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CHAPTER 45 DRUGS FOR HYPERTENSION

It is important to appreciate that we cannot cure HTN, we can only reduce symptoms
- treatment must continue lifelong, making noncompliance a significant problem

I. CLASSIFICATION OF BLOOD PRESSURE

A. NORMAL
- systolic BP <120 mm Hg and diastolic BP <80 mm Hg

B. PREHYPERTENSION
- indicates increased risk of cardiovascular disease – even though outright
HTN has not yet developed
- those with pressure in the prehypertension range have a 2- to 3-fold
increased risk of cardiovascular
events
- to reduce risk, people should adopt certain health promoting lifestyle
changes

C. HYPERTENSION
- systolic BP >140 mm Hg or diastolic BP >90 mm Hg

isolated systolic hypertension (ISH) – systolic BP >140 mm Hg


and diastolic BP <90 mm Hg

- should be based on several BP readings, not just one


- if initial screen shows that BP is elevated (but does not represent
an immediate danger),
measurement should be repeated on two subsequent visits
- at each visit, two measurements should be made, at least 5
minutes apart
- patient should be seated in a chair – not an examination
table – with his or her feet on
the floor
- if the mean of all readings shows that systolic BP is indeed >140
mm Hg or diastolic BP is >90 mm Hg, HTN should be diagnosed

II. TYPES OF HYPERTENSION

A. PRIMARY (ESSENTIAL) HYPERTENSION


- HTN that has no identifiable cause
- diagnosis is made by ruling out probable specific causes of BP elevation
- chronic, progressive disorder
- at risk: older people are at higher risk than younger people
African Americans and Mexican Americans are at higher risk than
white Americans
postmenopausal women are at higher risk than premenopausal
women
obese people are at higher risk than lean people
- although the cause of primary HTN is unknown, the condition can be
successfully treated
- treatment is not curative; drugs can lower BP, but they do not
eliminate the underlying
pathology
- treatment must continue lifelong
- also referred to as essential HTN

B. SECONDARY HYPERTENSION
- elevation of BP brought on by an identifiable primary cause
- it may be possible to treat that cause directly rather than relying
on drugs for symptomatic relief
- some individuals can actually be cured
- when cure is not possible, secondary HTN can be managed with the same
drugs used for primary
HTN

III. CONSEQUENCES OF HYPERTENSION


- left untreated, prolonged elevation of BP can lead to heart disease
(myocardial infarction [MI], heart
failure, angina pectoris), kidney disease, and stroke
- degree of injury is directly related to the degree of pressure elevation:
the higher the pressure, the
greater the risk
- HTN-related deaths result largely from cerebral hemorrhage, renal failure,
heart failure, and MI

IV. MANAGEMENT OF CHRONIC HYPERTENSION

A. BASIC CONSIDERATIONS
1. Benefits of Lowering Blood Pressure
- when the BP of hypertensive individuals is lowered, morbidity is
decreased and life is
prolonged

2. Patient Evaluation
a. Hypertension with a Treatable Cause – some forms of HTN
result from treatable
causes, such as Cushing’s syndrome,
pheochromocytoma, and oral
contraceptive use
- patients should be evaluated for these causes
and managed
appropriately
- direct treatment of the underlying cause can control
BP, eliminating the need
for further antihypertensive therapy

b. Factors that Increase Cardiovascular Risk


When the following factors are present, aggressive
therapy is indicated:
i. target-organ damage:
heart disease
retinopathy
stroke / transient ischemic attack
chronic kidney disease peripheral
arterial disease

ii. major cardiovascular risk factors:


cigarette smoking obesity
diabetes
inadequate exercise dyslipidemia
microalbuminuria advancing age (>55 for
men, >65 for women)
family history of premature cardiovascular
disease

c. Diagnostic Tests – should be done in all patients:


- electrocardiogram
- complete urinalysis
- hemoglobin and hematocrit
- blood levels of sodium, potassium, calcium, creatinine,
glucose, uric acid,
triglycerides, and cholesterol (total, LDL, and HDL)

