Blood pressure in a hypertensive patient is controlled by the
same mechanisms that are operative in normotensive subjects. Regulation
of blood pressure in hypertensive patients differs from healthy
patients in that the baroreceptors and the renal blood volume–pressure
control systems appear to be “set” at a higher
level of blood pressure. All antihypertensive drugs act by interfering with
these normal mechanisms. Effective lowering of pressure has been
shown to prevent damage to blood vessels and to reduce morbidity
and mortality rates substantially. The strategies for treating high
blood pressure are based on these determinants of arterial pressure.
These strategies include inhibition of sympathetic tone (sympatholytics),
inhibition of vascular smooth muscle contraction (vasodilators),
inhibition of angiotensin II formation (renin inhibitors and ACE
inhibitors) and receptor activation (angiotensin receptor antagonists),
and reduction of blood volume (diuretics). Thus, antihypertensive
drugs are organized around a clinical indication, the need to treat
a disease, rather than a single receptor type. A graphic overview
of the sites of action of the antihypertensive drug classes with
specific drug examples is presented in Figure 7–3, and
an outline of the various classes of antihypertensive drugs is presented
in Figure 7–4.
Sympatholytic antihypertensive drugs may be further divided into
those that are antagonists at adrenoceptors, act within the central
nervous system (CNS) to decrease sympathetic outflow, inhibit sympathetic
activity at the autonomic ganglia, or modulate postganglionic neuronal
function in the target tissue (Figure 7–3).
The α1, α2,
and β1 receptors all play a modulatory
role in controlling blood pressure. The mechanisms of action and the
physiologic effects of inhibiting these receptors were discussed
in Chapter 6.
receptorantagonists such asprazosin,
doxazosin, and terazosin are used for chronic treatment of
hypertension as well as benign prostatic hyperplasia. These drugs
decrease blood pressure by dilation of the arterial and, to a lesser
extent, venous vasculature.
Orthostatic hypotension and reflex
tachycardia both occur, although reflex tachycardia is less common
with the α1-selective blocking drugs.
Cardiovascular applications include
hypertension, angina, and cardiac arrhythmias. Treatment of chronic
heart failure is a newer application for these drugs. Several large
clinical trials have shown that certain β blockers
(labetalol, carvedilol, and metoprolol) reduce morbidity and mortality
when used properly in heart failure (Chapter 9).
Beta blockade of the heart may
result in bradycardia, atrioventricular blockade, and acute heart
failure. Additional care should be taken to watch for brochoconstriction
in patients with asthma or chronic obstructive lung disease, and rhythm
disturbances in patients with abrupt medication termination.
Alpha2-selective agonists such as clonidine,guanfacine, and methyldopa cause a decrease in sympathetic
outflow by a mechanism that involves activation of α2 receptors
in the CNS (Figure 7–3). These drugs readily enter the
CNS when given orally. Methyldopa is a prodrug and is converted
to methylnorepinephrine in the brain. Clonidine, guanfacine, and
methyldopa reduce blood pressure by reducing cardiac output, vascular
resistance, or both.
The major compensatory response
is salt retention. Sudden discontinuation of clonidine may cause
rebound hypertension, which may be quite severe. This rebound increase
in blood pressure can be controlled by reinstitution of clonidine
therapy. Clonidine also increases the risk of mental depression
and should be used with caution in patients at risk. Methyldopa
occasionally causes hematologic immunotoxicity, detected initially
by test tube agglutination of red blood cells (positive Coombs test)
and, in some patients, progresses to hemolytic anemia. All these
drugs may cause sedation and dry mouth; methyldopa more so.
Drugs that inhibit the nicotinic NN receptors in the
ganglia are very efficacious, but because their adverse effects
are severe, they are considered obsolete. Hexamethonium and trimethaphan are prototypical and
are extremely powerful blood pressure–lowering drugs. The
major compensatory response is salt retention. Toxicities reflect
parasympathetic blockade (blurred vision, constipation, urinary
hesitancy, sexual dysfunction) and sympathetic blockade (sexual
dysfunction and orthostatic hypotension).
