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.
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).
Fig. 12.1 The heart.
(From Waugh A, Grant A 2001 Ross and Wilson anatomy and physiology in health and illness, 9th edn. Churchill Livingstone, Edinburgh. With permission of Elsevier.)
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 BLOOD VESSELS
Like the heart, the walls of the blood vessels consist of three layers: the fibrous outer tunica adventitia; the middle muscular layer, the tunica media; and the smooth lining, the tunica intima. The outer coat of an artery allows it to stand open, whereas a vein collapses when it is cut. The proportion of muscle tissue depends on the size of the vessel, with much more in arteries than in veins. Some veins have valves that allow the blood to flow back to the heart but prevent flow in the opposite direction. The walls of the capillaries are only one cell thick; this readily facilitates gaseous and nutrient exchange (Fig. 12.2).
POSITIVE INOTROPIC DRUGS
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).
LOOP DIURETICS
ANTIARRHYTHMIC DRUGS
DISORDERS OF CONDUCTION
SUPRAVENTRICULAR ARRHYTHMIAS
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).
Fig. 12.4 Phases of an action potential in the Purkinje fibre cell and the cationic changes that take place.
Phase 2.
This phase is known as the plateau phase. There is a slow current of calcium ions into the cell, which is balanced by a small outward current of potassium ions. These calcium ions are important to the strength of cardiac contraction, which is discussed under calcium antagonists (p. 211).
ANTIARRHYTHMIC DRUGS
TREATMENT OF SUPRAVENTRICULAR AND VENTRICULAR ARRHYTHMIAS
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.
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.)
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).
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.