Epidemiologic studies have estimated that parenchymal renal disease accounts for only 3% to 4% of the secondary causes of hypertension. However, as mentioned above, most patients with advanced kidney disease will develop hypertension—of those with a glomerular filtration rate (GFR) of 12 ml/min/1.73 m², 95% will develop hypertension.² One study³ estimates that 5.6 million Americans have an elevated serum creatinine (SCr); 70% of these have elevated blood pressure. The prevalence of hypertension also varies with the etiology of the parenchymal disease. In glomerular and small-artery diseases, the prevalence is higher than in interstitial diseases, estimated as 85% versus 62.6 %.² This difference is present even when renal function is well preserved.³ Within the glomerular category, postinfectious acute glomerulonephritis, diabetic nephropathy, and focal segmental glomerulonephritis have the highest prevalence. Hypertension is found frequently (close to 50% of patients) with some interstitial diseases such as polycystic kidney.² Lower GFR, higher body mass index, black race, increasing age, and male gender have been identified as independent predictors of hypertension in CKD.³ Hypertension is found in 40% of acute renal failure cases.⁴ In this setting, hypertension is also more prevalent in glomerular vascular disease than in interstitial disease (eg, acute tubular necrosis).

It has been estimated that in patients with abnormal SCr levels, elevated blood pressure is controlled in only 11% of the 3.6 million Americans with these conditions.⁵ Better blood pressure control needs to be achieved.

CKD alters the pharmacologic characteristics of multiple medications, including the antihypertensive medications. Knowledge of the pharmacokinetic and pharmacodynamic changes allows the clinician to achieve better therapeutic results and avoid iatrogenic morbidity. It is not the goal of this chapter to examine in depth the basic pharmacologic principles; for such an in-depth review, readers are referred to pharmacology textbooks. Renal disease can affect almost all pharmacokinetic and pharmacodynamic phases. Drug binding, gastric edema, nausea and vomiting, and enteropathy can all affect the absorption (bioavailability) of medications. Losses of binding sites and higher free-fraction drug also change the distribution. Metabolism is affected at multiple levels. Hepatic and renal metabolic rates are decreased. The diminished renal function can prolong the elimination of the parent drug and/or its metabolites, thus extending the half-life. The metabolic effects of CKD can modify drug distribution at the effector site and increase or decrease its therapeutic effect.

Most classes of antihypertensive medication can be used to treat patients with CKD. An estimation of the GFR is an indispensable piece of information for classifying the patient under the new Kidney Disease Outcomes Quality Initiative (K/DOQI) of the National Kidney Foundation⁵ (Table 1). Several bedside formulas can be used for this purpose. One of the most commonly used is the Cockroft and Gault formula. More recently, the National Kidney Foundation has proposed the use of the modified MDRD formula now available on the internet and for use with hand-held devices (www.nephron.com/mdrd/default.html).

The general approach for prescribing drugs in CKD has been either to decrease the maintenance dose without changing dosing intervals, or to keep the usual dose but prolong the dosing intervals, or use of a combination of these interventions. Each drug should be evaluated individually (Table 2).

Antihypertensive medications are divided into different categories. Within each category are examples of medications that will need adjustment when prescribed for hypertensive patients with CKD. The following section discusses some of the most commonly used medications of each category.

Diuretics:

Diuretics are probably the drugs most often prescribed for the treatment of hypertension. An increase in their use is probably expected after the results of the ALLHAT Study.⁷ This study found that thiazide diuretics are as, or more effective than newer antihypertensive drugs as first line drugs in the treatment of hypertension. Most difficult-to-control hypertensive patients will require a diuretic as part of their regimen. The antihypertensive mechanism of diuretics is believed to occur by a reduction of the intravascular volume. This decrease in cardiac output triggers contraregulatory humoral and renal mechanisms that restore and reestablish a new steady state for sodium. This new state is established within 3 to 9 days, in the presence of decreased volume.⁸ Studies have shown that, after chronic diuretic use, intravascular volume returns toward normal; however, total peripheral resistance decreases.

In spite of being considered a mainstay in the management of hypertension, diuretics are frequently prescribed erroneously, especially in patients with CKD. This error results from a lack of understanding of diuretics' basic pharmacodynamic and pharmacokinetic properties. Some general principles are worth noting.

