Flecainide is of value for serious symptomatic ventri-cular arrhythmias and paroxysmal atrial fibrillation. It delays intracardiac conduction, but it may precipitate serious arrhythmias in certain patients. It should be initiated in hospital under specialist supervision.


Procainamide is used to control ventricular arrhythmias. The rate of metabolism will depend if the patient is a fast or slow acetylator. (Variation in the N-acetyltransferase gene divides people into slow acetylators and fast acetylators [see Ch. 8], with very different half-lives and blood concentrations of such important drugs as isoniazid as well as procainamide.)


Propafenone is used for the prophylaxis and treat-ment of ventricular arrhythmias and also for some supraventricular arrhythmias. It is rapidly absorbed after oral administration but can cause antimuscarinc side effects, including constipation, blurred vision and dry mouth.


Quinidine may be effective in suppressing supraventricular and ventricular arrhythmias and is rarely used now. It is best used under specialist advice.





β-ADRENOCEPTOR BLOCKING DRUGS


Adrenaline (epinephrine) and noradrenaline (nor-epinephrine), which are produced by the adrenal glands and at sympathetic nerve endings, exercise their physiological actions via a and beta adrenoceptors (see Ch. 9).


Beta adrenoceptors are widely distributed in the body, being present in the heart, bronchi, blood vessels, eyes, pancreas, liver and gastrointestinal tract. The b receptors can be divided into two groups:




Stimulation of β1 adrenoceptors in the heart and coronary arteries will lead to an increase in heart rate, increase in conduction velocity and force of contraction in the heart, and vasodilatation of coronary arteries. Excitation of β2 adrenoceptors will lead to dilatation of peripheral arteries.


Beta adrenergic blocking agents interfere with catecholamine binding at beta adrenoceptors. Several beta-blockers (acebutolol, atenolol, bisoprolol and metoprolol) are said to be cardioselective. These agents have the ability to antagonise the action of catecholamines at β1 receptors at doses smaller than those required to block β2 receptors. They are not, however, cardiospecific. They have a smaller effect on airways’ resistance but are not free of this side-effect. Others block both β1 and β2 receptors (i.e. cardiac plus bronchial plus peripheral blood vessel receptors) and are called non-selective beta-blockers. Blocking β2 receptors causes bronchospasm, which may be of little consequence in normal subjects but in asthmatic patients may make bronchospasm worse and increase dyspnoea. Beta-blockers should be used only in patients with asthma or in those with a history of obstructive airways disease when no alternative treatment is available.


Some beta-blockers (pindolol, oxprenolol, acebutolol and celiprolol) demonstrate various degrees of intrinsic sympathomimetic activity, which represents the capacity of beta-blockers to stimulate as well as block adrenergic receptors. These drugs cause a slight agonist response at the beta receptor while blocking the effect of endogenous catecholamine. Patients given a drug with intrinsic sympathomimetic activity experience a smaller reduction in resting heart rate than those receiving a beta-blocker without intrinsic sympathomimetic activity. They tend to cause less bradycardia and less coldness of the extremities than the other beta-blockers, which is a problem particularly in patients with peripheral vascular disease.


Some beta-blockers are water-soluble and some are lipid-soluble. Lipophilic beta-blockers are able to cross the blood–brain barrier and exert effects on the central nervous system. Nightmares and hallucinations are more of a problem with the lipophilic agents. The most water-soluble are atenolol, celiprolol, nadolol and sotalol. They are less likely to enter the brain and may therefore cause fewer sleep disturbances and nightmares. Water-soluble beta-blockers are excreted by the kidneys, and dose reduction may be required in renal impairment.


All beta-blockers slow the heart; the output of blood is reduced and the work done by the heart is thus decreased. They should not therefore be given to patients with heart block.


Labetalol is a mixed alpha-and non-selective beta-adrenergic antagonist that reduces peripheral resistance but has little effect on heart rate or cardiac output. Positive hypotension occurs. Labetalol may be useful in hypertension of pregnancy and in patients with renal failure.


Beta-blockers are contraindicated in asthma or obstructive airways disease, second- or third-degree heart block, sinus bradycardia, sick sinus syndrome, severe peripheral arterial disease and uncompensated cardiac failure.


The side effects of beta-blockers include fatigue, cold extremities, bronchoconstriction, interference with autonomic and metabolic responses to hypoglycaemia, bradycardia, heart block, negative inotropic effect and impotence.

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May 13, 2017 | Posted by in NURSING | Comments Off on Drug treatment of cardiovascular disorders

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