CARDIOLOGY 3B: FINALS responsiveness to vasoconstrictor

agents
HYPERTENSIVE VASCULAR DISEASE - proposed to be present in 35 to 50%
of essential hypertensive persons
- common, asymptomatic, readily detectable, usually easily treatable - common in patients with non-
- often leads to lethal complications if left untreated insulin-dependent diabetes mellitus
- in 90 to 95% of cases the etiology is unknown (NIDDM) or obesity
- hyperinsulinemia
PREVALENCE  produces renal sodium
- depends on both the racial composition of the population studied and the retention (at least acutely) and
Insulin Resistance increases sympathetic activity
criteria used to define the condition
- higher prevalence has been documented in the non-white population  vascular smooth-muscle
- ratio of hypertension frequency in women versus men increases from 0.6 to hypertrophy secondary to the
0.7 at age 30 to 1.1 to 1.2 at age 65. mitogenic action of insulin
 modifies ion transport across
ESSENTIAL HYPERTENSION the cell membrane

- primary, essential, or idiopathic hypertension (most common type)
- no definable cause
- a generalized or functional abnormalities may be the cause of hypertension
- complexity of the interrelations of these systems:
 peripheral and/or central adrenergic
 renal
 hormonal
 vascular
Genetic Considerations inheritance is probably multifactorial
salt intake, obesity, occupation,
Environment alcohol intake, family size, and
crowding
60% of hypertensives is particularly
Salt Sensitivity responsive to the level of sodium
intake
- some abnormalities are primary and
some are secondary
- abnormality in sodium transport
Cell Membrane Defect
leads to an abnormal accumulation of
calcium in vascular smooth muscle,
resulting in a heightened vascular
- enzyme secreted by the JG cells
ROLE OF RENIN
of the kidney
- more common in individuals of African
descent than in white patients
Low-Renin Essential Hypertension
- not hypokalemic
- reduced adrenal response to sodium
restriction
- these individuals make up 25 to 30% of
the hypertensive population
Non-modulating Essential - plasma renin activity levels that are
normal to high
Hypertension - hypertension that is salt-sensitive
because of a defect in the kidney's
ability to excrete sodium appropriately
- more insulin-resistant
- can be corrected by converting-
enzyme inhibitor (ACEi)
- approximately 15% of patients with
essential hypertension
High-Renin Essential
- elevated renin levels and blood
Hypertension pressure may both be secondary to an
increase in adrenergic system activity
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 FACTORS THAT MODIFY THE COURSE
- the younger the patient when hypertension is first noted, the greater is the
reduction in life expectancy
- females with hypertension fare better than males up to the age of 65
- prevalence of hypertension in premenopausal females is substantially less
than that in age-matched males or postmenopausal women
- elevated serum cholesterol, glucose intolerance, and/or cigarette smoking,
significantly enhance the effect of hypertension on mortality rate regardless of
age, sex, or race
- positive correlation exists between obesity and arterial pressure
SECONDARY HYPERTENSION
- a specific structural organ or gene defect is responsible for hypertension
- should not be ignored for at least two reasons
 correction of the cause may cure their hypertension
 may provide insight into the etiology of essential hypertension
RENAL HYPERTENSION
- activation of the renin-angiotensin system (RAAS)

RISK FACTORS FOR ADVERSE PROGNOSIS IN

HYPERTENSION
Black race
Youth
Male sex
Persistent diastolic pressure > 115 mmHg
Diabetes mellitus
Hypercholesterolemia
Obesity
Excess alcohol intake
Evidence of end organ damage
1. Cardiac
a. Cardiac enlargement (HPN for ≥7 years)
b. ECG signs of ischemia or LV strain
c. Myocardial infarction
d. Congestive heart failure
2. Eyes
a. Retinal exudates and hemorrhages - including preeclampsia and eclampsia
b. papilledema - Renal parenchymal hypertension
3. Renal: impaired renal function
4. Nervous System: cerebrovascular accident - excess secretion of renin by juxtaglomerular cell tumors or nephroblastomas

 hyperaldosteronism, hypertension, hypokalemia, and overproduction

SOKOLOW CRITERIA: R-wave in V5 or V6 + S-wave in V1 > 35mV of aldosterone
 peripheral renin activity is elevated

