Week 3 Study Guide
Chapter 16: Drugs Affecting the Cardiovascular and Renal Systems
ACEIs, ARBs and Direct Renin Inhibitors: MOAs,
indications, Their action on the renin-angiotensin-aldosterone (RAA) system lowers blood
pressure (BP) and reduces the adverse affects of diabetes on the kidney. The DRIs are related
but act uniquely by direct blocking of renin itself, not on its genesis or on the angiotensin
components of the RAA. ACEIs improve oxygenation to heart muscle and decrease
inappropriate remodeling of heart muscle after myocardial infarction (MI) or with heart
failure (HF). Their mild and usually transient adverse effects and their ease of dosing make
them popular drugs. ARBs have similar roles and profiles in hypertension (HTN). The DRIs
and most ARBs do not have HF indications except candesartan and valsartan.
absolute contraindications, There are only three absolute contraindications to the use of these
three drug classes: bilateral renal artery stenosis, angioedema, and pregnancy.
precautions,
monitoring, Baseline BP and a pulse reading should be taken before initiating therapy and
with each change in dosage. Weight and other indicators of fluid status should also be
monitored. See Chapter 40 for further BP monitoring guidelines and other related
chapters for monitoring guidelines for the various disease processes for which these drugs
are used.
During administration of ACEIs, ARBs, and DRIs, monitoring renal function is important.
Serum creatinine levels should be drawn before beginning therapy, after the first week of
therapy, monthly during the first 3 months, and when increasing the dose. The ACEI dose
should be reduced if serum creatinine is more than 2.5 mg/dL. Potassium levels are also
obtained at baseline and with the other labs suggested.
adverse drug reactions, Angioedema, Most common are those associated with hypotension
(dizziness, headache, fatigue, orthostatic hypotension).
drug interactions Losartan levels are significantly lowered by inhibitors of cytochrome P450
(CYP450) 3A4 and 2C9. Irebesartan has a similar problem with CYP450 2C9. Drugs that
inhibit this system (e.g., cimetidine) may cause increased levels of free drug. The clinical
significance of these inhibitions is negligible, however, because the active metabolite is
unaffected. Alsikren has minor issues in the CYP 3A4 system but greater ones in other meds
with P-glycoprotein (e.g., cyclosporine and itraconazole).
Typically, additive hypotensive effects occur with diuretics, but the DRIs make furosemide
less effective. Additive hypotension may also occur with other antihypertensives, nitrates,
phenothiazines, and acute alcohol ingestion. Due to the interference with aldosterone
secretion, the concurrent use of potassium supplements, potassium-sparing diuretics, or
cyclosporine may result in hyperkalemia. The antihypertensive response is reduced by
NSAIDs because of their effect on prostaglandins. Other specific drug interactions and the
appropriate actions to prevent them are given in Table 16-3.
,CCBs: MOA, As shown in Figure 16-2, contraction of smooth muscles is triggered by an
influx of calcium through transmembrane calcium channels. CCBs directly block the influx of
calcium at the onset of the cycle, like the sodium channel blockade in local anesthetics. The
drugs act from the inner side of the membrane and bind to channels in depolarized
membranes, converting the mode of operation of the channel from frequent openings to rare
openings. The result is a marked decrease in transmembrane calcium content and prolonged
vascular smooth muscle relaxation.
indications, CCBs have multiple indications, including angina, HTN, and selected
tachyarrhythmias. Unlabeled indications include migraine headache prophylaxis, Raynaud's
syndrome, cardiomyopathy, and esophageal spasm. Laboratory evidence indicates that CCBs
may interfere with platelet aggregation and reduce the development of atherosclerotic
lesions.
precautions, Verapamil has the strongest negative inotropic effect and should be avoided in
HF, in which this effect can worsen the disorder. It also has the strongest effect on nodal
conduction and can significantly worsen bradycardia. Diltiazem also affects nodal conduction
and can worsen or cause bradycardia, although less than verapamil. None of the CCBs are
drugs of choice immediately after MI, but diltiazem has shown some benefit in reducing
mortality in non–Q-wave MI for a selected group of patients whose ejection fractions are
above 40%. For those with ejection fractions below 40% and for all other patients early after
MI, type 1 CCBs are contraindicated because of their negative inotropic and bradycardic
effects. Patients with ventricular dysfunction, SA or AV nodal conduction disturbances, and
SBPs below 90 mm Hg should not be treated with type 1 CCBs because of the high risk for
induction of HF and significant hypotension.
