Chapter 83 Vasodilators and antihypertensives
Vasodilators are a generic group of drugs that are primarily used in the intensive care unit (ICU) for the management of acute hypertensive states and emergencies. In addition, they have an important role in the management of hypertension and cardiac failure.1
PHYSIOLOGY
Blood pressure is controlled by a complex physiological neurohormonal system involving all components of the cardiovascular system.2,3 Traditionally, clinical practice has focused on the arterial circulation as the major regulator of systemic pressure. The importance of venous circulation in determining mean arterial pressure and cardiac output is discussed in Chapter 82.
The role of the peripheral vasculature, including both arteriolar and venous systems, in the regulation of blood pressure may be conceptually regarded as a balance between vasodilatation and vasoconstriction3 (Figure 83.1).

Figure 83.1 Schematic diagram of the neurohormonal factors determining vasomotor tone. Mechanism of action of vasodilators is shown by (−) for inhibition, (+) for stimulation. ACEI, angiotensin-converting enzyme inhibitors; A-II, angiotensin II; IL, interleukin; NF, nuclear factor; PGI2, prostacyclin; SNP, sodium nitroprusside.
CALCIUM FLUX
The concentration of intracellular ionised calcium is the primary determinant of vascular smooth muscle tone: increases lead to smooth muscle contraction, decreases cause relaxation. Control of calcium influx and efflux is determined by adrenergic receptor occupation and changes in membrane potential, mediated through voltage gated channels (see Chapter 82, Figure 82.2).
ENDOTHELIAL SYSTEM
The endothelium has a central role in blood pressure homeostasis by secreting substances such as nitric oxide, prostacyclin and endothelin.3 These substances are continuously released by the endothelium and are integral in regional autoregulation.4
Prostacyclin is synthesised via the arachidonic pathway and has a minor role in the control of vascular tone.
Endothelin is an endothelium-derived vasoconstrictor peptide that is associated with increases in vascular smooth muscle intracellular calcium. It acts as endogenous ligand to regulate voltage-gated calcium channels, thereby producing vasoconstriction, usually in response to shear stresses, tissue hypoxia, angiotensin II and inflammatory mediators (e.g. interleukin-6 and nuclear factor κB).
RENIN–ANGIOTENSIN–ALDOSTERONE SYSTEM
Angiotensinogen is converted by renin to form angiotensin I, which is subsequently converted to angiotensin II by angiotensin-converting enzyme (ACE). Angiotensin II has a number of effects that are responsible for blood pressure homeostasis. These include release of aldosterone, direct activation of α-adrenergic receptors on vascular smooth muscle and a direct effect in the endothelium. These effects are directed at defending blood pressure and are integral in the stress response. Angiotensin-converting enzyme is also responsible for the inactivation of bradykinins that have predominantly vasodilatory effects, coupled to arachidonic acid synthesis and generation of prostacyclin.
ADRENERGIC SYSTEM
The sympathetic nervous system is integrally involved with all of the above systems, regulating vascular tone at central, ganglionic and local neural levels. Adrenergic stimulation of β-receptors is associated with vasodilatation; α-receptor stimulation results in vasoconstriction. The vascular effects of the catecholamines and vasopressors are discussed in Chapter 82.
Adrenergic stimulation is the predominant system in regulating venous tone.5 This is due to endothelial differences in veins resulting in less production of nitric oxide and reduced responsiveness to angiotensin II.
PATHOPHYSIOLOGY
Hypertensive states develop as a result of impaired or abnormal homeostatic processes, causing an imbalance between vasoconstrictive and vasodilatory effects.
Essential hypertension is the most common cause of hypertension and is due to abnormal neurohormonal regulation, particularly exaggerated effects of renin–angiotensin activity.
Secondary causes of hypertension include structural abnormalities such as aortic stenosis or renal artery stenosis; endocrine conditions such as phaeochromocytoma, Cushing’s syndrome and pregnancy-induced hypertension; or central causes such as hypertensive encephalopathy or raised intracranial pressure.