Sympathetic Blocking Drugs
Drugs that deplete the adrenergic nerve terminal of its norepinephrine
stores or that deplete and block release of these stores can lower
blood pressure (Figure 7–5). Reserpine is
a prototypical drug that acts by the depletion mechanism; guanethidine acts by both depleting
and blocking release. The major compensatory response is salt retention. In
high dosages, both reserpine and guanethidine are very efficacious
but produce a high incidence of adverse effects. Reserpine is still
occasionally used in low doses as an adjunct to other agents. Guanethidine
is rarely used. Reserpine readily enters the CNS; guanethidine does
not. Both have long durations of action in the order of days to
weeks. The most serious toxicities associated with reserpine are
behavioral depression and pseudoparkinsonism, which may require
discontinuation of the drug. The major toxicities of guanethidine
are orthostatic hypotension and sexual dysfunction. Guanethidine
requires the catecholamine reuptake pump to reach its intracellular
site of action in the postganglionic nerve terminal. Therefore,
drugs that inhibit uptake of guanethidine into the adrenergic terminal
or the vesicle (cocaine, tricyclic antidepressants, amphetamines)
will interfere with the antihypertensive action of guanethidine.
Pharmacodynamic mechanisms of drugs that act at the
postganglionic sympathetic synapses to deplete or block the release
of norepinephrine (NE). Reserpine blocks the uptake of NE into the vesicle
(2). Guanethidine (G) both depletes NE in the vesicle (2) and prevents
the release of NE into the synapse (1). Cocaine, tricyclic antidepressants
(TCAs), tyramine, amphetamines, and reserpine may decrease the effectiveness
of G (2, 3, and 4). Decreased effectiveness may occur by inhibiting
uptake of G into the presynaptic terminal or the vesicle, or inappropriate
release of G from the vesicle.
Drugs that dilate blood vessels by acting directly on smooth
muscle cells through nonautonomic mechanisms are useful in treating
some hypertensive patients. The four major mechanisms utilized by
vasodilators are set forth in Table 7–1. Compensatory responses
are marked for some vasodilators, especially hydralazine and minoxidil,
and include salt retention and reflex tachycardia.
Table 7–1. Mechanisms
of Action of Vasodilators
That Cause Release of Nitric Oxide
Hydralazine is an older vasodilator
that has more effect on arterioles than on veins, is orally active,
and is suitable for chronic therapy. Hydralazine apparently acts
through the release of nitric oxide from endothelial cells. However,
the drug is rarely used at high dosages because of its toxicity;
therefore, its efficacy is limited. Toxicities of the drug include
tachycardia, salt and water retention, and drug-induced lupus erythematosus.
However, the latter effect is uncommon at dosages below 200 mg/day
and is reversible upon stopping the drug. Nitroprusside is
a short-acting agent (duration of action is a few minutes) that
must be infused continuously and is used in hypertensive emergencies.
The drug’s mechanism of action involves the release of nitric
oxide from the drug molecule itself. The released nitric oxide stimulates
guanylyl cyclase and increases cyclic guanosine monophosphate (cGMP)
concentration in smooth muscle, resulting in smooth muscle relaxation
and vasodilation. The toxicity of nitroprusside includes excessive hypotension,
tachycardia, and, if infusion is continued over several days, accumulation
of cyanide or thiocyanate in the blood.
That Cause Cell Hyperpolarization
Minoxidil is another older vasodilator
that has more effect on arterioles than on veins and is orally active. Minoxidil
is a prodrug; its metabolite, minoxidil sulfate, hyperpolarizes
and relaxes vascular smooth muscle by opening potassium channels.
Minoxidil is reserved for severe hypertension owing to its multiple
side effects. Clinical use of minoxidil generally requires coadministration
of a diuretic and β-receptorantagonist to minimize
compensatory responses. The toxicity of minoxidil consists of severe
compensatory responses, hirsutism, and pericardial abnormalities. Diazoxide is given as intravenous
boluses or as an infusion and has a duration of action of several
hours. Like minoxidil sulfate, diazoxide opens potassium channels,
hyperpolarizing and relaxing smooth muscle cells. This parenteral
vasodilator is used in hypertensive emergencies. The drug also reduces
insulin release and can be used to treat hypoglycemia caused by
insulin-producing tumors. The toxicity of diazoxide includes hypotension,
hyperglycemia, and salt and water retention.
