Drugs Used in Renal Disease
Renal disease may affect drug pharmacokinetics through several mechanisms, especially effects on drug binding, distribution and elimination. Acidic drugs bind mainly to albumin. In renal failure, a decrease in serum albumin, an increase in serum urea, and the competition of endogenous substrates and drug metabolites for plasma protein binding sites lead to a decrease in the plasma protein binding of drugs. Highly protein-bound drugs have an increased unbound, active, free fraction. Under these circumstances, there may be an increase in the volume of distribution. Drugs are metabolized in the liver to water-soluble, inactive metabolites. Although uraemia has an effect on the intermediary metabolism of the liver, it does not seem to affect hepatic drug metabolism in humans.
The duration of action of most drugs administered by bolus or short-term infusion is dependent on redistribution and not elimination. It is usually not necessary to decrease the initial loading dose in patients with renal dysfunction, but subsequent maintenance doses may cause drug accumulation and should be reduced appropriately. The inactive water-soluble metabolites of drugs are eliminated by passive filtration at the glomerulus. A reduction in glomerular filtration in renal disease patients may lead to accumulation of these metabolites.
All anaesthetic agents may cause a generalized depression of renal function which is transient and clinically insignificant. However, nephrotoxic drugs can impair renal function permanently. For example, they may lead to severe sodium and water depletion, reduction in renal blood supply, direct renal damage or renal obstruction (Table 10.1). Some drugs impair renal function by more than one mechanism.
Sodium and water depletion
Reduced renal perfusion
Direct renal toxicity
Some of the fluorinated inhalation agents have well-recognized nephrotoxic effects, because they increase the serum inorganic fluoride concentration. Prolonged exposure of the renal tubules to fluoride ions impairs their ability to concentrate urine, leading to dehydration, hypernatraemia and increased plasma osmolarity. Experience with methoxyflurane (no longer in clinical use) has suggested that a plasma fluoride level of 50 μmol L−1 is potentially nephrotoxic. Although halothane and isoflurane do not seem to have a significant effect, prolonged administration of enflurane may lead to potentially nephrotoxic fluoride ion concentrations.
Sevoflurane undergoes approximately 5% metabolism and one of the primary metabolites is fluoride. There were initial concerns that sevoflurane may be similar to methoxyflurane and impair the ability of the kidneys to concentrate urine. However, after sevoflurane administration is stopped, there is a rapid decrease in plasma fluoride concentration because of its insolubility and rapid pulmonary elimination. Also, the metabolic production of fluoride within the kidney is much less with sevoflurane than with methoxyflurane. Though it would appear that sevoflurane renal toxicity is not a problem in clinical practice, prolonged administration of sevoflurane is not recommended in patients with significantly impaired renal function.
Aprotinin is a serine-protease inhibitor and an antifibrinolytic agent occasionally administered during major surgery to improve haemostasis. It undergoes active reabsorption by the proximal tubules and is metabolized by enzymes in the kidney. There is some controversy about its effect on renal function. Although some studies have shown a low incidence of reversible renal dysfunction, others have shown changes in biochemical markers of tubular damage without evidence of renal impairment.
Other drugs with potential for impairing renal function include aminoglycosides, NSAIDs, radiocontrast agents and various chemotherapeutic drugs. The potential for renal damage with these drugs is increased in the presence of hypovolaemia, dehydration and sepsis.
Several drugs have been investigated for protection against renal damage or dysfunction in patients at risk, for example those undergoing cardiac or aortic surgery, or ICU patients with sepsis. However, there is little convincing evidence that any specific drug effectively prevents perioperative renal dysfunction, and some of the drugs used may be harmful. These are discussed below.
Dopamine is an endogenous catecholamine precursor of noradrenaline and adrenaline, and is a neurotransmitter in its own right. It has complicated dose-dependent pharmacodynamic effects, including positive inotropy, chronotropy, vasoconstriction, and renal and splanchnic vasodilatation. Dopamine is inactive orally and has to be administered as an intravenous infusion, because it is metabolized within minutes by the enzymes dopamine β-hydroxylase and monoamine oxidase (t1/2 < 2 min). Dopamine must be diluted before infusion.