CALCIUM ANTAGONISTS
Calcium antagonists have numerous effects on the cardiovascular system, influencing heart rate conduction, myocardial contractility and vasomotor tone. Entry of calcium through voltage-gated calcium channels is a major determinant of arteriolar, but not venous, tone.6
Magnesium is a physiological calcium antagonist, and is used therapeutically as magnesium sulphate.
NIFEDIPINE
Nifedipine is a predominant arteriolar vasodilator, with minimal effect on venous capacitance vessels and no direct depressant effect on heart rate conduction.
It may be administered intravenously, orally or sublingually, and has a rapid onset of action (2–5 minutes) and duration of action of 20–30 minutes.
Nifedipine is frequently used to treat angina pectoris, especially that due to coronary artery vasospasm. Peripheral vasodilatation results in decreased systemic blood pressure, often associated with sympathetic stimulation resulting in increased cardiac output and heart rate that may counter the negative inotropic, chronotropic and dromotropic effects of nifedipine. Nevertheless, nifedipine may be associated with profound hypotension in patients with ventricular dysfunction, aortic stenosis and/or concomitant β-blockade. For this reason, the use of sublingual nifedipine as a method of treating hypertensive emergencies is no longer recommended.7
Nifedipine and related drugs may cause diuretic-resistant peripheral oedema that is due to redistribution of extracellular fluid rather than sodium and water retention.
NIMODIPINE
Nimodipine is a highly lipid-soluble analogue of nifedipine. High lipid solubility facilitates entrance into the central nervous system where it causes selective cerebral arterial vasodilatation.
It may be used to attenuate cerebral arterial vasospasm following aneurysmal subarachnoid haemorrhage. Improved outcomes have been demonstrated in patients with Grade 1 and 2 subarachnoid haemorrhage.8 Systemic hypotension may result from peripheral vasodilatation that may compromise cerebral blood flow in susceptible patients. Similarly, cerebral vasodilatation may increase intracranial pressure in patients with reduced intracranial elastance.
It may be given by intravenous infusion or enterally with equal effect.
AMLODOPINE
Amlodipine is an oral preparation that has a similar pharmacodynamic profile to nifedipine. In addition to arteriolar vasodilatory and cardiac effects, amlodipine has been shown to exert specific anti-inflammatory effects in hypertension, diabetic nephropathy and in modulating high-density lipoprotein (HDL) in patients with hypercholesterolaemia.9 These effects have seen amlodipine increasingly being used for treatment of hypertension in high-risk patients, and may have a role in stable critically ill patients with associated comorbidities.
VERAPAMIL
The primary effect of verapamil is on the atrioventricular node and this drug is principally used as an antiarrhythmic for the treatment of supraventricular tachyarrhythmias. For this reason, concomitant therapy with β-blockers or digoxin is not recommended.
Verapamil is not as active as nifedipine in its effects on smooth muscle and therefore causes less pronounced decrease in systemic blood pressure and reflex sympathetic activity. It has a limited role as a vasodilator.10
DILTIAZEM
Diltiazem has a similar cardiovascular profile to verapamil, although its vasodilatory properties are intermediate between nifedipine and verapamil. Diltiazem exerts minimal cardiodepressant effects and is unlikely to potentiate β-blockers.
MAGNESIUM SULPHATE
Magnesium regulates intracellular calcium and potassium levels by activation of membrane pumps and competition with calcium for transmembrane channels. Physiological effects are widespread, affecting cardiovascular, central and peripheral nervous systems and the musculoskeletal junction.11
Consequently, it has an established role in the treatment of pre-eclampsia and eclampsia,12 perioperative management of phaeochromocytoma13 and treatment of autonomic dysfunction in tetanus.14
DIRECT-ACTING VASODILATORS
These drugs act directly on vascular smooth muscle and exert their effects predominantly by increasing the concentration of endothelial nitric oxide. These drugs are also known as nitrovasodilators.15
SODIUM NITROPRUSSIDE
Sodium nitroprusside is a non-selective vasodilator that causes relaxation of arterial and venous smooth muscle. It is compromised of a ferrous ion centre associated with five cyanide moieties and a nitrosyl group. The molecule is 44% cyanide by weight.