3. Treatment Goals
- ultimate goal is to reduce cardiovascular and renal morbidity and
mortality
- hopefully, this can be accomplished without decreasing
quality of life with the drugs
employed
Stage 1 or 2 HTN – maintain systolic BP<140 mm Hg and diastolic
BP<90 mm Hg
Diabetes or Chronic Kidney Disease – target BP <130/<80 mm Hg
Over 50 – reducing systolic pressure

4. Therapeutic Interventions
Blood Pressure Reductions:
- patients with prehypertension = implement healthy lifestyle
changes
- patients with HTN = treat with antihypertensive drugs
combined with healthy lifestyle
changes

B. LIFESTYLE MODIFICATIONS
- when implemented before HTN develops, healthy lifestyle changes may
actually prevent HTN
- when implemented after HTN develops, healthy lifestyles changes can
lower BP, decreasing or
eliminating the need for drugs
- can decrease other cardiovascular risk factors

1. Weight Loss – can reduce BP and can enhance responses to


antihypertensive drugs
- goal is to achieve a body mass index in the normal range (18.5 –
24.9)

2. Sodium Restriction – can lower BP and can enhance hypotensive effects


of drugs
- restriction benefits are short lasting: over time, BP returns to its
original level,
despite continued salt restriction
- patients should be given information on salt content of foods

3. DASH Eating Plan – diet rich in fruits, vegetables, and low-fat dairy
products, and low in total fat, saturated fats, and cholesterol
- encourages intake of whole grain products, fish, poultry, and nuts
- recommends minimal intake of red meat and sweets

4. Alcohol Restriction – excessive alcohol consumption can raise BP and


create resistance to
antihypertensive drugs
- most men should consume no more than 1 ounce/day
- most women should consume no more than 0.5 ounce/day

5. Aerobic Exercise – regular exercise can reduce BP


- facilitates weight loss, reduces the risk of cardiovascular disease,
and reduces all cause
mortality

6. Smoking Cessation – smoking is a major factor for cardiovascular


disease and may reduce the effects
of antihypertensive drugs
- cardiovascular benefits of quitting become evident within a year
7. Maintenance of Potassium and Calcium Intake – in hypertensive
patients, potassium can lower BP
- preferred sources are fresh fruits and vegetables
- in hypokalemic patients, potassium supplement, potassium-sparing
diuretic or a potassium
containing salt substitute may be necessary

V. MANAGEMENT OF CHRONIC HYPERTENSION: PHARMACOLOGIC THERAPY

A. PHARMACOLOGIC THERAPY
- many medications are used to treat chronic HTN
- all can lower BP, however, the difference is the site of the drug action

B. CLASS OF ANTIHYPERTENSIVE DRUGS

1. Diuretics – mainstay of antihypertensive therapy


- reduce BP when used alone, and can enhance the effects of other
hypotensive drugs

a. Thiazide Diuretics – hydrochorothiazide


- reduce BP by:
reduction of blood volume = responsible for initial
antihypertensive
effects
reduction of arterial resistance = develops over
time and is responsible
for long-term antihypertensive effects
- principal adverse effect is hypokalemia which can be
minimized by
consuming potassium rich foods and using
potassium supplements or
potassium sparing diuretic
- other adverse effects include dehydration,
hyperglycemia, and hyperuricemia

b. High-Ceiling (Loop) Diuretics – greater diuresis than thiazides


- possible amount of fluid loss that can be produced is
greater than needed or
desirable - - are not routinely used
- reserved for: patients who need greater diuresis
than can be achieved with
thiazides
patients with a low GFR (thiazides do not
work when GFR is
low)
- lower BP by reducing blood volume and promoting
vasodilation
- adverse effects: hypokalemia, dehydration,
hyperglycemia, and
hyperuricemia
- can cause hearing loss

c. Potassium Sparing Diuretics – degree of diuresis is small


- have only modest hypotensive effects
- can play an important role in an antihypertensive
regimen
- role is to balance potassium loss caused by
thiazides or loop
diuretics

- most significant adverse effect is hyperkalemia


- must not be used in combination with one
another or with potassium
supplements
- should not be used routinely with ACE inhibitors
or angiotensin II
receptor blockers, both of which promote
hyperkalemia

