ACADS: Hypertension

SLMC QC 2014-2015
HYPERTENSION  The URINE Na-to-K ratio is a STRONGER
Introduction CORRELATE of BP than is either Na or K
 Hypertension is one of the leading alone.
causes of global burden of disease  Alcohol consumption, psychosocial stress
 7.6 M deaths and 92M DALYs and low levels of physical activity also
 Doubles the risk of cardiovascular may contribute to HPN.
diseases, including coronary heart  Blood Pressure heritabilities are in the
disease (CHD), CHF, ischemic and range 15-35%
hemorrhagic stroke, renal failure and  In twin studies, heritability estimates of
peripheral arterial disease BP are ~60% for males and 30-40% in
females
EPIDEMIOLOGY  HYPERTENSION before 55 years occurs
 In industrialized societies, BP increases 3.8 times more frequently among persons
steadily during the first two decades of with family history
life.
 In children and adolescents, BP is GENETICS
associated with growth and maturation  Alpha-adducin gene: associated with
 In the US, average systolic BP is higher for increased renal tubular absorption of
men than for women (EARLY sodium; associated with hypertension
ADULTHOOD); but in older ages, age- and salt sensitivity of BP
related rate of rise is higher in women
 Among 60 and older, SBP of women are MECHANISMS of HYPERTENSION
higher than men  Two determinants of Arterial Pressure:
 Adults: DBP increases with age until ~55 o Cardiac Output
years old and then decreases thereafter
 SV x HR
(consequence: WIDE PULSE PRESSURE at
 SV is related to
60 years old)
myocardial
 There is a 90% probability that a middle- contractility and to the
aged or elderly individual will develop size of the vascular
HYPERTENSION in his/her lifetime. compartment
 NHANES (National Health and Nutrition o Peripheral Resistance
Examination Survey):30% of adults, or  Determined by
atleast 65 million individuals have
functional and
HYPERTENSION (SBP> or equal to 140; anatomic changes in
DBP > or equal to 90)
small arteries (lumen
 African Americans diameter 100-
o Hypertension appears earlier 400micrometers) and
o Generally MORE SEVERE arterioles
o Results in higher rates of
morbidity and mortality from INTRAVASCULAR VOLUME
stroke, LVH, CHF and ESRD o Vascular volume is a primary
 OBESITY and WEIGHT GAIN: strong determinant of arterial pressure
independent risk factors for hypertension over the long term
 60% of hypertensives are >20% o SODIUM: predominant
overweight extracellular ion; primary
 Hypertension is also related to HIGH NaCl determinant of ECF
intake. o High NaClvascular volume
 Low dietary intakes of CALCIUM and expandsCO increases
POTASSIUM may also contribute to the
risk of Hypertension
2 MIYADI: Transcription for Tuberculosis

 ANS maintains cardiovascular

homeostasis via pressure, volume and
chemoreceptor signals.
 Initial elevation of BP in response to vascular  Three endogenous catecholamines (role
volume expansion may be related to an in tonic and phasic cardiovascular
increase of C.O.; however, overtime, peripheral regulation):
resistance INCREASES and C.O. reverts toward o Norepinephrine
normal. o Epinephrine
 As arterial pressure increases in response to a o Dopamine
high NaCl intake, urinary Na excretion  Adrenergic receptors:
increases and Na balance is maintained at the o Alpha 1 and 2
expense of an increase in arterial pressure  Alpha 1: are located on
o Mechanism for thie “pressure- POSTsynaptic cells in
natriuresis”: smooth msc and elicit
 Subtle increase in GFR VASOCONSTRICTION
 Decreased absorbing  In Kidneys:
capacity of the renal increases
tubules tubular
 Hormonal factors: atrial reabsorption
natriuretic factor of Na
 Alpha 2: PRESYNAPTIC
of postganglioninc
nerve terminals that
synthesize
Norepinephrine
 NEGATIVE
FEEDBACK:
inhibits
 NaCl-dependent hypertension may be a further
consequence of a decreased capacity of Norepinephri
the kidney to excrete sodium, due either ne release
to intrinsic renal disease or to increased o Beta 1 and 2
production of a salt-retaining hormone  Beta 1: STIMULATES
(mineralocorticoid) resulting in increased rate and strength of
renal tubular reabsorption of Na. cardiac contraction;
 Salt-wasting disorders are associated INCREASES C.O.
with low BP  Stimulates
 ESRD an example of a volume-dependent RENIN
hypertension release from
 ~80% of ESRD patients, vascular volume kidney
and HPN can be controlled with  Beta 2: RELAXES
adequate dialysis; in the other 20%, it is vascular smooth
related to increased RAAS (likely muscle and causes
responsive to blockade of Renin- vasodilation
Angiotensin)  ALPHA receptors: are occupied and
activated more avidly by
NOREPINEPHRINE than by epinephrine
AUTONOMIC NERVOUS SYSTEM and the REVERSE is true for Beta
receptors. (MNEMONICS: “NABE”-
 ACADS: Hypertension
SLMC QC 2014-2015
norepinephrine for alpha and beta for arteriole (BARORECEPTOR
epinephrine) Mechanism)
 DOWNREGULATION of receptors can be o sympathetic nervous system
a consequence of sustained high levels of stimulation of renin-secreting
catecholamines and provides an cells bia Beta 1 adrenoreceptors
explanation for DECREASING  Angiotensin II directly inhibits renin
RESPONSIVENESS, or TACHYPHYLAXIS, secretion due to angiotensin II type 1
to catecholamines receptors on juxtaglomerular cells, and
o ex: Orthostatic hypotension in renin secretion increases in response to
Pheochromocytoma; due to lack pharmacologic blockade of ACE or
of norepinephrine-induced Angiotensin II.
vasoconstriction with
assumption of upright posture
 Chronic reduction of neurotransmitter,
ADRENORECEPTORS MAY INCREASE IN
NUMBER or UPREGULATE, causing
temporary hypersensitivity to
sympathetic stimuli
o Ex: Clonidine (centrally acting
alpha 2 agonist) can cause
Rebound hypertension as a
cause of upregulation of alpha 1
receptors
 Sympathetic Outflow is increased in
obesity-related hypertension and in
hypertension associated with OSA