Diuretics exert their action on the luminal side of the renal tubule. All reach their site of action by being secreted into the tubular fluid, except for osmotic diuretics that are filtered and spironolactone that binds to the cytosolic aldosterone receptor entering the cell through its basolateral membrane. Most diuretics are secreted by organic acid (eg, thiazides, loop diuretics) or organic base (eg, amiloride, traimterene) secretory pathways in the proximal tubule.⁹ CKD diminishes the amount of drug reaching its site of action by delivering less drug to the kidney, as renal blood flow diminishes with lower GFR and endogenous byproducts accumulate that compete for the secretory pathways. Therefore, higher doses are needed in the presence of CKD.

Thiazide diuretics are considered weak diuretics when compared with loop diuretics. Thiazide diuretics can increase the fractional excretion of sodium by 5% to 8% compared with 20% for the loop diuretics. They are rarely used in patients with CKD. They are not recommended therapy if the creatinine clearance is below 40 to 50 mL/min because the amount of diuretic reaching the urine is insufficient to provoke a response. A higher dose will be required. However, this issue has not been extensively studied, and most clinicians prefer a loop diuretic instead. Theoretically, a higher thiazide dose can provoke more side effects and undesirable metabolic effects than the ones observed with recommended maximal doses for those with normal renal function. Hydrochlorothiazide, chlorothiazide, and chlorthalidone are excreted unchanged in the urine. Indapamide is metabolized primarily by the liver.

Loop diuretics—furosemide, bumetanide, and torsemide—as mentioned above, are the diuretics most commonly used in CKD. They are not long-acting drugs; bumetanide has a half-life of 1 hour, furosemide 1-1/2 to 2 hours, and torsemide 3 to 4 hours. Thus, patients with normal renal function require frequent doses. As discussed, CKD patients require higher doses to achieve natriuresis. Furosemide elimination half-life is prolonged with CKD; therefore, less frequent dosing schedules are possible. In spite of better bioavailability and nonrenal clearance of torsemide, this loop diuretic seems to have equivalent antihypertensive responses in patients with CKD in head-to-head comparisons with furosemide.

The potassium-sparing diuretics, including the aldosterone blocking agents like aldactone and eplerenone, are weak diuretics. They increase the fractional excretion of sodium by only 3%.⁸ The risk of provoking hyperkalemia in patients with CKD makes them a poor choice as antihypertensive therapy in this population.

ß-Adrenergic Blockers:

The antihypertensive mechanism of these drugs is not well understood. Some of the explanations put forward are:

1. inhibition of ß₁-receptors at the juxtaglomerular apparatus, thereby decreasing renin release, at least in the short term;
2. inhibition of ß₂-receptors in the vascular wall, thus decreasing peripheral resistance; and
3. inhibition of central nervous system sympathetic outflow.

A decrease in cardiac output is also seen, but this effect seems to be independent of blood pressure reduction.¹⁰

ß-Adrenergic blockers can be divided (Table 3) into nonselective, nonselective with partial agonist activity, ß₁-selective, ß₁-selective with partial agonist activity, and nonselective ß and α antagonists. These pharmocodynamic properties should be taken into consideration for each individual patient. It is beyond the scope of this chapter to discuss the specific indications for each category; however, those most frequently used and those requiring dose adjustment will be discussed.

Nonselective ß-Adrenergic Blockers
Timolol, nadolol, and propranolol are metabolized mainly by the liver. Only nadolol has a minimal first-pass hepatic metabolism, and 75% of the amount absorbed is excreted in the urine. A reduction in the dose is necessary for patients with CKD.

Nonselective with Partial Agonist Activity
Carteolol, penbutolol, and pindolol are representative of this category. All three require dose adjustment in advanced CKD. With carteolol, 70% of the dose is excreted in the urine. The penbutolol active metabolite is renally cleared, and 40% of the pindolol dose is eliminated unchanged by the kidney.

ß₁-Selective
This class comprises the ß-adrenergic blockers most frequently used to treat hypertension.

Atenolol is eliminated primarily in the urine, with little hepatic metabolism. CKD patients will require a dose reduction. It is probably not an optimal choice for initial therapy in this population.

Metoprolol, on the other hand, has an extensive first-pass metabolism, and is cleared by biotransformation. Hence, a dose adjustment is not necessary with decreased renal function.

Betaxolol is metabolized primarily by the liver; however a prolonged half-life has been observed in patients with CKD because a small percentage of the active drug and all its metabolites are excreted by the kidney. Dose adjustment is necessary.

Bisoprolol has a low first-pass metabolism and is eliminated equally by renal and nonrenal mechanisms. One-half of the drug is eliminated unchanged in the urine. Decreased renal function prolongs its half-life, requiring dose adjustment.

