Basic Pharmacology of Commonly Used Cardiovascularly Active Drugs

The sympathomimetic catecholamines produce effects that depend upon their relative specificity for alpha, beta 1 and beta 2 receptors.

Adrenaline: With both alpha and beta effects this will produce an augmentation in heart rate, systolic blood pressure and cardiac output. In addition it produces relaxation of bronchial smooth muscle. However these effects occur at the expense of increased myocardial oxygen demand and reduced perfusion of skin, kidneys and other organs. It is used for its inotropic effect at doses of 0.01-0.02 μg/kg/min titrated according to response.

Noradrenaline: This has predominantly alpha effects but also slight beta effects on the heart. It produces an increase in both systolic and diastolic pressure but its principle effect is to increase peripheral resistance. This is disadvantageous when peripheral resistance is normal as it then produces an increase in resistance and raises cardiac afterload. However it is useful when the peripheral resistance is inappropriately low, eg in septic shock and mean arterial pressure is inadequate for coronary perfusion. In this situation Noradrenaline is titrated to increase peripheral vascular resistance back up towards normal levels. The usual intravenous rate is 0.01-0.02μg/kg/min titrated against response. A pulmonary artery catheter should usually be present to measure SVR when Noradrenaline is considered necessary. In the absence of a PA catheter, the Noradrenaline may be titrated to increase the diastolic blood pressure to 45 mmHg.

Isoprenaline: This has predominantly beta effects. Through its beta 1 effects it increases cardiac output, contractility and heart rate. Through its beta 2 effects it dilates vascular beds producing a fall in SVR, and thus afterload and diastolic pressure. There is little effect on systolic blood pressure. It also affects the pulmonary vascular bed and is a useful pulmonary vasodilator in patients with pulmonary hypertension following mitral valve replacement.

The beta 2 effects also produce relaxation of bronchial smooth muscle. Isoprenaline is used predominantly for its chronotropic and pulmonary vasodilating effects, by intravenous infusion. The usual rate is 0.01-0.1 μg/kg/min titrated against response.

Dopamine: This has alpha and beta effects and also acts on specific dopaminergic receptors. Its effects are dose dependent although the exact dose at which different responses occur differs in individual patients. At a dose of 3 μg/kg/min the effects are predominantly dopaminergic and produce an increase in renal blood flow. At 5-10 μg/kg/min the beta effects predominate with positive inotropic activity. At doses above 10 μg/kg/min the alpha effects become more apparent with a tendency to increasing vascular resistance and increased afterload with reduced renal blood flow.

In this unit, Dopamine is normally only used at a rate of 3 μg/kg/min for its effect on renal blood flow.

Dobutamine: This is a synthetic compound, primarily a beta agonist with more beta 1 than beta 2 activity. It produces relatively less tachycardia than Isoprenaline for a similar inotropic effect. Dobutamine is used for its inotropic action and is usually given by continuous infusion at a dose of 5-10 μg/kg/min. It also produces a fall in systemic vascular resistance due to its beta 2 activity.

Metaraminol: This is a relatively specific alpha agonist usually used by intravenous bolus to treat hypotension although it can also be given by infusion. The usual bolus dose is 0.5-1 mg which may be repeated.

Milrinone: This is a phosphodiesterase inhibitor which exerts a positive inotropic effect together with marked vasodilatation: an "inodilator."

Alpha and Beta Blockers

There are two main groups of sympathomimetic receptor blocking agents of relevance. These are the alpha and beta adrenoreceptor blocking drugs: they act by competing with catecholamines for the receptor sites. The alpha blockers tend to lower blood pressure at the expense of a compensatory tachycardia. These agents have a use in management of post-operative hypertension with is resistant to the more conventional agents. Examples of alpha blockers include Phentolamine, Phenoxybenzamine, Chlorpromazine. In the vasoconstricted patient these agents may be useful but adequate colloid replacement should be available as overdosage may precipitate profound hypotension.

Alpha Blockers 

Phentolamine: A short acting agent, usually given by small bolus doses of 1 mg and titrated against response.

Phenoxybenzamine: A longer acting agent, not to be given without consultant consent.

Beta Blockers

A more diverse group of drugs which are classified into cardioselective and non- cardioselective agents. In reality, there is a variable degree of selectivity amongst the agents of cardioselective groups. In pharmacological terms, they are selective for the beta 1 receptor, whereas the non-selective group act on both beta 1 and beta 2 receptors. Examples of selective beta blockers include Atenolol and Metoprolol. The non-selective group include Timolol and Propranolol.