It is reconstituted from a powdered form. The solution is light-sensitive requiring protection from exposure to light by wrapping administration sets in aluminium foil. Prolonged exposure to light may be associated with an increase in release of hydrogen cyanide, although this is seldom clinically significant.
When infused intravenously, sodium nitroprusside interacts with oxyhaemoglobin, dissociating immediately to form methaemoglobin while releasing free cyanide and nitric oxide. The latter is responsible for the vasodilatory effect of sodium nitroprusside.
Onset of action is almost immediate with a transient duration, requiring continuous intravenous infusion to maintain a therapeutic effect.
Tachyphylaxis is common, particularly in younger patients. Large doses should not be used if the desired therapeutic effect is not attained, as this may be associated with toxicity.
Sodium nitroprusside produces direct venous and arterial vasodilatation, resulting in a prompt decrease in systemic blood pressure. The effect on cardiac output is variable. Decreases in right atrial pressure reflect pooling of blood in the venous system, which may decrease cardiac output. This may result in reflex tachycardia that may oppose the overall reduction in blood pressure. In patients with left ventricular failure, the effect on cardiac output will depend on initial left ventricular end-diastolic pressure. Sodium nitroprusside has unpredictable effects on calculated systemic vascular resistance. Homeostaticmechanisms in preserving cardiac output may explain tachyphylaxis to prolonged infusions.
Sodium nitroprusside may increase myocardial ischaemia in patients with coronary artery disease by causing an intracoronary steal of blood flow away from ischaemic areas by arteriolar vasodilatation. Secondary tachycardia may also exacerbate myocardial ischaemia.
Due to its non-selectivity, sodium nitroprusside has direct effects on most vascular beds. In the cerebral circulation, sodium nitroprusside is a cerebral vasodilator, leading to increases in cerebral blood flow and blood volume. This may be critical in patients with increased intracranial pressure. Rapid and profound reductions in mean arterial pressure produced by sodium nitroprusside may exceed the autoregulatory capacity of the brain to maintain adequate cerebral blood flow.
Sodium nitroprusside is a pulmonary vasodilator and may attenuate hypoxic pulmonary vasoconstriction, resulting in increased intrapulmonary shunting and decreased arterial oxygen tension. This phenomenon may be exacerbated by associated hypotension.
The prolonged use of large doses of sodium nitroprusside may be associated with toxicity related to the production and cyanide and, to a lesser extent, methaemoglobin.16
Toxicity should be considered in patients who become resistant to sodium nitroprusside despite maximum infusion rates and who develop an unexplained lactic acidosis. In high doses, cyanide may cause seizures.
Treatment of suspected cyanide toxicity is cessation of the infusion and administration of 100% oxygen. Sodium thiosulphate (150 mg/kg) converts cyanide to thiocyanate, which is excreted renally. For severe cyanide toxicity, sodium nitrate may be infused (5 mg/kg) to produce methaemoglobin and subsequently cyanmethaemoglobin. Hydroxocobalamin, which binds cyanide to produce cyanocobalamin, may also be administered (25 mg/hour to maximum of 100 mg).
GLYCERYL TRINITRATE
Glyceryl trinitrate is an organic nitrate that generates nitric oxide through a different mechanism from sodium nitroprusside.
The pharmacokinetics allows glyceryl trinitrate to be given by infusion, with a longer onset and duration of action than sodium nitroprusside. Glyceryl trinitrate may also be administered sublingually, orally or transdermally.
