Influence of Renal Disease on Pharmacokinetics

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.

Influence of Drugs on Renal Function

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.

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

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 (t_1/2 < 2 min). Dopamine must be diluted before infusion.

Dopexamine

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

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

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.

Adenosine also slows the heart rate and impairs atrioventricular conduction and is used in the treatment of supraventricular tachycardias (Ch 47).

Calcium Channel Blockers

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.

Because of their vasodilator effects, CCBs are used in the management of conditions associated with pathological vasoconstriction, such as Prinzmetal’s angina, migraine and Raynaud’s disease.

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.

Angiotensin-Converting Enzyme (ACE) Inhibitors

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.

Noradrenaline/Adrenaline/Phenylephrine

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.

The efferent arterioles are the major sites of flow resistance in the kidney and determine renal blood flow, perfusion pressure and GFR. In hypotension or septic shock, restoring the perfusion pressure of the kidney is of the utmost importance. An infusion of one of these vasoconstrictors may improve renal perfusion pressure, provided fluid resuscitation has been adequate. In septic shock, noradrenaline is preferred.

Antidiuretic Hormone (Vasopressin) and Desmopressin (DDAVP)

Antidiuretic hormone (ADH) is a naturally occurring hormone, produced in the hypothalamus, transported by nerve axons down to the posterior pituitary gland and thence secreted into the blood. The release of ADH is regulated by the osmolarity of the extracellular body fluids, changes in arterial pressure and intravascular volume, and the sympathetic nervous system. An increase in blood osmolarity and hypovolaemia stimulate the hypothalamic osmoreceptors and arterial baroreceptors as part of the stress response. ADH is released and acts primarily on receptors in the distal convoluted tubule and collecting ducts of the nephron to increase free water reabsorption and restore the plasma volume. The presence or absence of ADH determines to a large extent whether the kidney excretes a dilute or a concentrated urine. ADH is also termed vasopressin, because it has a very potent vasoconstrictor effect, even more powerful than that of angiotensin.

Vasopressin decreases splanchnic and renal blood flow and is sometimes used to treat bleeding oesophageal varices. There is some evidence that vasopressin may reduce progression to renal failure and mortality in ICU patients with septic shock.

Desmopressin (DDAVP, 1-desamino-8-D-arginine vasopressin) is a synthetic form of vasopressin that does not cause vasoconstriction. It is used in cases of central diabetes insipidus (i.e. spontaneous diuresis with a urine osmolarity < 200 mosm L^–1).

DDAVP also has an influence on the coagulation system by increasing factor VIII von Willebrand (VIII:vWF), factor VIII coagulant (VIII:C), and factor VIII-related antigen (VIIIr:Ag) activity by stimulating their release from the storage sites. A dose of 0.3 μg kg^–1 is often used in the treatment of haemorrhage in haemophiliacs.

Platelet dysfunction often occurs in renal disease when plasma urea concentrations are high. The increase in bleeding time (> 15 min), despite a normal platelet count (> 100 × 10⁹ L^–1), can be corrected before major surgery. The most appropriate treatment currently is the administration of DDAVP in the same dose as above. It has also been used prophylactically to reduce bleeding after cardiac surgery.

DDAVP cannot be used repeatedly because the endothelial storage sites of factor VIII:C become depleted, resulting in tachyphylaxis. Because it also seems to release tissue plasminogen activator, DDAVP enhances fibrinolysis and the simultaneous use of an antifibrinolytic agent has to be considered. Although vasopressin is a vasoconstrictor, rapid injection of DDAVP may cause acute hypotension as a result of vasodilatation.

 glomerulus and proximal renal tubule – e.g. osmotic diuretics, carbonic anhydrase inhibitors

 ascending limb of the loop of Henle – e.g. loop diuretics

 distal tubule – e.g. thiazides, potassium-sparing diuretics

 collecting ducts – e.g. aldosterone antagonists.

Carbonic Anhydrase Inhibitors

Osmotic Diuretics

Loop Diuretics

Loop diuretics act primarily on the medullary part of the ascending limb of the loop of Henle. After initial glomerular filtration and proximal tubular secretion, they inhibit the active reabsorption of chloride in the thick portion of the ascending limb. This leads to chloride, sodium, potassium and hydrogen ions remaining in the tubule to maintain electrical neutrality, and their increased excretion in the urine. The extent of the following diuresis is determined by the concentration of active drug in this part of the tubule. Because the ascending limb plays an important role in the reabsorption of sodium chloride in the kidney, these drugs produce a potent diuretic response. The decrease in sodium chloride reabsorption leads to a reduced urine-concentrating ability of the normally hypertonic medullary interstitium. Furosemide, bumetanide and torasemide are classified as loop diuretics because of their common site of action. Furosemide is the most commonly used.

Thiazide Diuretics

Although thiazide diuretics are seldom used by anaesthetists, many patients scheduled for surgery are receiving these drugs for chronic hypertension or heart failure. There are a large number of thiazides available, all with a similar dose–response curve and diuretic effect. Bendroflumethiazide, chlorothiazide, hydrochlorothiazide and chlorthalidone are a few examples of the better known thiazide diuretics. The majority have a duration of action of 6–12 h. In comparison with loop diuretics, thiazides have a longer duration of action, act at a different site, have a low ‘ceiling’ effect and are less effective in renal failure.