That Block Calcium Channels
Calcium channel blockers include nifedipine,
verapamil, and diltiazem; they
are effective vasodilators. Because they are orally active, these
drugs are suitable for chronic use in hypertension of any severity.
Many analogs of nifedipine are also available. Because they produce
fewer compensatory responses, the calcium channel blockers are usually
preferred to hydralazine and minoxidil. Their mechanism of action
and toxicities are discussed in greater detail in Chapter 8.
Vasodilator That Activates Dopamine (D1) Receptor
Dopamine D1 receptor activation by fenoldopamcauses
prompt, marked, arteriolar vasodilation. This drug is given by intravenous
infusion. The drug has a short duration of action of 10 minutes
and is used for hypertensive emergencies.
The sequence of angiotensin II formation is presented in Figure
7–6. Renin enzymatically converts angiotensinogen into
angiotensin I (inactive peptide), which is subsequently converted
into angiotensin II (active) by ACE. The three primary drug classes
that alter the physiologic actions of this system are the renin
inhibitors, ACE inhibitors, and the angiotensin II receptor (AT1)
antagonists. Of these drug classes, the most extensively used are
the drugs that inhibit the enzyme variously known as ACE, kininase
II, or peptidyl dipeptidase. Angiotensin II is a major stimulant
of aldosterone release. The renin inhibitors, ACE inhibitors, and
angiotensin receptor antagonists all reduce aldosterone levels.
The action of renin inhibitors, angiotensin-converting
enzyme inhibitors (ACE inhibitors), and angiotensin receptor (AT1)
antagonists. Renin converts angiotensinogen to angiotensin I. ACE
is responsible for converting angiotensin I into the vasoconstrictor
angiotensin II and for inactivating bradykinin. Bradykinin is a
vasodilator normally present in very low concentrations. Blockade
of ACE decreases the vasoconstrictor angiotensin II and increases
the vasodilator bradykinin. The renin inhibitors and AT1 receptor
antagonists lack the effect on bradykinin levels, which may explain
the lower incidence of cough observed with these drug classes.
Blockade of aldosterone release and its effects may lead to hyperkalemia.
This potassium accumulation may be marked, especially if the patient
has renal impairment, is consuming a high-potassium diet, or is
taking potassium-sparing diuretics. Under these circumstances, potassium concentrations
may reach toxic levels. For additional information, see the section
on Diuretic Medications below.
Inhibition of renin prevents the initiation of the renin-angiotensin-aldosterone
cascade (Figure 7–6). Previous renin inhibitors were peptides
and demonstrated low potency and bioavailability. Aliskiren represents
a new class of low molecular weight, orally active renin inhibitors.
Bioavailability of aliskiren is low at 2 to 3%, yet this
drug produces a dose-dependent decrease in angiotensins I and II
and aldosterone. Clinically, aliskiren produces a dose-dependent
reduction in blood pressure in patients with essential hypertension.
The most important adverse effect associated with aliskiren is decreased
glomerular filtration. When aliskiren is used alone, hyperkalemia
is minimal in patients with normal renal function. Concomitant use
of aliskiren with either of the drug classes that inhibit the renin-angiotensin-aldosterone
system, or potassium-sparing diuretics, increases the risk of hyperkalemia.
Hyperuricemia, gastrointestinal distress, and skin rash are also
associated with use. The exception to the generally high safety
of this class of drugs applies to pregnancy because they may cause
renal damage in the fetus. This class of drugs appears to have considerable
promise in the treatment of patients with renal disease, hypertension,
and other cardiovascular dysfunctions.
The prototypical drug for this class is captopril. ACE
inhibition results in a reduction in blood levels of angiotensin
II and aldosterone and probably an increase in endogenous vasodilators
of the kinin family such as bradykinin (Figure 7–6). ACE
inhibitors have a low incidence of serious adverse effects when
given in normal dosage, and produce minimal compensatory responses.