2. Sympatholytics (Adrenergic Antagonists)


- suppress the influence of the sympathetic nervous system on the
heart, blood vessels, and other structures

a. Beta-Adrenergic Blockers – among the most widely used


antihypertensive drugs
- less effective in African American patients than in white
patients
- adverse effects: bradycardia, decreased
atrioventricular (AV) conduction,
and reduced contractility, bronchoconstriction, can
mask signs of
hypoglycemia, depression, insomnia, bizarre
dreams and sexual
dysfunction

Useful Actions: blockade of cardiac beta1 receptors


decreases heart rate and
contractility, decreasing cardiac output
beta blockers can suppress reflex
tachycardia caused by
vasodilators in the regimen
blockade of beta1 receptors on
juxtaglomerular cells of the
kidney reduces release of rennin,
reducing
angiotensin II-mediated
vasoconstriction and
aldosterone-mediated volume
expansion
long-term use of beta blockers reduces
peripheral vascular
resistance

- intrinsic symathomimetic activity – can produce mild


stimulation of beta
receptors while blocking receptor stimulation by
strong agonists
(norepinephrine)
- heart rate at rest is slowed less than with
other beta blockers
- if symptomatic bradycardia with another
beta blocker
develops, switching to one of these
may help

b. Alpha1 Blockers – doxazosin, terazosin


- prevent stimulation of alpha1 receptors on arterioles
and veins, preventing
sympathetically mediated vasoconstriction
- resultant vasodilation reduces both
peripheral resistance and
venous return to the heart
- most disturbing side effect is orthostatic hypotension
- not used as first line therapy for HTN - - diuretic is
clearly preferred to the
alpha blocker

c. Alpha/Beta Blockers: Carvedilol and Labetalol – can block


alpha1 receptors as well as
beta receptors

Useful actions: alpha blockade promotes dilation of


arterioles and veins
blockade of cardiac beta1 receptors reduces
heart rate and
contractility
blockade of beta1 receptors on
juxtaglomerular cells
suppresses release of rennin

- share the ability of other beta blockers to reduce


peripheral vascular
resistance
- can exacerbate bradycardia, AV heart block, and
asthma
- can produce postural hypotension
d. Centrally Acting Alpha2 Agonists – clonidine, methyldopa
- act within the brainstem to suppress sympathetic
outflow to the heart and
blood vessels
- result is vasodilation and reduced cardiac output,
both of which help
lower BP
- can dry mouth, sedation, severe rebound HTN if
treatment is abruptly
discontinued, hemolytic anemia, and liver
disorders

e. Adrenergic Neuron Blockers – guanethidine, guanadrel,


reserpine
- decrease BP through actions in the terminals of
postganglionic sympathetic
neurons
- guanethidine and guanadrel inhibit release of
norepinephrine
- reserpine causes norepinephrine depletion
- both actions result in decreased sympathetic
stimulation of the heart
and blood vessels
- major adverse effect of guanethidine and guanadrel =
severe orthostatic
hypotension, resulting from decreased
sympathetic tone to veins
- last choice agents for chronic HTN
- major adverse effect of reserpine = depression

3. Direct Acting Vasodilators:


Hydralazine and Minoxidil
- both reduce BP by promoting arteriolar dilation
- both have little or no effect on veins, producing very little
orthostatic hypotension
- with both drugs, lowering BP may be followed by reflex
tachycardia, rennin release,
and fluid retention
- reflex tachycardia can rennin release can be prevented
with a beta blocker
- fluid retention can be prevented with a diuretic

Adverse Effects:
hydralazine – syndrome resembling systemic lupus
erythematosus (SLE)
- rare at recommended doses
- if SLE-like reaction occurs, hydralazine should be
withdrawn
- 3rd drug of choice for HTN treatment

minoxidil – substantially more toxic than hydralazine


- by causing fluid retention, can promote
pericardial effusion
(accumulation of fluid beneath the
myocardium) that can
progress to cardiac tamponade (compression
of the heart)
- less serious effect is Hypertrichosis (excessive
hair growth)
- not routinely used in chronic HTN
- reserved for patients with severe HTN