Tachyphylaxis is common with glyceryl trinitrate; doses should not be increased if patients no longer respond to standard doses. Glass bottles or polyethylene administration sets are required as glyceryl trinitrate is absorbed into standard polyvinylchloride sets.
The effects on the peripheral vasculature are dose dependent, acting principally on venous capacitance vessels to produce venous pooling and decreased ventricular afterload. These are important mechanisms in patients with cardiac failure.
Glyceryl trinitrate primarily dilates larger conductance vessels of the coronary circulation, resulting in increased coronary blood flow to ischaemic subendocardial areas, thereby relieving angina pectoris. This is in contrast to sodium nitroprusside that may cause a coronary steal phenomenon.
Reductions in blood pressure are more dependent on blood volume than sodium nitroprusside. Precipitous falls in blood pressure may occur in hypovolaemic patients with small doses of glyceryl trinitrate. In euvolaemic patients, reflex tachycardia is not as pronounced as with sodium nitroprusside. At higher doses, arteriolar vasodilatation occurs without significant changes in calculated systemic vascular resistance.
Glyceryl trinitrate is a cerebral vasodilator and should be used with caution in patients with reduced intracranial elastance. Headache due to this mechanism is a common side-effect in conscious patients.
ISOSORBIDE DINITRATE
Isosorbide dinitrate is the most commonly administered oral nitrate for the prophylaxis of angina pectoris. It has a physiological effect that lasts up to 6 hours in doses of 60–120 mg. The mechanism of action is the same as glyceryl trinitrate. Hypotension may follow acute administration, but tolerance to this develops with chronic therapy.17
HYDRALAZINE
Hydralazine is a potent, arterioselective, direct-acting vasodilator that acts via stimulation of cGMP and inhibition of smooth muscle myosin light chain kinase.
Following intravenous administration, hydralazine has a rapid onset of action, usually within 5–10 minutes. It may also be administered intramuscularly or orally. The drug is partially metabolised by acetylation, for which there is marked inter-individual variability (35% population are slow acetylators). Whilst this does not have much clinical significance regarding the antihypertensive effects, it is important with respect to toxicity.17
Chronic use of hydralazine may be associated with immunological side-effects including a lupus syndrome, vasculitis, haemolytic anaemia and rapidly progressive glomerulonephritis.
DIAZOXIDE
Diazoxide is chemically related to the thiazide diuretics and is a potent, non-selective, direct-acting vasodilator. The mechanism of action is unclear, but it is a predominantly arteriolar vasodilator.18 Diazoxide is administered intravenously or intramuscularly. It has a rapid onset (3–5 minutes) and prolonged duration of action (1–2 hours), often with precipitous reductions in blood pressure. Diazoxide has similar cardiovascular effects to hydralazine and is associated with significant reflex sympathetic stimulation, resulting in increased cardiac output and heart rate.
It is associated with metabolic side-effects such as hyperglycaemia and sodium and water retention.
α-ADRENERGIC ANTAGONISTS
Several groups of compounds act as α-adrenergic blockers with variable affinity for populations of α-receptors. Physiology and pathophysiology may influence the responsiveness of the drug receptor–effector relationship. Receptor pathobiology is discussed in Chapter 82. Consequently, there may be marked inter- and intra-individual variability in the patient’s response to these drugs.
PHENTOLAMINE
Phentolamine is a non-selective, competitive antagonist at α1– and α2-receptors. At low doses, phentolamine causes prejunctional inhibition of noradrenaline release (via α2-receptor inhibition). At higher doses, more complete α-receptor blockade is achieved, with enhancement of effects of β-agonists due to increased local concentration of noradrenaline produced by α2-blockade (see Chapter 82, Figure 82.3a).
Arteriolar and venous vasodilatation reduces systemic blood pressure, without significant changes in calculated systemic vascular resistance. Effects on cardiac output are variable, and there is modest reflex sympathetic stimulation without significant increases in heart rate.

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