Thiazide diuretics are administered orally, absorbed rapidly from the gastrointestinal tract and initiate a diuresis within 1–2 h. The major distinction between the available thiazides is their difference in elimination rate. They are distributed in the extracellular space and eliminated in the proximal tubule of the nephron by active secretion.

Thiazides inhibit the active pump for sodium and chloride reabsorption in the cortical ascending part of the loop of Henle and the distal convoluted tubule. Therefore, the urine-concentrating ability of the kidney is not impaired, as normally this area is responsible for less than 5% of sodium reabsorption. The diuresis achieved by the thiazides is therefore never as effective as that of the loop diuretics. It is mild but sustained. In contrast with loop diuretics, the excretion of calcium is decreased and hypercalcaemia may become a problem. In the presence of aldosterone activity, the increase in sodium delivery to the distal renal tubules is associated with increased potassium loss, similar to that of the loop diuretics. The reduced clearance of uric acid by thiazides may cause hyperuricaemia.

Thiazides are used extensively in low doses, and often combined with a low-sodium diet, for the management of essential hypertension. A reduction in extracellular fluid volume and mild peripheral vasodilatation are responsible for the sustained antihypertensive effect. The full antihypertensive effect may take up to 12 weeks to become established. Higher doses of thiazides are used for the management of congestive cardiac failure and other oedematous conditions such as nephrotic syndrome and liver cirrhosis.

The most common side-effects of the thiazides are probably dehydration and hypovolaemia. This may present as orthostatic hypotension. When administered chronically, these drugs lead typically to a diuretic-induced hypokalaemic, hypochloraemic, metabolic alkalosis. In combination with magnesium depletion, the hypokalaemia may trigger serious cardiac arrhythmias, in addition to digitalis toxicity, muscle weakness and the potentiation of non-depolarizing muscle relaxants.

Thiazides decrease the tubular secretion of urate, which may lead to hyperuricaemia and gout. They are sulphonamide derivatives and may therefore cause inhibition of insulin release from the pancreas and blockade of peripheral glucose utilization. This may precipitate hyperglycaemia or an increase in insulin requirements in a patient with diabetes mellitus. They also lead to an increase in total blood cholesterol.

Potassium-Sparing Diuretics

Only a small part of sodium reabsorption into the renal cells takes place via the sodium–potassium exchange mechanism in the distal tubules. The potassium-retaining diuretics act on the distal convoluted tubules and the collecting ducts and therefore cause only a limited diuresis. There are two subgroups in this category: drugs acting independently of the aldosterone mechanism (e.g. triamterene and amiloride) and aldosterone antagonists (e.g. spironolactone).

These drugs increase the urinary excretion of sodium, chloride and bicarbonate and lead to an increase in urinary pH. They prevent excessive loss of potassium that occurs with the loop and thiazide diuretics by reducing the sodium–potassium exchange. Potassium-sparing drugs do, however, augment the diuretic response of these drugs when given in combination.

Erythropoietin

Erythropoietin is a circulating hormone secreted by the kidneys. It stimulates the bone marrow to produce red blood cells. The ability of the kidney to secrete erythropoietin deteriorates as excretory function decreases. Patients with severe chronic renal failure are unable to produce adequate quantities of erythropoietin, which leads to diminished red blood cell production. The retention of toxic substances also contributes to bone marrow depression. In addition, red cell survival is reduced by 50% in advanced renal failure. Therefore these patients almost always develop a chronic anaemia.

Long-term administration of recombinant human erythropoietin (rHUEPO) in chronic renal failure patients results in global stimulation of the bone marrow, increasing red blood cell differentiation and maintaining cell viability, thereby improving anaemia. It also decreases bleeding by increasing platelet adhesion in haemodialysed uraemic patients. A side-effect of rHUEPO is the development of hypertension or exacerbation of existing hypertension.

Immunosuppression

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Flechner, S.M., Kobashigawa, J., Klintmalm, G. Calcineurin inhibitor-sparing regimens in solid organ transplantation: focus on improving renal function and nephrotoxicity. Clin. Transplant. 2008;22(1):1–15.

Garwood, S. Cardiac surgery-associated acute renal injury: new paradigms and innovative therapies. J. Cardiothorac. Vasc. Anesth. 2010;24(6):990–1001.

Gordon, A.C., Russell, J.A., Whalley, K.R., et al. The effects of vasopressin on acute kidney injury in septic shock. Intensive Care Med. 2010;36(1):83–91.

Gottlieb, S.S. Adenosine A1 antagonists and the cardiorenal syndrome. Curr. Heart Fail. Rep. 2008;5(2):105–109.

Guyton, A.C., Hall, J.E. Diuretics, kidney diseases (Ch 31). In: Guyton A.C., Hall J.E., eds. Textbook of Medical Physiology. eleventh ed. Philadelphia: WB Saunders; 2011:397–409.

Huang, D.T., Clermont, G., Dremsizov, T.T., et al. Implementation of early goal-directed therapy for severe sepsis and septic shock: a decision analysis. Crit. Care Med. 2007;35(9):2090–2100.

Lindvall, G., Sartipy, U., Ivert, T., et al. Aprotinin is not associated with postoperative renal impairment after primary coronary surgery. Ann. Thorac. Surg. 2008;86:13–19.

Schrier, R.W., Wang, W. Acute renal failure and sepsis. N. Engl. J. Med. 2004;351:59–69.