Dopamine acts on dopaminergic and adrenergic receptors in a dose-related fashion. Dopaminergic receptors are present in various sites in the body and have been classified into five subtypes. The two most important receptors in the peripheral cardiovascular and renal systems are DA1 and DA2.
The infusion of relatively low doses (< 2 μg kg–1 min–1) of dopamine activates postsynaptic DA1 receptors in splanchnic blood vessels and the renal tubules. Stimulation leads to vasodilatation and increases cortical renal blood flow, glomerular filtration rate (GFR), sodium excretion and urine output. There is also an increase in mesenteric blood flow. Activation of presynaptic DA2 receptors decreases intrarenal noradrenaline release, which leads to vasodilatation. It also causes inhibition of aldosterone secretion from the adrenal glands and a consequent decrease in sodium reabsorption. Theoretically, this should decrease renal oxygen consumption and improve the renal oxygen supply/demand relationship. At low infusion rates there is little change in cardiac output or heart rate. A reduction in arterial pressure may occur because of inhibition of the sympathetic nervous system by stimulation of the DA2 receptors, and by DA1-induced vasodilatation.
Increased infusion rates (2–5 μg kg–1 min–1) stimulate cardiac β1– and β2-adrenergic receptors, which causes an increase in myocardial contractility, stroke volume and cardiac output. At this infusion rate, the heart rate usually does not change.
Higher doses of dopamine (> 10 μg kg–1 min–1) lead to stimulation of the α-adrenergic receptors, causing vasoconstriction, an increase in peripheral vascular resistance and decreases in renal and splanchnic blood flow.
The dopamine infusion rates given above are guidelines and there is considerable intra- and inter-patient variation. The maximum dose at which dopamine affects only dopamine receptors is debatable. In addition, up- and downregulation of receptors occurs so the appropriate dose for a required effect may vary from hour to hour and doses must be individually titrated.
Dopamine has been used widely in ICU and surgical patients at risk of renal dysfunction, because of its effects on renal blood flow, diuretic and natriuretic effects and also because urine output is used as a surrogate marker of tissue perfusion. However, clinical studies have not demonstrated any benefit of ‘low-dose’ dopamine for the prevention and treatment of acute kidney injury in critically ill or surgical patients. In fact, it reduces regional redistribution of blood flow within the kidney by shunting blood away from the outer medulla to the cortex. This is potentially detrimental in acute kidney injury given that the outer medulla is very susceptible to ischaemic injury.
The use of higher doses of dopamine as a positive inotrope during cardiac failure, or a vasopressor during hypotension, is well established. Under these circumstances, it probably has a beneficial effect on renal function, but it is important to ensure that there is an adequate circulating blood volume.
Side-effects of dopamine include tachyarrhythmias, vasoconstriction with acute hypertension, and nausea and vomiting because of a direct effect on receptors within the chemoreceptor trigger zone. Intravenous administration of dopamine does not result in central nervous system effects as dopamine does not cross the blood–brain barrier. Other potentially detrimental effects of low-dose dopamine in the critically ill patient include the following.
Dopexamine is a synthetic catecholamine with structural and pharmacological similarities to dopamine; it is used for its increase in cardiac output and renal and splanchnic vasodilator effects. It is inactive orally and, because of its short half-life (~ 6 min), it is administered i.v. as an infusion. Infusion rate starts at 0.5 μg kg–1 min–1 and is titrated to a therapeutic response (up to 6 μg kg–1 min–1). Tolerance can occur and is usually associated with receptor downregulation. It is metabolized by the recognized pathways for all the catecholamines.
Dopexamine is an agonist at vascular and renal dopaminergic DA1 and DA2 receptors. It also stimulates cardiac and vascular β2-receptors, and has a limited indirect β1 effect. It therefore combines vasodilator, chronotropic and mild inotropic activity and is used in low cardiac output states where specific renal and hepatosplanchnic vasodilatation is considered beneficial. The heart rate is increased in a dose-related manner and it produces a natriuresis and diuresis. The protective effect of dopexamine on the kidneys is theoretical and an effect on outcome still has to be proven.