The adverse effects of ACE inhibitors include a chronic cough in
up to 30% of patients. Decreases in glomerular filtration
rate may occur in patients with preexisting renal vascular disease,
although these drugs are protective in diabetic nephropathy. Hyperkalemia
may occur in up to 11% of patients taking these drugs,
and increases further when combined with potassium-sparing diuretics,
renin inhibitors, or the subsequently discussed angiotensin receptor antagonists. As with the renin inhibitors, these drugs may cause renal
damage in the fetus, and are, therefore, absolutely contraindicated
Drugs in this class are commonly referred to as angiotensin receptor blockers (ARBs).
The protypical drug in this class is the orally active agent losartan; this drug and its many analogs
competitively inhibit angiotensin II at its AT1 receptor
site (Figure 7–6). Losartan, valsartan,
irbesartan, candesartan, and other analogs appear to be as
effective in lowering blood pressure as the ACE inhibitors. The adverse
effects of these drugs are similar to those of the ACE inhibitors;
however, there is a lower incidence of chronic cough. They do cause
fetal renal toxicity like that of the other drug classes inhibiting
the renin-angiotensin-aldosterone system, and are thus contraindicated
The tubular transport systems of the nephron regulate the solute,
electrolyte, and water loss from the tubule. Each tubular segment
has a unique major transport system. These transporters are found
on the luminal (urinary) side of the epithelium. Diuretics are divided
into several subgroups (Figure 7–7) based on their inhibition
of these different tubular transporters. Because the mechanisms
for these diuretic subgroups differ, their adverse effects also
differ. Table 7–2 highlights the electrolyte and systemic
pH changes that result from the clinical use of these subgroups.
The subgroups of the diuretics are based on anatomic
sites and cellular processes in the nephron. The effects of the
diuretic agents are predictable from a knowledge of the function
of the segment of the nephron in which they act. Each segment of
the nephron has a different mechanism for reabsorbing sodium and
other ions. Abbreviations for the different segments of the nephron
are as follows: proximal convoluted tubule (PCT), thick ascending
limb of the loop of Henle (TAL), distal convoluted tubule (DCT),
and cortical collecting tubule (CCT).
Table 7–2. Electrolyte
and Systemic pH Changes Produced by the Various Diuretic Subgroups ||Download (.pdf)
Table 7–2. Electrolyte
and Systemic pH Changes Produced by the Various Diuretic Subgroups
|Amount in Urine|
|Carbonic anhydrase inhibitors||↑||↑↑↑||↑||Acidosis|
|K+-sparing diuretics||↑||–||↓ ||Acidosis|
A summary of the passage of fluid through the nephron and tubular
transport systems is provided in Figure 7–8. At the glomerulus,
fluid is freely filtered through the glomerular membrane and into
Bowman’s space. Because the total plasma volume (about
4 L) is filtered many times daily (total filtrate about 180 L/day),
the major function of the remainder of the nephron is to reabsorb essential
substances. The proximal convoluted tubule carries out isosmotic
reabsorption of amino acids, glucose, and numerous ions. This is
also the major site for sodium chloride and sodium bicarbonate reabsorption.
Bicarbonate itself is poorly reabsorbed through the luminal membrane, but
conversion of bicarbonate to carbon dioxide via carbonic acid permits
rapid reabsorption of the carbon dioxide. Bicarbonate can then be
regenerated from carbon dioxide within the tubular cell and transported
into the interstitium and back into the blood. Carbonic anhydrase
is required for the bicarbonate reabsorption process and resides
on the brush border and in the cytoplasm. This enzyme is the target
of carbonic anhydrase inhibitor diuretic drugs. Sodium is separately reabsorbed
from the lumen in exchange for hydrogen ions at the luminal surface
of the cells and then transported into the interstitial space by
the sodium pump at the basolateral surface. The proximal tubule
is responsible for 60 to 70% of the total reabsorption
of sodium and water. Active secretion and reabsorption of weak acids
and bases also occurs in the proximal tubule. Uric acid transport
is especially important and is targeted by some of the drugs used
in treating gout (Chapter 34).
