2 Cardiovascular system

• Be able to describe the functions of the heart and blood

• Know which drugs affect heart function and circulating blood, and understand how they do so

• Be aware of any indications, contraindications and adverse drug reactions.

The heart

Basic concepts

The heart is a pump which together with the vascular system supplies the tissues with blood containing oxygen and nutrients, and removes waste products.

The flow of blood around the body is as follows (Fig. 2.1):

• Deoxygenated blood from body tissues reaches the right atrium through the systemic veins (the superior and inferior venae cavae).

• Blood flows into the right ventricle, which then pumps the deoxygenated blood via the pulmonary artery to the lungs, where the blood becomes oxygenated before reaching the left atrium via the pulmonary vein.

• Blood flows from the left atrium into the left ventricle. From here it is pumped into the systemic circulation via the aorta, to supply the tissues of the body.

Fig. 2.1 Blood flow through the heart chambers.

(Redrawn from Page et al. 2006.)

Cardiac rate and rhythm

The sinoatrial node (SAN) and the atrioventricular node (AVN) govern the rate and timing of the cardiac action potential. The SAN is located in the superior part of the right atrium near the entrance of the superior vena cava; the AVN is located at the base of the right atrium. The SAN discharges at a frequency of 80 impulses/min; it is the pacemaker for the heart and as such determines the heart rate. The action potential generated by the SAN spreads throughout both atria, reaching the AVN. The AVN delays the action potential arising from the SAN to encourage the complete emptying of the atria before the ventricles contract.

The secondary action potential generated by the AVN descends into the interventricular septum via the bundle of His. The bundle of His splits into left and right branches making contact with the Purkinje fibres, which conduct the impulse throughout the ventricles, causing them to contract (Fig. 2.2).

Fig. 2.2 Regional variation in action potential configuration throughout the heart. (AV, atrioventricular; SA, sinoatrial.)

(Redrawn from Page et al. 2006.)

Cardiac action potential

The shape of the action potential is characteristic of the location of its origin (i.e. whether from nodal tissue, the atria or the ventricles) (Fig. 2.2).

Non-nodal cells

The resting membrane potential across the ventricular cell membrane is approximately − 85 mV; this is because the resting membrane is more permeable to potassium than to other ions. Four phases occurring at the ventricular cell membrane are (Fig. 2.3):

• Phase 0 or depolarization: Occurs when the membrane potential reaches a critical value of − 60 mV. The upstroke of the action potential is due to the transient opening of voltage-gated sodium channels, allowing sodium ions into the cell. In addition, potassium conductance falls to very low levels.

• Phase 1 (partial repolarization): Occurs as a result of the inactivation of the sodium current, and a transient outward potassium current.

• Phase 2 (plateau phase): The membrane remains depolarized at a plateau of approximately 0 mV. This is due to the activation of a voltage-dependent slow inward calcium current (conducting positive charge into the cell) and a delayed rectifier potassium current conducting positive charge out of the cell.

• Phase 3 (repolarization): Repolarization is due to the inactivation of the calcium current and an increase in potassium conductance.

Fig. 2.3 Configuration of a typical ventricular action potential showing the ionic currents, the phases and where class I, III and IV antiarrhythmic drugs act. (0, 1, 2 and 3, phases of the action potential; I_Na, fast inward Na⁺ current; I_si, slow inward Ca²⁺ current; I_to, transient outward K⁺ current; I_K, delayed rectifier K⁺ current; I_Ki, inward rectifier K⁺ current.)

(Redrawn from Page et al. 2006.)

Nodal cells

The resting membrane potential of nodal cells is approximately − 60 mV.

In nodal cells, there is no fast sodium current. Instead, the action potential is initiated by an inward calcium current, and, because calcium spikes conduct slowly, there is a delay of approximately 0.1 s between atrial and ventricular contraction.

Nodal cells have a phase known as phase 4 (the pacemaker potential). This phase involves a gradual depolarization that occurs during diastole and is known as the f current (I_f′ funny). The f current is activated by hyperpolarization at − 45 mV, and consists of sodium and calcium ions entering the cell (Fig. 2.4).

Fig. 2.4 Configuration of a typical sinoatrial node action potential showing the ionic currents, the phases and where class Ia and II antiarrhythmic drugs act. (4, phase of the action potential; I_si, an inward current carried by Ca²⁺ ions; I_f, a ‘funny’ current carried by Na⁺ and Ca²⁺ ions; I_st, the sustained inward Na⁺ current; I_K, the delayed rectifier current which is an outward K⁺ current.)

(Redrawn from Page et al. 2006.)