contraindications,
adverse drug reactions, The more common adverse reactions of CCBs are extensions of their
actions. Reduction in BP secondary to vasodilation may result in dizziness, headache,
hypotension, and syncope. These lead to HF with congestion, shortness of breath, cough, and
palpitations; though a potential class effect, HF is worse with verapamil, diltiazem, and
nifedipine. Gastrointestinal (GI) symptoms can include dry mouth, nausea, vomiting, reflux,
and constipation. Although not common, sexual dysfunction and gynecomastia may occur.
Hyperglycemia is also uncommon but may affect the choice of the drug in patients with
diabetes, especially with nifedipine, verapamil, and diltiazem at high doses. Photosensitivity
and facial telangiectasia can occur with amlodipine, nifedipine, and diltiazem. These drugs
are also associated with hyperpigmentation (Drucker & Rosen, 2011).
drug interactions, Additive hypotensive effects are major concerns with all CCBs given
concurrently with other antihypertensives, nitrates, quinidine, or alcohol. Antihypertensive
effects may be decreased with concurrent use of NSAIDs. Verapamil, diltiazem, and some
dihydropyridines have an additive bradycardic effect with BBs or digoxin. Serum digoxin
levels may be increased with risk of toxicity when it is concurrently used with verapamil,
diltiazem, or nifedipine. Verapamil may decrease the effectiveness of rifampin, and the
effectiveness of verapamil may be decreased by concurrent administration of vitamin D and
calcium. Verapamil may also alter serum lithium levels.
CYP3A4 isoenzymes are involved in the metabolism of all CCBs. Drugs that inhibit this
system, including grapefruit juice, may increase free drug levels. Both verapamil and
, diltiazem increase the risk of myalgia in simvastatin. Food interactions also occur for
several of the CCBs. Specific drug and food interactions and appropriate actions to prevent
them are found in Table 16-6.
differences between dihydropyridines and dihydropyridines, Although this is true of all classes of
CCBs, the greater degree of vasodilation seen in the dihydropyridines causes sufficient reflex
increase in sympathetic tone to overcome the negative inotropic effects. The dihydropyridines
are less dependent on the heart for their effects, but they are still not the drugs of choice
after MI. Dihydropyridines should also be avoided for patients with significant peripheral
edema. Their strong peripheral vasodilating effects result in peripheral pooling of blood and
may lead to reflex tachycardia. They are also contraindicated in unstable angina because of
their potential to cause tachycardia. If it is necessary to give a dihydropyridine to a patient
who has peripheral edema or a tachyarrhythmia disturbance, the sustained-release forms are
preferred. All CCBs should be used cautiously in severe hepatic impairment, with dosage
reduction recommended for most agents. Non-dihydropyridines, of which there are only two currently
used clinically, comprise the other two classes of CCBs. Verapamil (phenylalkylamine class), is relatively selective for
the myocardium, and is less effective as a systemic vasodilator drug. This drug has a very important role in treating
angina (by reducing myocardial oxygen demand and reversing coronary vasospasm) and
arrhythmias. Diltiazem (benzothiazepine class) is intermediate between verapamil and dihydropyridines in its
selectivity for vascular calcium channels. By having both cardiac depressant and vasodilator actions, diltiazem is able
to reduce arterial pressure without producing the same degree of reflex cardiac stimulation caused by
dihydropyridines.
patient education, The drug should be taken exactly as prescribed, at the same time each day.
Sustained-release drugs taken once daily are best taken in the morning for therapeutic effect.