Overview of the tubule transport systems and sites of
action of diuretics.
The thick ascending limb of the loop of Henle reabsorbs sodium,
potassium, and two chloride molecules out of the urine into the
interstitium of the kidney (Figure 7–9). The segment is
also a major site of calcium and magnesium reabsorption. Reabsorption
of sodium, potassium, and chloride are all accomplished by a single
carrier, which is the target of the loop diuretics. This cotransporter
provides the concentration gradient for the countercurrent-concentrating
mechanism in the kidney and is responsible for the reabsorption
of 20 to 30% of the sodium filtered at the glomerulus.
Because potassium is pumped into the cell from both the luminal
and basal sides, an escape route must be provided; this occurs via
a potassium-selective channel into the lumen. Because the potassium
diffusing through these channels is not accompanied by an anion,
a net positive charge is set up in the lumen. This positive potential
drives the reabsorption of calcium and magnesium.
Ion transport pathways across the luminal and basolateral
membranes of the thick ascending limb cell. The lumen-positive electrical
potential created by K+ back diffusion
drives divalent (and monovalent) cation reabsorption via the paracellular
pathway. The major transport system is a Na+/K+/2Cl– (NKCC2)
cotransporter located in the luminal membrane.
The distal convoluted tubule actively pumps sodium and chloride
out of the lumen of the nephron via an electrically neutral cotransporter
(Figure 7–10). This cotransporter is the target of the
thiazide diuretics. The distal convoluted tubule is responsible
for approximately 5 to 8% of sodium reabsorption. Calcium
is also reabsorbed in this segment under the control of parathyroid hormone (PTH), and its
role in osteoporosis is discussed in Chapter 25. Reabsorption of
calcium from the tubule requires the Na+-Ca2+ exchanger
discussed in more detail in Chapter 9. Facilitation of this exchange
and Ca2+ reabsorption is the reason these medications
are occasionally used in the treatment of chronic renal stone formation.
Ion transport pathways across the luminal and basolateral
membranes of the distal convoluted tubule cell. As in all tubular
cells, Na+/K+ ATPase
is present in the basolateral membrane. The primary Na+ and
Cl– cotransporter (NCC) is electrically neutral
and located in the luminal membrane. “R” represents the
The cortical collecting tubule is the last tubular site of sodium
reabsorption and the final site of K+ excretion.
Sodium reabsorption in this segment is controlled by aldosterone
(Figure 7–11). This segment is responsible for reabsorbing
2 to 5% of the total filtered sodium. The reabsorption
of sodium occurs via channels and is accompanied by an equivalent
loss of potassium or hydrogen ions. The collecting tubule is thus
the primary site of potassium excretion and of urine acidification.
The aldosterone receptor and the sodium channels are sites of action
of the potassium-sparing diuretics. Reabsorption of water occurs
in the medullary collecting tubule under the control of ADH (Figure
Ion transport pathways across the luminal and basolateral
membranes of collecting tubule and collecting duct cells. Inward
diffusion of Na+ leaves a lumen-negative potential,
which drives reabsorption of Cl– and efflux
of K+. The Na+-K+ exchange
function is regulated by aldosterone, which binds to an intracellular
receptor (R). ADH acts on a receptor to facilitate insertion of
aquaporins (water channels) into the luminal surface and reabsorption
of water from the tubule. Hydrogen ion (H+)
secretion into the tubule with bicarbonate (HCO3–)
reabsorption is also regulated here.
Six subgroups of diuretic classes have been characterized based
on their pharmacodynamic mechanisms. These subgroups are osmotic,
carbonic anhydrase inhibitors, loop, thiazide, potassium-sparing
diuretics, and ADHantagonists (Figure 7–7). These drugs
reduce vascular volume by either modifying salt excretion, water
excretion, or both (Figure 7–8). Currently, only loop,
thiazide, and potassium-sparing diuretics are commonly used to decrease
vascular volume in the treatment of hypertension. Carbonic anhydrase
inhibitors such as acetazolamide are
used to reduce intraocular pressure in glaucoma, to treat acute
high-altitude sickness, and for edematous conditions associated
with metabolic alkalosis. ADH antagonists such as demeclocycline and the newer “vaptans” are
used in the treatment of the syndrome of inappropriate ADH secretion
(SIADH). SIADH is associated with some neoplasms, with neurologic
and pulmonary disorders, and as an adverse effect of some drugs.
