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

Nitric oxide is synthesised from L-arginine by nitric oxide synthases. It is released under the influence of endothelial agonists such as noradrenaline (norepinephrine), acetylcholine and substance P and in response to mechanical factors such as endothelial shear forces and pulsatile flow. Nitric oxide diffuses into underlying smooth muscle where it activates guanylate cyclase to increase cyclic guanosine monophosphate (cGMP). Subsequent phosphorylation results in relaxation of underlying smooth muscle and vasodilatation.

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.

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

It acts as a direct arteriolar and venous vasodilator causing reductions in blood pressure. Modulation of centrally mediated and peripheral sympathetic tone results in variable effects on cardiac output and heart rate.

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

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

Free cyanide produced by the dissociation of sodium nitroprusside reacts with methaemoglobin to form cyanmethaemoglobin, or is metabolised by rhodenase in the liver and kidneys to form thiocyanate. A healthy adult can eliminate cyanide at a rate equivalent to a sodium nitroprusside infusion of 2 μg/kg per min or up to 10 μg/kg per min for 10 minutes, although there is marked inter-individual variability.

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

Hydralazine causes predominantly arteriolar vasodilatation that is widespread but not uniform. It is associated with direct and reflex sympathetic activity, so that cardiac output and heart rate are increased. Prolonged use of hydralazine stimulates renin release and is associated with sodium and water retention. Consequently, hydralazine is frequently administered with β-blockers and/or diuretics.

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 a useful drug in accelerated hypertension associated with acute renal failure such as glomerulonephritis and has been used in severe pregnancy-induced hypertension and eclampsia. Stimulation of catecholamine release prohibits the use of diazoxide in patients with phaeochromocytoma.

It is associated with metabolic side-effects such as hyperglycaemia and sodium and water retention.

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).

Phentolamine is administered intravenously and may be given intermittently or by infusion. Onset is rapid (within 2 minutes), with a duration of action of 10–15 minutes.

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.