strategy to minimize risk of developing diabetes.89

The magnitude of fasting glucose increases with thiazide

diuretics is variable and dose dependent. Patients with diabetes

and high risk for diabetes because of elevated fasting glucose

exhibit the greatest glucose increases, and patients without diabetes exhibit the smallest increases. When increases in serum

glucose concentration occur in patients without diabetes, they

are typically on average 3.6 to 6.7 mg/dL after multiple years

of thiazide diuretic therapy.41,133 It appears that these changes

are not clinically relevant because CV events are reduced despite

these changes. Moreover, diabetes is not a contraindication to

diuretic use; it is a compelling indication (Fig. 14-3) because risk

of CV events is reduced in patients with diabetes who are treated

with a thiazide diuretic.89,91

B.A.’s fasting glucose concentration is still considered normal.

Her fasting glucose values should be documented and monitored at least once a year to detect any increases. Adding either

an ACEI or ARB is a reasonable option for B.A. She should be

315Essential Hypertension Chapter 14

encouraged to continue dietary modifications, and response to

therapy should be re-evaluated in 2 to 4 weeks.

HYPOKALEMIA

CASE 14-4, QUESTION 6: When is potassium correction

needed to manage diuretic-induced hypokalemia?

B.A.’s potassium is within the normal range. Potassium

replacement is not indicated. Diuretic-associated hypokalemia

should be treated when serum concentrations are below normal regardless of whether symptoms (e.g., muscle cramps) are

present. Serum potassium should be measured at baseline and 2

to 4 weeks after initiating therapy or increasing the diuretic dose.

Potassium-rich foods (e.g., dried fruit, bananas, potatoes,

avocados) may help prevent small decreases in potassium, but

they cannot be used as sole therapy to correct hypokalemia.

For instance, one medium-size banana has only 11.5 mEq of

potassium. The usual replacement dose of prescribed potassium

chloride is 20 to 40 mEq/day but can range from 10 to more

than 100 mEq/day. Potassium chloride, bicarbonate, gluconate,

acetate, and citrate salts are available for potassium replacement

therapy. Rather than supplement potassium, which does not

effectively correct the underlying mechanisms responsible for

hypokalemia, a more appropriate and effective strategy to manage diuretic-induced hypokalemia is to add a potassium-sparing

diuretic. Hypomagnesemia often accompanies diuretic-induced

hypokalemia, and must be normalized before hypokalemia can

be effectively reversed.

OTHER METABOLIC ABNORMALITIES

CASE 14-4, QUESTION 7: How should the increase in B.A.’s

uric acid be managed?

Thiazide diuretics can increase serum uric acid concentrations

in a dose-dependent fashion. Uric acid increases also occur with

loop diuretics, but to a lesser extent. Increased proximal tubular renal reabsorption, decreased tubular secretion, or increased

postsecretory reabsorption of uric acid contribute to diureticinduced hyperuricemia. Thiazide-induced hyperuricemia is usually small (≤0.5 mg/dL) and is not clinically significant in patients

without a history of gout.133 For patients with a history of gout,

diuretics are not contraindicated, but an increase in serum uric

acid may require a decrease in dose or possibly discontinuation of the diuretic, especially for those not on preventive antihyperuricemic therapy (e.g., allopurinol, febuxostat). Acute

gouty arthritis precipitated by diuretic therapy should be treated,

and the diuretic should be discontinued, at least temporarily.

Future use of the diuretic will depend on whether long-term antihyperuricemic therapy is to be added and the risk versus benefit

for continuing the diuretic. B.A.’s serum uric acid concentration

is elevated, but switching to a different agent or lowering the

dose of HCTZ is unnecessary because she is not symptomatic of

gout.

It should be noted that changes in parameters such as uric

acid can be informative regarding dosing. When a given dose of

a diuretic fails to lower BP, it is often unclear as to whether the

failure is a result of mechanisms other than volume driving the

hypertension, or a result of the diuretic dose being insufficient to

achieve the desired physiologic effect. For example, the absence

of an increase in uric acid suggests that the administered dose

was insufficient, and that a higher dose merits consideration.