Missed doses should be taken as soon as remembered unless it is almost the time for the next
dose. Doses should not be doubled. Sudden withdrawal may precipitate myocardial ischemia,
so withdrawal is gradual. CCBs cannot relieve acute anginal attacks; they only have a role in
prevention. For patients taking isradipine or nifedipine, anginal attacks sometimes occur 30
minutes after administration because of reflex tachycardia. This is usually temporary and not
necessarily an indication for stopping the drug, but this symptom should be reported to the
health-care provider who needs to consider if other therapy is warranted. Some CCBs have
food interactions, especially with high-fat or high-carbohydrate meals and with grapefruit
juice. The patient should be informed so that the interactions can be avoided. Drug
interactions also occur with some OTC and prescription drugs and with alcohol. CCB can be
taken safely with calcium supplements; the extra calcium does not impair drug effect.
short acting vs long acting CCB side effects Short-acting forms of CCBs have been associated
with more adverse drug reactions. In several trials, the short-acting form of nifedipine was
associated with increased mortality in post-MI patients. All type 2 CCBs cause vasodilation
that results in reflex tachycardia and peripheral pooling of blood. These actions are greatly
reduced in the long-acting forms. To reduce adverse drug reactions and improve adherence,
long-acting forms are suggested
Cardiac Glycosides: indications, They have been medically recognized in the treatment of HF
since 1785.
MOA, All CGs are strong and highly selective inhibitors of the sodium-potassium-adenosine
triphosphatase (ATPase) system: the “sodium pump.” The preferential binding of CGs to
ATPase occurs following phosphorylation of the alpha subunit of the enzyme. Extracellular
potassium promotes dephosphorylation of the enzyme and decreases the affinity of the
, enzyme for the CG. This may explain why increased extracellular potassium reverses some of
the toxic effects of these drugs.
adverse drug reactions, The GI tract is the most common site of adverse drug reactions,
including anorexia, nausea, vomiting, and diarrhea. These result from CNS actions, including
chemoreceptor trigger zone stimulation. Other CNS-based adverse responses include fatigue,
disorientation, and hallucinations, especially in older adults, and visual disturbances,
including yellow vision and green halos around lights. The visual disturbances are considered
classic signs of toxicity but actually occur rarely. Atrial arrhythmias and atrial tachycardia
with AV block are the most common signs of toxicity in children. Cardiac adverse reactions
are extensions of the therapeutic action of these drugs (bradycardia, junctional and AV block
arrhythmias, premature ventricular contractions [PVCs], and bigeminy). Gynecomastia is a
rare adverse reaction.
contraindications, CGs are contraindicated in AV blocks and uncontrolled ventricular
arrhythmias because their action on the AV node may worsen the arrhythmia. They are used
for rate control only after BB; verapamil or diltiazem cannot be used or are inadequate to
achieve the desired rate range. Patients with idiopathic hypertrophic subaortic stenosis
(IHSS) may develop worsening outflow tract obstruction with CG use owing to the action on
myocardial contractility. CG use in cor pulmonale is questionable. Toxicity risk increases in
the presence of hypoxia from any cause.
cautions,
toxicity, Toxicity typically occurs with serum levels greater than 2 ng/mL. Toxicity is commonly
caused by excessive administration of a CG, too much diuresis resulting in hypokalemia,
concurrent development of renal insufficiency, or by administration of drugs that interfere
with excretion of digoxin (see the section “Drug Interactions”). This is especially common in
older adults who have polypharmacy changes. Each of these common etiologies and the
patient's calcium and magnesium levels should be considered in the differential diagnosis.
drug and potassium, Potassium and CGs interact by inhibiting each other's binding to sodium-
potassium-ATPase. Hyperkalemia reduces the enzyme-inhibiting actions of CGs, and
hypokalemia facilitates these actions. Hyperkalemia, however, inhibits the abnormal cardiac
automaticity seen in excessive doses of CGs so that moderately increased extracellular
potassium reduces toxic effects of CGs.
calcium and Mg interactions, Calcium facilitates the toxic actions of CGs by overloading the
intracellular calcium stores. Hypercalcemia increases the risk of CG-induced arrhythmias.
Magnesium has the opposite effects to calcium. Hypomagnesemia is a risk factor for
arrhythmias.