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RENOVASCULAR
Plasma Renin
elevated
Activity
Cardiac Output slightly elevated
Circulatory
Response (Tilting less exaggerated
and Valsalva)
low
Blood Volume (severe unilateral
hypertension)
- abrupt onset of severe
hypertension and/or the
onset of hypertension of any
severity in a patient under the
age of 25 or over the age of
50 (Differential:
Pheochromocytoma)
- presence of an abdominal
bruit
DIAGNOSIS
Renal Insufficiency: elevated
creatinine or blood urea
nitrogen level, associated with
proteinuria and hematuria
- rapid-sequence IVP
- the captopril-enhanced
RENAL radionuclide renal scan
PARENCHYMAL - duplex Doppler flow study
elevated far less - magnetic resonance (MRI)
angiography and spiral
frequently
computed tomography (CT)
scan - most sensitive and
normal specific screening test
(except uremia and
anemia)
renal angiogram
exaggerated - establishes the presence of a
renal arterial lesion and aids
in the determination of
whether the lesion is due to
high atherosclerosis or to one of
(severe disease) the fibrous or fibromuscular
dysplasias
renal vein renin
determinations
- used to assess the functional
significance of any lesion
noted on arteriography
Polycystic Renal - the ischemic kidney has a
Disease: bilateral significantly higher venous
upper abdominal plasma renin activity than the
normal kidney, by a factor of
masses
1.5 or more
- correction may be
anticipated in at least 80% of
patients
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 ENDOCRINE HYPERTENSION
- aldosterone-induced sodium retention
- hypokalemia is a prominent feature
- aldosterone levels are high
- plasma renin activity levels are suppressed
and respond sluggishly to sodium depletion
- tumor or bilateral adrenal hyperplasia
DIAGNOSIS:
PRIMARY ALDOSTERONISM
- usually exhibit hypokalemia
- aldosterone concentration or excretion
rate is high and plasma renin activity is
low
- aldosterone: renin ratio – high
- unilateral or bilateral
- removal of the lesion - reduces arterial
pressure only in patients with unilateral
disease.
- sodium-retaining effect of large amounts
of glucocorticoids
- increased production of
mineralocorticoids has also been
documented in some patients
- angiotensin-mediated hypertension
- adrenogenital syndrome - due to C-11 or
C-17 hydroxylase deficiency
 deoxycorticosterone accounts for
the sodium retention
accompanied by suppression of plasma
renin activity
CUSHING'S SYNDROME DIAGNOSIS:
- 24-h urine test for cortisol and creatinine
- Dexamethasone Challenge (screening)
 administration of 1 mg of
dexamethasone at bedtime,
followed by the measurement of
plasma cortisol at 7 to 10 A.M.
- urine cortisol level of >2750 nmol (100 ug)
or suppression of the plasma cortisol level
to <140 nmol/L (5 ug/dL) effectively rules
out Cushing's syndrome.
- increased secretion of epinephrine and
norepinephrine
- diagnosis is confirmed by demonstrating
increased urinary excretion of epinephrine
and norepinephrine and/or their
PHEOCHROMOCYTOMA metabolites
DIAGNOSIS
-Rule of 10: 10% bilateral, 10% malignant,
10% extra-adrenal
- abrupt onset of severe hypertension
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 and/or the onset of hypertension of any
severity in a patient under the age of 25 or
over the age of 50 (Differential: Renal
Vascular Disease)
- history of headaches, palpitations, anxiety
attacks, unusual sweating, hyperglycemia,
and weight loss
- measurement of catecholamines and their
metabolites in a 24-h urine sample
- occurs in up to one-third of patients with
hyperparathyroidism
o can be attributed to renal
parenchymal damage due to
HYPERCALCEMIA
nephrolithiasis and
nephrocalcinosis
o increased calcium levels can also
have a direct vasoconstrictive
effect
- the mechanism is likely to be activation of
the RAS
- estrogen component of oral contraceptive
agents - stimulates the hepatic synthesis of
the renin
- the hypertension will remit within 6
months of stopping the drug
- Other mechanisms:
(1) increase vascular sensitivity to
ORAL CONTRACEPTIVES
angiotensin II
(2) the presence of mild renal disease
(3) familial factors (over one-half have a
positive family history for hypertension)
(4) age (hypertension is significantly
more prevalent in women over age 35)
(5) estrogen content of the
contraceptive
(6) obesity
EFFECTS OF HYPERTENSION
- most common cause of death is heart disease
- stroke and renal failure also frequent, particularly in patients with significant
retinopathy.
- concentric LVH, ultimately cavity dilates, and the
symptoms and signs of heart failure appear
- angina pectoris - accelerated coronary arterial disease and
HEART increased myocardial oxygen requirements
- heart is enlarged and has a prominent left ventricular
impulse
- A2 is accentuated
- faint murmur of aortic regurgitation
- Presystolic heart sounds (S4)
- protodiastolic (ventricular, third) heart sound or
summation gallop rhythm may be present
- ECG substantially underestimates the frequency of
cardiac hypertrophy compared with that observed with the
echocardiogram
- divided into central nervous system and retinal changes
- Central nervous system dysfunction
 manifestations are due to vascular occlusion,
NEUROLOGIC
hemorrhage, or encephalopathy
 cerebral hemorrhage - the result of both the
elevated arterial pressure and the development of
cerebral vascular microaneurysms (Charcot-
Bouchard aneurysms)
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- Hypertensive encephalopathy
 consists of the following symptom complex:
severe hypertension, disordered consciousness,
increased intracranial pressure, retinopathy with
papilledema, and seizures
- Keith-Wagener-Barker classification of the retinal
changes in hypertension
- Arteriosclerotic lesions of the afferent and efferent
arterioles and the glomerular capillary tufts
 result in a decreased glomerular filtration rate and
tubular dysfunction
 Proteinuria and microscopic hematuria occur
because of glomerular lesions
RENAL