The most common side-effect is a tachycardia and ventricular ectopic beats when higher doses are used. Nausea and vomiting, probably caused by stimulation of DA2 receptors in the chemoreceptor trigger zone, have been reported.
Fenoldopam is a selective DA1 agonist. It may be administered orally or intravenously and has been used for the management of congestive cardiac failure, hypertension and renal protection after cardiac surgery, though current data are inconclusive. Its effects are slightly different to dopamine because of its DA1 selectivity: fenoldopam may preferentially increase flow to the outer renal medulla, but it may also have anti-inflammatory effects.
Adenosine is a natural purine and is an important mediator in the control of renal blood flow and glomerular filtration. After i.v. administration it causes peripheral vasodilatation and decreased arterial pressure. Adenosine-induced arterial hypotension inhibits renin release by the juxtaglomerular cells and has an interesting effect on the renal vasculature, causing transient vasoconstriction of the afferent arterioles, combined with vasodilatation of the efferent arterioles. This results in decreases in renal blood flow and glomerular filtration pressure and rate. Adenosine A1 receptor antagonists increase GFR, urine production and sodium excretion without immediate effects on cardiac haemodynamics, and are being investigated for use in heart failure.
Calcium channel blockers (CCBs) (Ch 8) are predominantly used in the treatment of hypertension. They act selectively on calcium channels in the cellular membrane of cardiac and vascular smooth muscle (VSM) cells. Free calcium within the VSM enhances vascular tone and contributes to vasoconstriction. CCBs reduce the transmembrane calcium influx in VSM cells, causing vasodilatation. In addition, CCBs have a direct diuretic effect that contributes to their long-term antihypertensive action. Nifedipine increases the urine volume and sodium excretion, and may inhibit aldosterone release. This diuretic action is independent of any change in renal blood flow or GFR.
In addition to renal vasodilatation, CCBs decrease calcium influx and production of oxygen free radicals in renal ischaemia. They therefore have theoretical benefits in patients undergoing renal transplantation. In transplant recipients, CCBs have been shown to improve intrarenal circulation, decrease the incidence of post-transplant acute tubular necrosis, and they may reduce the vasoconstrictive action of ciclosporin. However, despite these apparent benefits, CCBs have failed to improve graft survival. They may also cause hypotension and thereby decrease renal perfusion and there is no good clinical evidence that they have significant renal protective effects. CCBs may also enhance the effects of depolarizing and non-depolarizing neuromuscular blocking agents and this combination should be used with caution in patients with renal dysfunction.
Most patients with heart failure and many with hypertension have increased activity of the renin–angiotensin–aldosterone system (RAAS). This leads to increased systemic vascular resistance, further decreases in cardiac output and renal perfusion, and more sodium and fluid retention. These patients are often receiving diuretics, which in itself triggers the RAAS. Angiotensin-converting enzyme (ACE) inhibitors (e.g. captopril, enalapril, lisinopril) are being used increasingly in this scenario, in place of, or in combination with, diuretics.
ACE inhibitors have a much greater affinity for the active site on the ACE than the natural substrate, angiotensin I. Consequently, the conversion of angiotensin I to angiotensin II is blocked. ACE is also responsible for the breakdown of bradykinin, a potent vasodilator. Therefore, ACE inhibitors lead not only to vasodilatation but, because of the decreases in aldosterone formation and sodium re-uptake, also have an indirect potassium-retaining diuretic effect. The combination of ACE inhibitors and the potassium-saving diuretics should be avoided because of the risk of hyperkalaemia.
Angiotensin II is important for the maintenance of an adequate glomerular filtration pressure in patients with decreased renal perfusion. In the presence of renal artery stenosis, the use of ACE inhibitors may lead to an impairment of renal function by decreasing renal perfusion pressure, caused by the decrease in arterial pressure together with dilatation of the efferent arteriole of the glomerulus. Underlying renal impairment should therefore always be excluded before using ACE inhibitors, and patients receiving these agents should be monitored carefully.
Although noradrenaline and adrenaline also have β-receptor effects, all three of these drugs are very potent vasoconstrictors acting on the vascular α-receptors (Ch 8). Their use is often accompanied by fear of inducing decreases in renal blood flow, GFR and renal function.