monitoring, Routine monitoring of digoxin levels is generally overdone. Monitoring should
occur in addition to clinical judgment, rather than as a substitute for it. I
patient education, If two doses are missed, the health-care provider should be contacted for
instructions. The drug should not be stopped or the dosage altered without first contacting
the health-care provider. Although the presence of food in the gut does not alter absorption of
CGs, the ingestion of a high-fiber meal may decrease absorption. Tablets can be crushed and
administered with food for patients who have difficulty swallowing. Patients should eat a diet
high in potassium (bananas, orange juice, tomato juice, spinach, melons, dates, raisins,
soybeans, prunes, potatoes, and molasses), unless also taking a potassium-sparing diuretic or
Chapter 16: Drugs Affecting the Cardiovascular and Renal Systems
ACEIs, ARBs and Direct Renin Inhibitors: MOAs,
indications, Their action on the renin-angiotensin-aldosterone (RAA) system lowers blood
pressure (BP) and reduces the adverse affects of diabetes on the kidney. The DRIs are related
but act uniquely by direct blocking of renin itself, not on its genesis or on the angiotensin
components of the RAA. ACEIs improve oxygenation to heart muscle and decrease
inappropriate remodeling of heart muscle after myocardial infarction (MI) or with heart
failure (HF). Their mild and usually transient adverse effects and their ease of dosing make
them popular drugs. ARBs have similar roles and profiles in hypertension (HTN). The DRIs
and most ARBs do not have HF indications except candesartan and valsartan.
absolute contraindications, There are only three absolute contraindications to the use of these
three drug classes: bilateral renal artery stenosis, angioedema, and pregnancy.
precautions,
monitoring, Baseline BP and a pulse reading should be taken before initiating therapy and
with each change in dosage. Weight and other indicators of fluid status should also be
monitored. See Chapter 40 for further BP monitoring guidelines and other related
chapters for monitoring guidelines for the various disease processes for which these drugs
are used.
During administration of ACEIs, ARBs, and DRIs, monitoring renal function is important.
Serum creatinine levels should be drawn before beginning therapy, after the first week of
therapy, monthly during the first 3 months, and when increasing the dose. The ACEI dose
should be reduced if serum creatinine is more than 2.5 mg/dL. Potassium levels are also
obtained at baseline and with the other labs suggested.
adverse drug reactions, Angioedema, Most common are those associated with hypotension
(dizziness, headache, fatigue, orthostatic hypotension).
drug interactions Losartan levels are significantly lowered by inhibitors of cytochrome P450
(CYP450) 3A4 and 2C9. Irebesartan has a similar problem with CYP450 2C9. Drugs that
inhibit this system (e.g., cimetidine) may cause increased levels of free drug. The clinical
significance of these inhibitions is negligible, however, because the active metabolite is
unaffected. Alsikren has minor issues in the CYP 3A4 system but greater ones in other meds
with P-glycoprotein (e.g., cyclosporine and itraconazole).
Typically, additive hypotensive effects occur with diuretics, but the DRIs make furosemide
less effective. Additive hypotension may also occur with other antihypertensives, nitrates,
phenothiazines, and acute alcohol ingestion. Due to the interference with aldosterone
secretion, the concurrent use of potassium supplements, potassium-sparing diuretics, or
cyclosporine may result in hyperkalemia. The antihypertensive response is reduced by
NSAIDs because of their effect on prostaglandins. Other specific drug interactions and the
appropriate actions to prevent them are given in Table 16-3.
,CCBs: MOA, As shown in Figure 16-2, contraction of smooth muscles is triggered by an
influx of calcium through transmembrane calcium channels. CCBs directly block the influx of
calcium at the onset of the cycle, like the sodium channel blockade in local anesthetics. The
drugs act from the inner side of the membrane and bind to channels in depolarized
membranes, converting the mode of operation of the channel from frequent openings to rare
openings. The result is a marked decrease in transmembrane calcium content and prolonged
vascular smooth muscle relaxation.
indications, CCBs have multiple indications, including angina, HTN, and selected
tachyarrhythmias. Unlabeled indications include migraine headache prophylaxis, Raynaud's
syndrome, cardiomyopathy, and esophageal spasm. Laboratory evidence indicates that CCBs
may interfere with platelet aggregation and reduce the development of atherosclerotic
lesions.
precautions, Verapamil has the strongest negative inotropic effect and should be avoided in
HF, in which this effect can worsen the disorder. It also has the strongest effect on nodal
conduction and can significantly worsen bradycardia. Diltiazem also affects nodal conduction
and can worsen or cause bradycardia, although less than verapamil. None of the CCBs are
drugs of choice immediately after MI, but diltiazem has shown some benefit in reducing
mortality in non–Q-wave MI for a selected group of patients whose ejection fractions are
above 40%. For those with ejection fractions below 40% and for all other patients early after
MI, type 1 CCBs are contraindicated because of their negative inotropic and bradycardic
effects. Patients with ventricular dysfunction, SA or AV nodal conduction disturbances, and
SBPs below 90 mm Hg should not be treated with type 1 CCBs because of the high risk for
induction of HF and significant hypotension.