Stage Description
1 Mild to moderate narrowing of sclerosis of the arterioles
2 Moderate to marked narrowing of the arterioles
Local and/or generalized narrowing of arterioles
Exaggeration of the light reflex
Arteriovenous crossing changes
3 Retinal arteriolar narrowing and focal constriction - approximately 10% of the deaths caused by hypertension
Retinal edema
Cotton-wool patches
result from renal failure
Retinal hemorrhages
Hard exudates Table 35-1. Classification of Blood Pressure for Adults Aged 18 Years and Older
4 As for Group 3 plus optic disc swelling Category Systolic Pressure, mmHg Diastolic Pressure, mmHg
Optimal <120 <80
 associated with focal spasm and progressive Normal <130 <85
general narrowing of the arterioles, as well as the High Normal 130-139 85-89
Hypertensiona
appearance of hemorrhages, exudates, and
- Stage 1 (mild) 140-159 90-99
papilledema
- Stage 2 (moderate) 160-179 100-109
- Stage 3 severe 180-209 110-119
2
Based on the average of ≥2 readings taken at each of two or more visits after an initial screening

NOTE: NO MORE PRE-HYPERTENSION STAGE IN JNC-8

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 TREATMENT
Dietary Management
INDICATIONS FOR THERAPY
 mild dietary sodium restriction (up to 5 g NaCl per day) can be
 every patient with a diastolic arterial pressure that persistently achieved by eliminating all additions of salt to food that is prepared
exceeds 90mmHg normally
 any patient over 65 years of age with a systolic arterial pressure >160  increase in potassium and/or calcium intake
mmHg
 Restriction in the intake of cholesterol and saturated fats
 risk of developing hypertensive vascular complications
 Reducing alcohol intake to <15 mL daily
o greater in men than in women, in younger than in older
 Isotonic exercises (jogging, swimming)
persons
 Stop smoking
o diabetic than non-diabetic patients
DASH (Dietary Approaches to Stop Trial of Antihypertensive
Hypertension) Interventions and Management
Hypertension Optimal Treatment UK Prospective Diabetes Study
(TAIM) study
(HOT) study (UKPDS)
 uses natural foods that are  weight reduction (average
 no significant difference in  individuals with a blood
high in potassium and low in 4.4 kg over 6 months)
cardiovascular risk between pressure of 144/82 mmHg
saturated and total fat lowered blood pressure by
patients with treatment goal had a substantially lower risk
diastolic blood pressures of compared to those with a  significantly lowered blood 2.5 mmHg.
pressure in borderline and
90 and 80 mmHg blood pressure of 154/87
stage 1 hypertensive
 in patients with diabetes this mmHg
subjects
is not the case  similar finding in diabetic
subset

DRUG THERAPY FOR HYPERTENSION

Six Classes of Antihypertensive Drugs

GENERAL MEASURES

Nondrug therapeutic intervention  diuretics (thiazide)

 antiadrenergic agents
(1) relief of stress  vasodilators
(2) dietary management  calcium entry blockers
(3) regular aerobic exercise  angiotensin-converting enzyme (ACE) inhibitors
(4) weight reduction (if needed)  angiotensin receptor antagonists
(5) control of other risk factors contributing to the development of
arteriosclerosis *FIRST-LINE ANTI-HYPERTENSIVE DRUGS (JNC-8)