4. Calcium Channel Blockers


- dihydropyridines (nifedipine) and nondihydropyridines (verapamil
and diltiazem)
- promote dilation of arterioles
- verapamil and diltiazem have direct suppressant effects on the
heart
- can cause reflex tachycardia (greater risk from dihydropyridine and
minimal with verapamil
and diltiazem)
- verapamil and diltiazem must be used with caution in patients with
bradycardia, heart failure,
or AV heart block
- rapid-acting formulation of nifedipine has been associated with
increased mortality in patients
with MI and unstable angina

5. ACE Inhibitors
- lower BP by preventing formation of angiotensin II, preventing
angiotensin II-mediated
vasoconstriction and aldosterone-mediated volume expansion
- in diabetic patients with renal damage, these actions slow
progression of kidney injury
- less effective in African Americans than in white patients
- principal adverse effects are persistent cough, first dose
hypotension, angioedema, and
hyperkalemia (secondary to suppression of aldosterone
release)
- combined use with potassium supplements or potassium sparing
diuretics is generally avoided
- can cause fetal harm during 2nd and 3rd trimester

6. Angiotensin II Receptor Blockers


- lower BP in much the same way as ACE inhibitors, except ARBs do
their work by blocking the
actions of angiotensin II (ACE inhibitors block the formation)
- can cause fetal harm and must not be used during pregnancy
- do not induce cough or significant hyperkalemia
- causes angioedema

7. Aldosterone Receptor Blockers


- eplerenone and spirolactone (also potassium sparing diuretic)
- lower BP by promoting renal excretion of sodium and water
- promote renal retention of potassium, posing a risk of
hyperkalemia
- combined use with ACE inhibitors and ARBs is permissible, but
must be done with caution

C. FUNDAMENTALS OF HYPERTENSION DRUG THERAPY


- lifestyle changes should be instituted first
- drug therapy should be initiated – and lifestyle changes should continue
- treatment often begins with a single dose and, if needed, another drug
may be added or substituted
- possible reasons for failure of initial drug should be assessed
- insufficient dosage, poor compliance, excessive salt intake, and the
presence of secondary
hypertension may be among the reasons

1. Initial Drug Selection – determined by the presence or absence of a


compelling indication (comorbid
condition for which a specific class of antihypertensive drugs has
been shown to improve)

a. Patients WITHOUT Compelling Indications – for initial therapy


in the absence of a
compelling indication, thiazide diuretic is recommended
- can reduce morbidity and mortality
- well tolerated and inexpensive
- beta blockers reduce morbidity and mortality as a good
alternative
- ACE inhibitors, ARBs, CCBs, and alpha/beta blockers =
diuretics and beta
blockers in the ability to lower BP
- may not be as effective at reducing morbidity
and mortality
- reserved for special indications and for patients
who have not
responded to thiazide diuretics and beta
blockers
- centrally acting sympatholytics, adrenergic neuron
blockers, and direct acting
vasodilators are not well suited for initial
monotherapy

2. Individualizing Therapy
a. Patients with Comorbid Conditions – comorbid conditions
complicate treatment of HTN
- renal disease and diabetes are two especially
problematic conditions

i. renal disease – nephrosclerosis (hardening of the kidney)


secondary to HTN is
among the most common causes of progressive
renal disease
- renal insufficiency causes water retention,
causing BP to rise higher,
promoting even more renal injury, etc.
- ACE inhibitors and ARBs work best for these
patients
- as a rule, diuretics are used also
- advanced renal insufficiency, thiazide diuretics
are ineffective, hence
a loop diuretic should be employed
- potassium sparing diuretics should be avoided

ii. diabetes – in patients with diabetic nephropathy, ACE


inhibitors and ARBs can
slow progression of renal damage and reduce
albuminuria
- in diabetic patients, beta blockers and diuretics
can decrease
morbidity and mortality
- beta blockers can suppress glycogenolysis and
mask early signs of
hypoglycemia, therefore must be used with
caution
- thiazides and high-ceiling diuretics promote
hyperglycemia, therefore
should be used with caution