Finally, most diuretics act from the luminal side of the membrane
and must be present in the urine. They are filtered at the glomerulus
and some are also secreted by the weak acid-secretory carrier in
the proximal tubule. Aldosteronereceptor antagonists, such as spironolactone
and eplerenone, are exceptions in that they enter the collecting tubule
cell from the basolateral side and bind to the cytoplasmic aldosterone
Mannitol, the prototypical osmotic diuretic, is given intravenously.
Other drugs often classified with mannitol (but rarely used) include
glycerin, isosorbide, and urea. Because mannitol is freely filtered
at the glomerulus but poorly reabsorbed from the tubule, mannitol
remains in the lumen and “holds” water by virtue
of its osmotic effect. The major location for this action is the
proximal convoluted tubule, where the bulk of isosmotic reabsorption
normally occurs. Reabsorption of water is also reduced in the descending
limb of the loop of Henle and the collecting tubule.
The volume of urine is increased.
Most filtered solutes will be excreted in larger amounts unless
they are actively reabsorbed. Sodium excretion is usually increased
because the rate of urine flow through the tubule is greatly accelerated
and sodium transporters cannot handle the volume rapidly enough.
Mannitol can also reduce brain volume and intracranial pressure
by osmotically extracting water from the tissue into the blood.
A similar effect occurs in the eye.
These drugs were formerly used
to maintain high urine flow when renal blood flow is reduced or
in conditions of solute overload from severe hemolysis or rhabdomyolysis, but
are currently not used for these conditions. Mannitol and several
other osmotic agents are useful in reducing intraocular pressure
in acute glaucoma and intracranial pressure in neurologic conditions.
Removal of water from the intracellular
compartment may cause hyponatremia and pulmonary edema. As the
water is excreted, hypernatremia may follow. Headache, nausea, and
vomiting are common.
Furosemide is the prototypical
loop agent. Furosemide, bumetanide, and torsemide are sulfonamide derivatives. Ethacrynicacid is
a phenoxyacetic acid derivative but acts by the same mechanism.
Loop diuretics inhibit the cotransport of sodium, potassium, and
chloride (Figure 7–9). The loop diuretics are relatively short-acting.
Diuresis usually occurs over a 4-hour period following a dose.
The loop of Henle is responsible
for a significant fraction of total renal sodium chloride reabsorption;
therefore, a full dose of a loop diuretic produces a massive sodium
chloride diuresis. If tissue perfusion is adequate, edema fluid
is rapidly excreted and blood volume may be significantly reduced.
The diluting ability of the nephron is reduced because the loop
of Henle is the site of significant dilution of urine. Inhibition
of the Na+/K+/2Cl– transporter
also results in loss of the lumen-positive potential, which reduces
reabsorption of divalent cations as well. As a result, calcium excretion
is significantly increased. Ethacrynic acid is a moderately effective
uricosuric drug if blood volume is maintained.
The presentation of large amounts of sodium to the collecting
tubule as a function of loop diuresis may result in significant
potassium wasting and excretion of protons; hypokalemic alkalosis
may occur. The loop diuretics may also have pulmonary vasodilating
effects; the mechanism is not known. Finally, prostaglandins are
important in maintaining glomerular filtration. The efficacy of diuretics,
especially loop diuretics, decreases when synthesis of prostaglandins
is inhibited, as with nonsteroidal anti-inflammatory drugs (Chapter 34).
The major application of loop
diuretics is in the treatment of edematous states including heart
failure and ascites. They are particularly valuable in acute pulmonary
edema, in which the pulmonary vasodilating action plays a useful role.
They are used in hypertension if response to thiazides is inadequate,
but the short duration of the action of loop diuretics is a disadvantage
in this condition. A less common but important application is in
the treatment of severe hypercalcemia, which may occur in malignancy.