Beta blockers reduce myocardial contractility, the rate of conduction of cardiac excitation and hence both cardiac output and myocardial oxygen demand. These agents tend to be used predominantly for prophylaxis and control of post-operative arrhythmias; they may also be used in the control of refractory hypertension. Dosages are given in the section on class II antiarrhythmic agents. Abrupt withdrawal of these drugs postoperatively may provoke atrial fibrillation and therefore should be continued in the postoperative period, often at a half dose. In the control of hypertension, Labetolol has significant theoretical advantages due to its mixed alpha and beta effects. It tends to avoid the compensatory alpha-driven vasoconstriction that occurs with pure beta-blockers. It should be given cautiously initially 1 mg at the time to 5 mg as some patients are very sensitive. If 5 mg is ineffective then the dose may be increased in 5 mg increments to 50 mg or until effect achieved. If necessary it may then be given by infusion following the ward 26 algorithm.

Smooth Muscle Relaxants 

Control of hypertension in the post-operative patient is smoother with a continuous infusion technique, the commonly used agents being sodium nitroprusside and glyceryl trinitrate. Both these agents are short acting: in practice the effects of glyceryl trinitrate are abolished in about 2 minutes and those of sodium nitroprusside in about 30 seconds; this allows rapid correction to be achieved in the event of an excessive hypotensive effect.

Sodium nitroprusside: This acts directly on the vascular smooth muscle leading to vasodilation. Its effects are more marked in the arterial than venous vascular beds and for this reason tends to reduce afterload more than preload. It also has some effect as a pulmonary vasodilator. The usual infusion rate is 0.5-10 μg/kg/min. Sodium nitroprusside can cause cyanide poisoning in high doses. Made up to the concentration as outlined in the ITU algorithm, the infusion rate should not exceed 20 ml/h.

Glyceryl trinitrate also acts directly on vascular smooth muscle but its effects are more pronounced as a venodilator than as an arterial vasodilator. As a result it tends to have a greater effect on preload than afterload. It is also a pulmonary and coronary vasodilator. The usual infusion rate is 0.5-10 μg/kg/min.

Calcium Antagonists 

The calcium antagonist Nifedipine has also been used for the control of post-operative hypertension. It is given by placing the liquid from a capsule under the tongue. The slow release preparation is useful for control of hypertension in the late post-operative period. Nifedipine may also be used for the treatment of coronary artery or arterial graft spasm.

Angiotensin-Converting Enzyme Inhibitors

Angiotensin-converting enzyme (ACE) both converts angiotensin 1 to angiotensin 2 and also inactivates bradykinin. Angiotensin 2 has a direct vasoconstricting effect and also produces sodium retention through the release of Aldosterone. ACE inhibitors probably have their major mode of action through inhibiting peripheral conversion of angiotensin 1. Examples in use at present include Enalapril and Lisinopril. They are used in the treatment of hypertension and heart failure. Side effects include hypotension, impaired renal function and dry cough. These agents have an important role in the treatment of heart failure with a decrease in left ventricular filling pressure and a reduction in mortality and symptoms. They are associated with reduced systemic and pulmonary vascular resistances and an increased cardiac output.

Cardiac Glycosides

The cardiac glycosides, of which Digoxin is the best known, are used in the management of supraventricular arrhythmias, particularly atrial fibrillation. The effects are initiated by depression of conduction at the AV node and by increased vagal activity.

In AF, Digoxin achieves its effect predominantly by delaying conduction through the AV node, although conversion of atrial flutter to fibrillation may occur due to an increase in the atrial refractory period. The action of Digoxin is mediated through the inhibition of a sodium-potassium ATPase enzyme, leading to an increase in intracellular calcium. Hypokalaemia potentiates the effects of Digoxin and may precipitate toxicity. Amiodarone can also precipitate Digoxin toxicity.

The usual loading dose of Digoxin is 0.75 mg/m2 body surface area. This is generally given in divided doses over 8-15 hours, but is can be given more quickly if required. Digoxin toxicity can manifest as either atrial or ventricular arrhythmias and Digoxin levels should be checked.

This protocol is provided by the Freeman Hospital Regional Cardiothoracic Centre.