In B.A.’s case, the increase in uric acid confirms that the given

dose was sufficient to have had a physiologic effect, so adding

an antihypertensive agent from a different drug class would be

preferable to increasing the diuretic dose if further BP lowering

is necessary.

CASE 14-4, QUESTION 8: How much will HCTZ alter B.A.’s

cholesterol values?

Small increases in LDL-C and triglycerides are potential side

effects of diuretic therapy. Dietary fat restrictions help minimize,

but do not necessarily prevent, these effects. Contrary to other

biochemical disturbances, diuretic-induced changes in the lipid

profile are not dose related, and overall changes are small. Many

clinical trials lasting more than 1 year have shown that these alterations with diuretic therapy are not sustained with prolonged

use.132,133 Even if these changes are persistent, they are very small

and are not clinically significant. The presence of dyslipidemia

should never be a reason to avoid diuretic therapy.

CASE 14-4, QUESTION 9: What other potential electrolyte

abnormalities should be evaluated in B.A. because of her

thiazide diuretic therapy?

Hyponatremia is a serious, yet infrequent, adverse effect of

diuretics. Changes in sodium concentrations are usually small,

and the majority of patients are usually asymptomatic. Frail,

elderly women appear more susceptible to experiencing severe

hyponatremia (<120 mEq/L) from diuretics, which rarely occurs,

but definitely requires discontinuation of therapy. Attention

should be paid to the presence of other medications that can

contribute to hyponatremia (e.g., selective serotonin reuptake

inhibitors, psychotropic drugs), and patients should be counseled

to avoid excessive free water intake.

Hypomagnesemia is an often-overlooked metabolic complication of diuretic therapy. Both thiazide and loop diuretics

increase urinary excretion of magnesium in a dose-dependent

manner. Symptoms of significant hypomagnesemia include muscle weakness, muscle tremor or twitching, mental status changes,

and cardiac arrhythmias. Presence of these symptoms would

necessitate magnesium supplementation or use of a potassiumsparing agent as noted above if hypokalemia is also present.

Thiazide diuretics decrease urinary calcium excretion and can

be used to prevent calcium-related kidney stones. The retention

of calcium does not significantly increase serum calcium concentrations and does not place patients at risk for hypercalcemia.

This effect, however, may be beneficial in women at risk for osteoporosis (e.g., postmenopausal) such as B.A. or in patients with

osteoporosis. Conversely, loop diuretics increase renal clearance

of calcium.

Reasons for Inadequate BP Control

CASE 14-4, QUESTION 10: What are common reasons for

inadequate patient response to antihypertensive pharmacotherapy?

B.A. has been on her current dose of HCTZ for 4 weeks.

The full antihypertensive effect of HCTZ has been achieved, but

she still has uncontrolled hypertension. She has had a response,

but it remains inadequate. Potential reasons for an inadequate

response, or lack of attaining BP goal values, with an antihypertensive should be considered before modifying her drug therapy regimen (Table 14-11). A comprehensive medication history

and medical evaluation is needed to rule out identifiable causes,

in particular nonadherence to the prescribed regimen. Her BP

reduction with HCTZ is typical. Her kidney function is good,

and no evidence exists of edema, so volume overload is unlikely.

316 Section 2 Cardiac and Vascular Disorders

TABLE 14-11

Reasons for Not Attaining Goal Blood Pressure Despite Antihypertensive Pharmacotherapy

Drug Related Health Condition or Lifestyle Related Other

Nonadherence Volume overload Improper blood pressure measurement

Inadequate antihypertensive dose Excess sodium intake Resistant hypertension

Inappropriate antihypertensive combination therapy Volume retention from chronic kidney disease White-coat hypertension

Inadequate diuretic therapy Secondary disease causes (Table 14-3) Pseudohypertension

Secondary drug-induced causes (Table 14-3) Obesity

Clinician failure to intensify or augment therapy (i.e.,

clinical inertia)

Excessive alcohol intake

There are no apparent secondary causes of elevated BP. It is reasonable to conclude that B.A. needs additional therapy to achieve

her goal BP. It is very common that most patients require two or

more agents to attain BP goal values.