contraindications,
adverse drug reactions, The more common adverse reactions of CCBs are extensions of their
actions. Reduction in BP secondary to vasodilation may result in dizziness, headache,
hypotension, and syncope. These lead to HF with congestion, shortness of breath, cough, and
palpitations; though a potential class effect, HF is worse with verapamil, diltiazem, and
nifedipine. Gastrointestinal (GI) symptoms can include dry mouth, nausea, vomiting, reflux,
and constipation. Although not common, sexual dysfunction and gynecomastia may occur.
Hyperglycemia is also uncommon but may affect the choice of the drug in patients with
diabetes, especially with nifedipine, verapamil, and diltiazem at high doses. Photosensitivity
and facial telangiectasia can occur with amlodipine, nifedipine, and diltiazem. These drugs
are also associated with hyperpigmentation (Drucker & Rosen, 2011).
drug interactions, Additive hypotensive effects are major concerns with all CCBs given
concurrently with other antihypertensives, nitrates, quinidine, or alcohol. Antihypertensive
effects may be decreased with concurrent use of NSAIDs. Verapamil, diltiazem, and some
dihydropyridines have an additive bradycardic effect with BBs or digoxin. Serum digoxin
levels may be increased with risk of toxicity when it is concurrently used with verapamil,
diltiazem, or nifedipine. Verapamil may decrease the effectiveness of rifampin, and the
effectiveness of verapamil may be decreased by concurrent administration of vitamin D and
calcium. Verapamil may also alter serum lithium levels.
CYP3A4 isoenzymes are involved in the metabolism of all CCBs. Drugs that inhibit this
system, including grapefruit juice, may increase free drug levels. Both verapamil and
, diltiazem increase the risk of myalgia in simvastatin. Food interactions also occur for
several of the CCBs. Specific drug and food interactions and appropriate actions to prevent
them are found in Table 16-6.
differences between dihydropyridines and dihydropyridines, Although this is true of all classes of
CCBs, the greater degree of vasodilation seen in the dihydropyridines causes sufficient reflex
increase in sympathetic tone to overcome the negative inotropic effects. The dihydropyridines
are less dependent on the heart for their effects, but they are still not the drugs of choice
after MI. Dihydropyridines should also be avoided for patients with significant peripheral
edema. Their strong peripheral vasodilating effects result in peripheral pooling of blood and
may lead to reflex tachycardia. They are also contraindicated in unstable angina because of
their potential to cause tachycardia. If it is necessary to give a dihydropyridine to a patient
who has peripheral edema or a tachyarrhythmia disturbance, the sustained-release forms are
preferred. All CCBs should be used cautiously in severe hepatic impairment, with dosage
reduction recommended for most agents. Non-dihydropyridines, of which there are only two currently
used clinically, comprise the other two classes of CCBs. Verapamil (phenylalkylamine class), is relatively selective for
the myocardium, and is less effective as a systemic vasodilator drug. This drug has a very important role in treating
angina (by reducing myocardial oxygen demand and reversing coronary vasospasm) and
arrhythmias. Diltiazem (benzothiazepine class) is intermediate between verapamil and dihydropyridines in its
selectivity for vascular calcium channels. By having both cardiac depressant and vasodilator actions, diltiazem is able
to reduce arterial pressure without producing the same degree of reflex cardiac stimulation caused by
dihydropyridines.
patient education, The drug should be taken exactly as prescribed, at the same time each day.
Sustained-release drugs taken once daily are best taken in the morning for therapeutic effect.
Missed doses should be taken as soon as remembered unless it is almost the time for the next
dose. Doses should not be doubled. Sudden withdrawal may precipitate myocardial ischemia,
so withdrawal is gradual. CCBs cannot relieve acute anginal attacks; they only have a role in
prevention. For patients taking isradipine or nifedipine, anginal attacks sometimes occur 30
minutes after administration because of reflex tachycardia. This is usually temporary and not
necessarily an indication for stopping the drug, but this symptom should be reported to the
health-care provider who needs to consider if other therapy is warranted. Some CCBs have
food interactions, especially with high-fat or high-carbohydrate meals and with grapefruit
juice. The patient should be informed so that the interactions can be avoided. Drug
interactions also occur with some OTC and prescription drugs and with alcohol. CCB can be
taken safely with calcium supplements; the extra calcium does not impair drug effect.