ß₁-Selective with Partial Agonist Activity
Acebutolol is the only class representative that undergoes significant first-pass metabolism. The kidney clears diacetolol, its active metabolite. Dose adjustment is necessary when prescribing it for CKD patients.

Nonselective ß- and α-Antagonists
Labetalol and carvedilol have very extensive first-pass metabolism, with less than 5% and 2% of drug excreted unchanged in the urine, respectively. A dose adjustment is not necessary because their metabolism is unchanged in CKD.

Calcium Channel Blockers:

These groups of heterogeneous chemical compounds share their antihypertensive mechanism of action. However, their pharmacologic effects differ. They bind preferentially to the L-type high-voltage calcium channels.¹¹ Blockade of the entry of extracellular calcium diminishes the release of calcium to sarcoplasm, thereby modulating the contraction of the arterial vascular smooth muscle. Calcium channel blockers (CCBs) lower the total peripheral resistance.

Three different classes of CCBs exist: dihydropyridines (nifedipine, amlodipine, isradipine, felodipine, nicardipine, and nisoldipine); phenylalkylamines (verapamil); and benzothiazepines (diltiazem). As mentioned above, because they differ in their pharmacologic effect, they can be used in different clinical situations. However, the specific indications for each class are beyond the objectives of the current discussion.

All CCBs can be safely used in patients with CKD. CCBs vasodilate the afferent arteriole causing a transient increase in GFR—an effect that disappears with chronic use. Interestingly, they promote a natriuretic effect.¹² They all have excellent oral absorption rates of 80% to 90%. All achieve relatively rapid peak blood levels and maximal hypotensive response. No adjustment of CCB dose is needed in the presence of CKD. There are different effects of the CCB on the level of proteinuria. The dihydropyridine CCBs and not the nondihydropyridines CCBs increase the rate of protein excretion. However the clinical consequences of this effect are not clear yet.

Angiotensin-Converting Enzyme Inhibitors:

Angiotensin-converting enzyme (ACE) inhibitors lower blood pressure by lowering the levels of angiotensin II and aldosterone. They achieve this by blocking the conversion of angiotensin I to angiotensin II, which is mediated by angiotensin-converting enzyme, disrupting the renin-angiotensin-aldosterone system (Figure 1). In addition to lowering angiotensin II, a potent vasoconstrictor, the antihypertensive effects are also mediated by the lowering of postsynaptic norepinephrine release, inhibition of the RAAS at the vasomotor center in the medulla oblongata, and accumulation of bradykinin, a vascular vasodilator.¹³ ACE inhibitors cannot block the production of angiotensin II by non-ACE mechanisms (Figure 1); therefore, angiotensin II levels are not suppressed completely. Angiotensin II levels can return to normal, a phenomenon called "angiotensin escape."¹⁴ The net effect of ACE inhibitors is the lowered total peripheral resistance without significant change in heart rate or cardiac output. Three chemical categories exist: sulfhydril, carboxyl, and phosphinyl, according to the ligand of their zinc ion.

The sulfhydril ACE inhibitor (captopril) has the largest bioavailabity but the shortest half-life. The carboxyl ACE inhibitors (benazepril, enalapril, lisinopril, moexipril, quinapril, ramipril, trandolapril) as a group have a longer half-life, making them effective as once- or twice-a-day drugs, especially when used at lower end dosages. All except lisinopril are prodrugs that require hepatic hydrolysis. The only representative of the phosphinyl group, fosinopril, the product of which is activated by hydrolysis in the gastrointestinal mucosa and liver, also has a long half-life. Most ACE inhibitors will require dose adjustment in the presence of CKD. An exception is fosinopril, the hepatic elimination of which increases as renal function declines.¹⁵

ACE inhibitors can cause a temporary decline in GFR, manifested by increased SCr. This increase is seen mainly in states where an intact RAAS is necessary to maintain GFR-eg, hypovolemia, renal artery stenosis, congestive heart failure, or CKD. Most declines are clinically silent unless the SCr increases by more than 1 mg/dL.¹⁶ In CKD patients, a 30% increase in SCr is tolerated, if a new steady state is achieved. Hyperkalemia is another well-established complication of ACE inhibitor therapy. At risk are patients with diabetes, or those who take potassium-sparing diuretics and calcineurin inhibitors. SCr and potassium should be monitored within 1 week of starting ACE inhibitor therapy.¹⁶

Angiotensin II Receptor Blockers:

Angiotensin II receptor blockers (ARBs) lower blood pressure by lowering total peripheral resistance. They block the distal effects of angiotensin II by binding to one of its receptors, AT1 (Figure 1). Blockade of the AT1 receptor prevents angiotensin II-induced vasoconstriction. ARBs also decrease aldosterone production and therefore sodium retention. Some other putative effects include inhibition of the brain RAAS, inhibition of the central or peripheral sympathetic nervous system by antagonizing angiotensin II, and regression of vascular remodeling.¹⁷

By acting distally to the ACE inhibitors, ARBs do not increase bradykinin levels and probably ameliorate the effects mediated by angiotensin escape (see above).