3. Patients in Special Populations


a. African Americans – HTN is a major health problem
- develops earlier in blacks than in whites
- much higher incidence and more likely to be more
severe
- greater risk of heart disease, end-stage renal disease
and stroke

b. Elderly – incidence of HTN in people over 60 is about 65%


- since cardiovascular reflexes are blunted, treatment
carries a significant risk
of orthostatic hypotension

D. MINIMIZING ADVERSE EFFECTS


- antihypertensive drugs can produce many unwanted effects, including
hypotension, sedation, and
sexual dysfunction
- adverse effects caused by exacerbation of comorbid diseases are both
predictable and avoidable

1. Why Compliance can be Difficult to Achieve


- antihypertensive regimens can be complex and expensive
- treatment must continue lifelong
- antihypertensive drugs can cause a number of adverse effects,
ranging from sedation to
hypotension to disruption of sexual function
- difficult to convince people who are feeling good to take drugs that
may make them feel worse
- people may decide that exposing themselves to the negative
effects of therapy today is paying
too high a price to avoid the adverse consequences of HTN at
some indefinite time in
the future

a. Ways to Promote Compliance


i. Educate the Patient – compliance requires motivation, patient
education can help
provide it
- patients should be taught about the consequences of
HTN and benefits of
treatment
- patients must understand that, left untreated, HTN can
cause heart disease,
kidney, and stroke
- patients should appreciate that, with proper therapy,
the risks of long-term
complications can be minimized, resulting in a
longer and healthier life
- patients must understand that drugs do not cure HTN –
they only control
symptoms
- patients must understand that for treatment to be
effective, medication must
be taken lifelong

ii. Teach Self-Monitoring – patients should be taught the goal of


treatment (usually
maintenance of BP)
- they should also be taught to monitor and record their
BP daily
- this increases patient involvement and provides
positive feedback that can
help promote compliance

iii. Minimize Side Effects – adverse side effects can be minimized


by:
• encouraging patients to report side effects
• discontinuing objectionable drugs and substituting
more acceptable ones
• avoiding drugs that can exacerbate comorbid
conditions
• using doses that are low initially and then gradually
increased

iv. Establish a Collaborative Relationship – patient who feels like a


collaborative partner in
the treatment program is more likely to comply
than is the patient who
feels that treatment is being imposed
- collaboration allows the patient to help set treatment
goals, create the
treatment program, and evaluate progress
- facilitates communication about side effects, especially
with respect to drug-
induced sexual dysfunction

v. Simplify the Regimen – in order to promote compliance, steps


should be taken to make
the dosing schedule as simple as possible
- once effective regimen is established, an attempt
should be made to switch to
once-a-day or twice-a-day dosing
- if appropriate combination product is available,
substitute it for components
vi. Other Measures – positive reinforcement = therapeutic goals
achieved
- family member involvement
- schedule office visits at convenient times and following
missed appointments
- KEEP COSTS LOW

VI. DRUGS FOR HYPERTENSIVE DISORDERS OF PREGNANCY

A. PREECLAMPSIA AND ECLAMPSIA


preeclampsia = elevated BP and proteinuria that develops after the 20th
week of gestation
- risks factors include obesity, black race, chronic HTN, diabetes,
collagen vascular disorders,
and previous preeclampsia
- management is based on the severity of the disease, the status of
the mother and fetus, and
the length of gestation
- objective is to preserve the health of the mother and deliver
an infant that will not
require intensive and prolonged neonatal care
- requires close maternal and fetal monitoring
- delivery is the only cure
- drug of choice for lowering BP is hydralazine
- vitamins C and E may prevent development because both are
antioxidants and scavenge free
radicals that are believed to trigger this condition

eclampsia = elevated BP and proteinuria that develops after the 20th


week of gestation that leads to the
development of seizures
- seizure drug of choice is magnesium sulfate (anticonvulsant)
- magnesium blood levels should be monitored (target range is
4 – 7 mEq/L)

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