Autonomic control of the heart

Both the parasympathetic and sympathetic nervous systems influence the heart, though parasympathetic activity predominates. This explains why the heart rate is lower than the inherent firing frequency of the sinoatrial node (SAN).

The sympathetic nervous system mediates its effects through the cardiac nerve, and activation of β₁-adrenoceptors. These are linked to adenylyl cyclase and their activation causes increased levels of cyclic adenosine monophosphate (cAMP), and a subsequent increase in intracellular calcium levels.

The parasympathetic nervous system mediates its effects through the vagus nerve, and activation of M₂ receptors. These are also linked to adenylyl cyclase, but their activation causes decreased levels of cAMP, and a subsequent decrease in intracellular calcium levels.

The effects of the sympathetic and parasympathetic nervous systems on the heart are summarized in Figure 2.5.

Fig. 2.5 Effects of the sympathetic and parasympathetic nervous systems on the heart

Cardiac contractility

Myocardial contraction is the result of calcium entry through L-type channels, giving rise to an increase in cytosolic calcium in the myocytes (Fig. 2.6).

Fig. 2.6 Effects of drugs on cardiac contractility. (AC, adenylyl cyclase; β₁, β₁-adrenoceptor; G_s, stimulatory G-protein; PDE, phosphodiesterase.)

The calcium is derived from two sources:

• The sarcoplasmic reticulum within the cell

• The extracellular medium.

Extracellular calcium enters the cell, triggering larger amounts of calcium to be released from the sarcoplasmic reticulum, a process known as calcium-induced calcium release.

During contraction, the intracellular levels of calcium increase to levels 10 000 times greater than those at rest. Calcium binds to troponin C, thereby modifying the position of actin and myosin filaments, and allowing the cell to contract. Contraction ceases only once calcium has been removed from the cytoplasm. This occurs through two mechanisms:

• Calcium is pumped out of the cell via the electrogenic Na⁺/Ca²⁺ exchanger, which pumps one calcium ion out for every three sodium ions in.

• Calcium is re-sequestered into sarcoplasmic reticulum stores by a Ca²⁺ ATPase pump.

Cardiac dysfunction and treatment

Drugs used in heart failure

Cardiac glycosides

Prototypical cardiac glycosides are digoxin and digitoxin. The drugs in this class shift the Frank–Starling ventricular function curve to a more favourable position (Fig. 2.9).

Fig. 2.9 Normal cardiac output is determined by the pressure in the left ventricle at end-diastole. In CCF, the set point for cardiac output is reduced and cardiac output falls (1). Compensatory neurohumoral responses become activated which increase end-diastolic pressure and improve cardiac output; however, this can give rise to backward failure (2). Positive inotropic agents increase cardiac output (3). The improved cardiac output reduces the drive for a high end-diastolic pressure, and decompensation occurs to a new set point (4).

Chemically, cardiac glycosides have an aglycone steroid nucleus (the pharmacophore) that causes positive inotropic. An unsaturated lactone ring is responsible for cardiotonic activity and by adding additional sugar moieties the potency and pharmacokinetic distribution can be modulated.

Positive inotropic actions of cardiac glycosides improve the symptoms of CCF but there is no evidence they have a beneficial effect on the long-term prognosis of patients with CCF.

Cardiac glycosides act by inhibiting the membrane Na⁺/K⁺ ATPase pump (see Fig. 2.6). This increases intracellular Na⁺ concentration, thus reducing the sodium gradient across the membrane and decreasing the amount of calcium pumped out of the cell by the Na⁺/Ca²⁺ exchanger during diastole. Consequently, the intracellular calcium concentration rises, thus increasing the force of cardiac contraction and maintaining normal blood pressure.

In addition, cardiac glycosides alter the electrical activity of the heart, both directly and indirectly. At therapeutic doses they indirectly decrease the heart rate, slow atrioventricular (AV) conductance and shorten the atrial action potential by stimulating vagal activity. This is useful in atrial fibrillation. At toxic doses they indirectly increase the sympathetic activity of the heart, and cause arrhythmias, including heart block. The direct effects are mainly due to loss of intracellular potassium, and are most pronounced at high doses. The resting membrane potential is reduced, causing enhanced automaticity slowed cardiac conduction, and increased atrioventricular node (AVN) refractory period.

The increased cytosolic calcium concentration may reach toxic levels thereby saturating the sarcoplasmic reticulum sequestration mechanism and causing oscillations in calcium owing to calcium-induced calcium release. This results in oscillatory after-potentials and subsequent arrhythmias.

In addition, cardiac glycosides have a direct effect on α-adrenoceptors, causing vasoconstriction and a consequent increase in peripheral vascular resistance, which is further enhanced by a centrally mediated increase in sympathetic tone.