short acting vs long acting CCB side effects Short-acting forms of CCBs have been associated
with more adverse drug reactions. In several trials, the short-acting form of nifedipine was
associated with increased mortality in post-MI patients. All type 2 CCBs cause vasodilation
that results in reflex tachycardia and peripheral pooling of blood. These actions are greatly
reduced in the long-acting forms. To reduce adverse drug reactions and improve adherence,
long-acting forms are suggested
Cardiac Glycosides: indications, They have been medically recognized in the treatment of HF
since 1785.
MOA, All CGs are strong and highly selective inhibitors of the sodium-potassium-adenosine
triphosphatase (ATPase) system: the “sodium pump.” The preferential binding of CGs to
ATPase occurs following phosphorylation of the alpha subunit of the enzyme. Extracellular
potassium promotes dephosphorylation of the enzyme and decreases the affinity of the
, enzyme for the CG. This may explain why increased extracellular potassium reverses some of
the toxic effects of these drugs.
adverse drug reactions, The GI tract is the most common site of adverse drug reactions,
including anorexia, nausea, vomiting, and diarrhea. These result from CNS actions, including
chemoreceptor trigger zone stimulation. Other CNS-based adverse responses include fatigue,
disorientation, and hallucinations, especially in older adults, and visual disturbances,
including yellow vision and green halos around lights. The visual disturbances are considered
classic signs of toxicity but actually occur rarely. Atrial arrhythmias and atrial tachycardia
with AV block are the most common signs of toxicity in children. Cardiac adverse reactions
are extensions of the therapeutic action of these drugs (bradycardia, junctional and AV block
arrhythmias, premature ventricular contractions [PVCs], and bigeminy). Gynecomastia is a
rare adverse reaction.
contraindications, CGs are contraindicated in AV blocks and uncontrolled ventricular
arrhythmias because their action on the AV node may worsen the arrhythmia. They are used
for rate control only after BB; verapamil or diltiazem cannot be used or are inadequate to
achieve the desired rate range. Patients with idiopathic hypertrophic subaortic stenosis
(IHSS) may develop worsening outflow tract obstruction with CG use owing to the action on
myocardial contractility. CG use in cor pulmonale is questionable. Toxicity risk increases in
the presence of hypoxia from any cause.
cautions,
toxicity, Toxicity typically occurs with serum levels greater than 2 ng/mL. Toxicity is commonly
caused by excessive administration of a CG, too much diuresis resulting in hypokalemia,
concurrent development of renal insufficiency, or by administration of drugs that interfere
with excretion of digoxin (see the section “Drug Interactions”). This is especially common in
older adults who have polypharmacy changes. Each of these common etiologies and the
patient's calcium and magnesium levels should be considered in the differential diagnosis.
drug and potassium, Potassium and CGs interact by inhibiting each other's binding to sodium-
potassium-ATPase. Hyperkalemia reduces the enzyme-inhibiting actions of CGs, and
hypokalemia facilitates these actions. Hyperkalemia, however, inhibits the abnormal cardiac
automaticity seen in excessive doses of CGs so that moderately increased extracellular
potassium reduces toxic effects of CGs.
calcium and Mg interactions, Calcium facilitates the toxic actions of CGs by overloading the
intracellular calcium stores. Hypercalcemia increases the risk of CG-induced arrhythmias.
Magnesium has the opposite effects to calcium. Hypomagnesemia is a risk factor for
arrhythmias.
monitoring, Routine monitoring of digoxin levels is generally overdone. Monitoring should
occur in addition to clinical judgment, rather than as a substitute for it. I
patient education, If two doses are missed, the health-care provider should be contacted for
instructions. The drug should not be stopped or the dosage altered without first contacting
the health-care provider. Although the presence of food in the gut does not alter absorption of
CGs, the ingestion of a high-fiber meal may decrease absorption. Tablets can be crushed and
administered with food for patients who have difficulty swallowing. Patients should eat a diet
high in potassium (bananas, orange juice, tomato juice, spinach, melons, dates, raisins,
soybeans, prunes, potatoes, and molasses), unless also taking a potassium-sparing diuretic or