Chemically, ARBs are subdivided into three different categories: biphenyl tetrazoles (eg, candesartan, irbesartan, losartan, and olmesartan); nonbiphenyl tetrazoles (telmisartan); and the nonhetererocyclic compounds (valsartan). They are all nonpeptide compounds. As a group, they achieve a rapid peak blood level. Hepatic metabolism of losartan yields a pharmacologically active metabolite (E3174). Telmisartan has the longest half-life (24 hours). A lower dose is recommended for CKD patients only with candesartan.

Central α₂-Agonists:

The mechanism of action for this class of drugs is characterized by a direct effect on presynaptic and postsynaptic α₂-adrenergic receptors in the vasomotor center in the brain stem.¹⁸ These drugs cross the blood-brain barrier to reach their site of action. Stimulation of the central α₂-adrenergic receptors decreases the sympathetic outflow and increases vagal activity.¹⁰ The net effect is a reduction in norepinephrine release.¹⁰ At higher doses they can mediate peripheral α₂-adrenergic-mediated vasoconstriction. Overall, these drugs cause a decrease in total peripheral resistance and a slowing of the heart rate. The stimulation of the central α₂-adrenergic receptors probably mediates most of the well-known side effects of this group of drugs (eg, sedation, drowsiness, xerostomia, sexual dysfunction, depression, and decreased mental acuity).

The most commonly used drug in this class is clonidine. It reaches its peak plasma concentration in 3 to 5 hours, making it an effective drug for the treatment of hypertensive urgencies. A reduced dose should be used for patients with CKD. Forty to sixty percent is excreted unchanged in the urine, and its normal long half-life of 12 to 15 hours can be extended to more than 40 hours.

The rest of the drugs in this class—methyldopa, guanabenz, guanfancine, and reserpine—are seldom used in current practice because of their weak antihypertensive effects and their adverse side-effect profile. Of these, only methyldopa needs to be adjusted for patients with CKD.

Peripheral α₁-Adrenergic Blockers:

The antihypertensive mechanism of this class of drugs is mediated by inhibition of the postjunctional α₁-adrenergic receptors. This provokes dilation of the arterial and venous vessels.¹⁹ The net effect is a decrease in total peripheral resistance without an increase in renin, cardiac output, or reflex tachycardia. At the renal level, these agents have little effect on renal hemodynamics. However, a decrease in the fractional excretion of sodium has been noted, with expansion of the extracellular volume. The members of this group include doxazosin, prazosin, and terazosin. None requires adjustment in patients with CKD. The premature termination of the doxazosin arm of the recently published ALLHAT trial⁷ suggests that these medications should not be used as first-line therapy.

Direct Vasodilators:

The exact antihypertensive mechanism of this class of drugs is also not well understood. They have a direct effect on the vascular smooth muscle cell, dilating the arterial and venous system, primarily the arterial system.²⁰ It is thought that they alter intracellular calcium metabolism. The net effect is a decrease in total peripheral resistance associated with an increase in heart rate and cardiac output. This occurs by sympathetic activation that increases renin release and therefore activation of the RAAS system. This activation is thought to be responsible for most of the sodium and water retention (thus expanding the extravascular space) associated with their use.¹⁵ While these drugs are used mainly in difficult-to-control hypertension, they are rarely used as monotherapy because of the well-known complications of sodium and water retention and adverse side effects (tachycardia).

Hydralazine has a predominantly arterial effect and obtains rapid peak levels. Its half-life depends on the rate of liver acetylation. It is excreted mainly by the kidney; therefore, dose adjustment is necessary for patients with CKD.

Minoxidil, a more potent vasodilator, has a rapid onset of action. It is metabolized mainly by the liver and does not require dose adjustment.

In summary, most antihypertensive drugs can be used in the management of hypertension in CKD. An estimation of the patient's GFR, and dose adjustments accordingly, are necessary to achieve better outcomes and to avoid unnecessary side effects and morbidity.

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