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 THIAZIDES Central actions - clonidine,
- sodium diuresis and volume depletion methyldopa, guanabenz, and
- reduction in peripheral vascular guanfacine
resistance
- shown to reduce mortality and  predominantly a-receptor
morbidity in long-term trials agonists
- adverse metabolic effects -  Stimulation of a2 receptors in
hypokalemia, hyperuricemia, the vasomotor centers of the
carbohydrate intolerance, and brain reduces sympathetic
DIURETICS hyperlipidemia outflow, thereby reducing
arterial pressure
- Loop-acting diuretics - furosemide  baroreceptor reflex is intact -
and bumetanide postural symptoms are absent
- K sparing diuretics – spironolactone,  rebound hypertension may
ANTIADRENERGIC AGENTS occur probably secondary
triamterene and amiloride
 causes renal sodium loss by to an increase in
blocking the effect of norepinephrine release,
mineralocorticoids which is inhibited by these
 can produce hyperkalemia agents owing their agonist
effect on presynaptic a
receptors

Ganglionic blocking drugs –

trimethaphan, Guanethidine
 reserved for the rapid
lowering of arterial pressure
 orthostatic hypotension is a
frequent side effect.

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 Adrenergic Receptor Blockers  Cardioselective beta-
 pentolamine and blocking agents - e.g.,
phenoxybenzamine metoprolol, atenolol
ｧ block both presynaptic
(alpha2) and postsynaptic  Nonselective beta blockers -
alpha1 receptors, and the propranolol and timolol,
former action accounts for nadolol
the tolerance that
develops
 Prazosin  Pindolol and acebutolol -
ｧ blocks only postsynaptic partial agonist activity and,
alpha receptors therefore, produce less
ｧ tolerance occurs only bradycardia
infrequently  Labetalol exerts both alpha
and beta adrenergic blocking
Adrenergic Receptor Blockers actions
 most effective in reducing - more rapid onset of action but
cardiac output and in produces more postural
ANTIADRENERGIC AGENTS
ANTIADRENERGIC AGENTS lowering arterial pressure symptoms and chronic sexual
when there is increased dysfunction than the other
cardiac sympathetic nerve beta blockers
activity - useful in patients with a
 often used as first-line myocardial infarct or angina
therapy because it prevents an
 block the adrenergic nerve- increase in heart rate
mediated release of renin - may be ineffective in patients
from the renal previously treated with beta
juxtaglomerular cells blockers and is
 shown to reduce morbidity contraindicated in patients
and mortality in long-term with heart failure, asthma,
clinical trials bradycardia, or heart block
 can precipitate congestive - an alternative therapy in
heart failure and asthma patients with eclampsia who
 caution in diabetic patients - are unresponsive to
inhibit the usual sympathetic hydralazine.
responses to hypoglycemia

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 Hydralazine
 cause direct relaxation of
vascular smooth muscle
 acts mainly on arterial
resistance rather than on
venous capacitance vessels
 reflex increase in sympathetic
discharge that raises heart
rate and cardiac output
 side effect - lupus
erythematosus-like syndrome
Minoxidil
VASODILATORS  more potent than hydralazine
 produces significant
hypertrichosis and fluid
retention
 mainly limited to patients
with severe hypertension and
renal
insufficiency
Diazoxide, Nitroprusside and
Nitroglycerin
 are useful only for the
treatment of hypertensive
emergencies
 inhibit the generation of a
CALCIUM CHANNEL ANTAGONISTS
potent vasoconstrictor
(angiotensin II)
 retard the degradation of a
potent vasodilator
(bradykinin)
ACE INHIBITORS
 can modify the activity of the
adrenergic nervous system
 especially useful in renal or
renovascular hypertension
and in diabetic patients, as
well as in accelerated and
malignant hypertension
 in patients with bilateral renal
artery stenosis, rapid
deterioration of renal function
may occur
Enalipralat
- an intravenous form of the ACE
inhibitor enalapril, has also proven
effective, particularly in individuals with
left heart failure
 competitively inhibit its
binding to the angiotensin II
ANGIOTENSIN RECEPTOR AT1 receptor subtype
ANTAGONISTS  do not cause cough or
angioedema.
Three subclasses of calcium channel
antagonists
 Phenylalkylamine derivatives
(e.g., verapamil – CI: patients
with structural heart disease)
 Benzothiazepines (e.g.,
diltiazem)
 Dihydropyridines (e.g.,
amlodipine, Nifedipine – may
cause CVA)
 binds on the a1subunit of the
L-type voltage-dependent
calcium channel
 all three subclasses cause
vasodilation
 only dihydropyridines -
produce reflex tachycardia
 Diltiazem and verapamil - can
both slow atrioventricular
conduction
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  Short-acting nifedipine - APPROACH TO DRUG THERAPY
reported to increase the
incidence of acute coronary World Health Organization- Sixth U.S. Joint National Committee
events International Society of Hypertension (JNC) on Prevention, Detection,
(WHO-ISH) Evaluation, and Treatment of High
SYST-EUR (Systolic Hypertension in Blood Pressure (JNC VI)
Europe) trial
recommends initiating therapy with recommends starting with diuretics
 long-acting calcium channel
any of six classes of agents and/or beta blockers because they
antagonist reduced mortality
are the ones where mortality trials
to an extent equivalent to that
have demonstrated a positive effect
previously reported for
of treatment
diuretics and beta blockers