Loop diuretics cause potassium
wasting, ultimately resulting in hypokalemia (Table 7–2).
Large amounts of sodium are presented to the collecting tubules.
The potassium is excreted by the latter segment in an effort to
conserve sodium. The potassium wasting may be severe, and metabolic
alkalosis may also occur. Because they are so efficacious, the loop
diuretics can cause hypovolemia and associated orthostatic hypotension
and reflex tachycardia. Ototoxicity is also an important toxic effect of the loop agents. The sulfonamides in this group may cause a typical sulfonamide allergy.
Hydrochlorothiazide, the prototypical
agent, and all the other members of this group are sulfonamide derivatives.
Thiazides are active by the oral route and have a duration of action
of 6 to 12 hours, which is considerably longer than the loop diuretics.
The major action of thiazides is to inhibit sodium chloride transport
in the early segment of the distal convoluted tubule (Figure 7–10).
In full doses, thiazides produce
moderate but sustained sodium and chloride diuresis. Hypokalemic
metabolic alkalosis may occur (Table 7–2). Reduction in
the transport of sodium into the tubular cell reduces intracellular
sodium and promotes sodium-calcium exchange. As a result, reabsorption
of calcium from the urine is increased and urine calcium content
is decreased—the opposite of the effect of loop diuretics.
Because they act in a diluting segment of the nephron, thiazides
may interfere with excretion of water and cause dilutional hyponatremia.
Thiazides also reduce blood pressure, and the maximal pressure-lowering
effect occurs at doses lower than the maximal diuretic doses. When
a thiazide is used with a loop diuretic, a synergistic effect occurs
with marked diuresis.
The major application of thiazides
is in hypertension, for which their long duration and moderate intensity
of action are particularly useful. Chronic therapy of edematous
conditions such as mild heart failure is another important application,
although loop diuretics are preferred. Chronic renal calcium stone
formation can sometimes be controlled with thiazides because of
their ability to reduce urine calcium concentration.
Massive sodium diuresis with hyponatremia
is an uncommon but dangerous early effect of thiazides. As with
loop diuretics, chronic therapy is often associated with potassium
wasting potentially resulting in hypokalemia. Diabetic patients
may have significant hyperglycemia. Serum uric acid and lipid levels
are also increased in some individuals. Thiazides are sulfonamides
and share sulfonamide allergenic potential.
Spironolactone and eplerenone are steroid derivatives
that act as pharmacologic antagonists of aldosterone in the collecting tubules
(Figure 7–11). By combining with and blocking the intracellular
aldosterone receptor, these drugs reduce the expression of genes
controlling synthesis of epithelial sodium ion channels and Na+/K+ ATPase. Amiloride and triamterene act
by blocking the sodium channels in the same portion of the nephron.
Spironolactone and eplerenone have slow onsets and offsets of action
of 24 to 72 hours. Amiloride and triamterene have duration of action
of 12 to 24 hours.
All drugs in this class cause
an increase in sodium clearance and a decrease in potassium and
hydrogen ion excretion and therefore qualify as potassium-sparing
diuretics. They may also cause hyperkalemic metabolic acidosis (Table
Potassium wasting caused by chronic
therapy with loop or thiazide diuretics, if not controlled by dietary
potassium supplements, may be minimized by these drugs. The most
common use is in the form of products that combine a thiazide with
a potassium-sparing agent in a single pill. The aldosteronereceptor antagonists of this group are also used to treat aldosteronism.
Aldosteronism (elevated serum aldosterone levels) occurs in hepatic
cirrhosis and heart failure. Spironolactone and eplerenone have
been shown to have significant long-term benefits in heart failure
(Chapter 9). Some of this effect may occur in the heart, an action
that is not yet understood. Finally, spironolactone may also cause
endocrine abnormalities, including gynecomastia and antiandrogenic effects. Eplerenone has fewer antiandrogenic effects.
The most important toxic effect
is hyperkalemia. These drugs should never be given with potassium
supplements or potassium-containing salt substitutes. Other aldosterone antagonists such as renin inhibitors, ACE inhibitors and angiotensin
receptor antagonists, if used at all, should be used with great