Modifying Therapy

B.A.’s present dose of HCTZ is appropriate and should not be

increased to the maximal recommended dose of 50 mg daily

(considered high-dose therapy) because it may increase risk of

electrolyte and metabolic side effects. B.A.’s potassium dropped

to 3.8 mEq/L with HCTZ, and further dosage increases may

produce hypokalemia (<3.5 mEq/L) requiring correction. Her

hyperuricemia may also be worsened. The slightly increased antihypertensive response expected from increasing to 50 mg/day is

therefore not justified.130 Discontinuing HCTZ and starting a

different agent is an option, but it is not prudent to abandon the

HCTZ; she tolerated the treatment and experienced a reasonable BP response, and the HCTZ will augment the efficacy of

nearly any other agent that may be added, and may benefit her

osteoporosis.

TWO-DRUG REGIMENS

The role of two-drug regimens in the treatment of hypertension

is very clear. Most patients require multiple agents for BP control,

especially in populations with BP goals of less than 130/80 mm

Hg. Consensus guidelines recommend two-drug regimens as

initial therapy for patients in stage 2 hypertension, and list initial

two-drug regimen as an option in stage 1 hypertension.3,15,82,91

Adding a second agent to B.A.’s regimen is needed to reduce

BP to her goal. She is a primary prevention patient, so three

potential add-on antihypertensive agents that are considered firstline include an ACEI, ARB, or CCB. Ideally, a combination of two

drugs with different mechanisms of action should be selected to

produce a complementary effect to lower BP.

Adding an ACEI or ARB to B.A.’s HCTZ will result in additive antihypertensive effects that are independent of reversing

fluid retention. Diuretics reduce BP initially by decreasing fluid

volume, but maintain their antihypertensive effects by lowering

PVR. BP lowering, however, can stimulate renin release from the

kidney and activate the RAAS. This compensatory mechanism

is an in vivo attempt to neutralize BP changes and regulate fluid

loss. An ACEI or an ARB blocks the RAAS, explaining why combinations of these agents with diuretics are additive. Data from

the ACCOMPLISH trial support combination therapy for hypertension. In this randomized, double-blind trial, 11,506 patients

with hypertension were randomly assigned to the combination

of an ACEI with thiazide diuretic or an ACEI with CCB.115 After a

mean follow-up of 3 years, the risk of CV events was significantly

lower with the ACEI with CCB combination. Switching B.A.’s

HCTZ to an ACEI with CCB may be more effective in lowering CV events than adding an ACEI to her current HCTZ. This

would be an acceptable modification. However, considering her

response to HCTZ, simply adding an ACEI is also reasonable.

FIXED-DOSE COMBINATION PRODUCTS

Several fixed-dose combination products including two or three

drugs are available.

For tables showing fixed-dose combination

products that include two or three drugs, see

Online Tables 14-1 and 14-2 at

http://thepoint.lww.com/AT10e.

Although individual dose titration is not simple with fixeddose combination products, their use can reduce the number

of tablets or capsules taken by patients. This has been demonstrated to improve adherence compared with using two separate

single-drug products.141 Improved adherence may increase the

likelihood of achieving goal BP values.

Most fixed-dose combinations include a thiazide diuretic, and

many are available generically. Other fixed-dose combination

products combine a CCB with either an ACEI or ARB. These

combinations, similar to a thiazide with an ACE or ARB, are

highly effective in lowering BP. An economic advantage may even

exist to using a fixed-dose combination if it allows the patient

to receive two drugs for one medication copayment. The Simplified Treatment Intervention To Control Hypertension study

demonstrated that initiating therapy with a fixed-dose combination product according to a treatment algorithm was superior in

attaining goal BP values when compared with usual management

according to national guidelines.117 These data further support

using a fixed-dose combination product for initial therapy.

B.A. is a candidate for fixed-dose combination product. If the

combination of an ACEI with HCTZ is selected for her, many

options exist. All of the products with an ACEI also include HCTZ

at the dose she is currently on. If the combination of an ACEI

with a CCB is selected, fewer options exist, but there are products