Several critical caveats common to both approaches:

- pharmacologic treatment of essential hypertension is usually lifelong
2014 GUIDELINE MANAGEMENT ALGORITHM (JNC-8) - reducing diastolic blood pressure to <90 mmHg is appropriate and reduces
morbidity and/or mortality.

1. Start with a low dose of an agent and, if blood pressure is not controlled,
increase only moderately.

2. Start with an agent that may also treat and/or not harm a coexisting condition.

3. Add a second agent from a different, complementary class if blood pressure is

not controlled with a moderate dose of the first agent.

4. Start with an agent that the patient is likely to tolerate best; long-term
compliance is related to tolerability and efficacy of the first agent used.

5. Use a diuretic when two agents are used, in nearly all cases.

6. Use thiazide diuretics only at low doses, i.e., 25 mg/d of hydrochlorothiazide or

its equivalent, unless some pressing reason exists.

7. Use low-dose combination therapy when appropriate as initial therapy:

a. A diuretic with a beta blocker, ACE inhibitor, or angiotensin II antagonist;
b. A calcium channel blocker with an ACE inhibitor or a beta blocker

8. One or two agents will control blood pressure in 90% of hypertensive patients;
to achieve a diastolic blood pressure of <90 mmHg in the HOT study, two agents
were required in 70% of cases.

R C A M B I D A 2 0 1 5 | 11
 SPECIAL CONSIDERATIONS - nitroprusside and converting-
enzyme inhibitors - may cause
- ACE should be used cautiously in adverse effects on the fetus and are
patients with impaired renal contraindicated.
function, and renal function should
- marked blood pressure elevation
be assessed frequently (every 4 to 5
days) for the first 3 weeks - papilledema and retinal
- ACE are contraindicated in patients hemorrhages and exudates
with bilateral renal artery stenosis - manifestations of hypertensive
RENAL DISEASE - ACE - drugs of choice encephalopathy, such as severe
o patients with unilateral renal headache, vomiting, visual
artery stenosis and a normally disturbances (including transient
functioning contralateral kidney blindness), transient paralyses,
MALIGNANT HYPERTENSION
convulsions, stupor, and coma
o also in patients with chronic
renal failure with or without - cardiac decompensation
diabetes mellitus - rapidly declining renal function
- fibrinoid necrosis of the walls of
small arteries and arterioles
- ACE
- can be reversed by effective
- no known adverse effects on
antihypertensive therapy
glucose or lipid metabolism
- minimize the development of
diabetic nephropathy by
DIABETES MELLITUS
reducing renal vascular resistance
and renal perfusion pressure - the REFERENCE
primary factor underlying renal  Kotchen TA. Chapter 247. Hypertensive Vascular Disease.
deterioration in these patients In Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson JL,
Loscalzo J. (2012). Harrison’s Principles of Internal
- severe salt restriction and/or
diuretics are not used because of the Medicine, 18th ed. USA: McGraw-Hill.
associated increase in fetal wastage
- Beta blockers need to be used
cautiously for similar reasons
- Methyldopa and hydralazine, and to
PREGNANCY
a lesser extent calcium channel
antagonists
o are the antihypertensive agents
used most often, because they
have no known adverse effects on
the fetus

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