RENIN-ANGIOTENSIN-ALDOSTERONE

 Increased BP: Vasoconstrictor properties

of angiotensin II and Na-retaining
properties of aldosterone
 Once released into the circulation, active renin
 RENIN- synthesized as an inactive
cleaves a substrate, angiotensinogen, to form an
precurson- prorenin; an aspartyl
inactive decapeptide, angiotensin I.
protease
 A converting enzyme, located primarily but not
 Prorenin- may be secreted directly into
exclusively in the pulmonary circulation, converts
the circulation or may be activated within
angiotensin I to the active octapeptide, angiotensin
secretory cells and released as active
II, by releasing the C-terminal histidyl-leucine
RENIN.
dipeptide.
 Although human plasma contains 2 to 5
 ACE also cleaves other enzymes: inactivates
times more prorenin than renin; there is
BRADYKININ
no evidence that prorenin contributes to
 ANGIOTENSIN II:
the physiologic activity of this system
o Acts on angiotensin II type 1
 3 STIMULI for RENIN SECRETION:
receptors
o decreased NaCl transport in the
o Potent pressor
distal portion of TAL of the loop
o The PRIMARY TROPIC FACTOR
of Henle that abuts the
for the secretion of aldosterone
AFFERENT ARTERIOLE
by the adrenal zone glomerulosa
(Macula Densa)
o Potent mitogen that stimulates
o decreased pressure or stretch
vascular smooth muscle cell
within the renal afferent
4 MIYADI: Transcription for Tuberculosis
and myocyte growth
o Plays a role in
ATHEROSCLEROSIS. (via its
action on the vessel wall)
o Angiotensin II type II receptor:
 Mostly in kidneys
 Opposite functional
effects of type I
receptor
 Vasodilation
 Sodium excretion
 Inhibition of cell
growth and matrix
formation
 Experimental evidence suggests that the
AT2 receptor improves vascular
remodeling by stimulating smooth muscle
cell apoptosis, and contributes to the
regulation of GFR.
 AT1 receptor blockade induces an
increase in AT2 receptor activity
 Renin-secreting tumors are clear
examples of renin-dependent
hypertension
o Benign hemangiopericytomas of
juxtaglomerular apparatus, and
infrequently renal carcinomas,
including Wilm’s tumors
 Renin-producing carcinomas can also be
seen in:
o Lung
o Liver
o Pancreas
o Colon
o Adrenals
 Obstruction of the renal artery leads to
decreased renal perfusion pressure,
thereby stimulating renin secretion.
 Angiotensinogen, renin and angiotensin II
are also synthesizes locally in many
tissues, including:
o Brain
o Pituitary
o Aorta
o Arteries
o Heart
o adrenal glands
o kidneys
o adipocytes
o leukocytes
o ovaries
o testes
o uterus
o spleen
o skin
 Although acute elevations of
adrenocorticotropic hormone (ACTH)
increase aldosterone secretion, ACTH is
NOT an important tropic factor for the
chronic regulation of aldosterone.
 Aldosterone:
o Potent mineralocorticoid that
increases AMILORIDE-
SENSITIVE epithelial Na
channels (ENaC) on the apical
surface of the principal cells of
the renal cortical collecting duct
o Electric neutrality is maintained
by exchanging Na+ for K+ and
H+
o Leads to HYPOKALEMIA and
METABOLIC ALKALOSIS
o HYPOKALEMIA SHOULD BE
CORRECTED before a patient is
evaluated for
Hyperaldosteronism (K+
depletion may inhibit
aldosterone synthesis)
o Receptors are also present in
the Colon, Salivary Glands and
Sweat Glands (Cortisol also
binds here but is a less potent
mineralocorticoid than
aldosterone because it is
converted to CORTISONE by the
enzyme 11 Beta-hydroxysteroid
dehydrogenase type 2.
CORTISONE has NO affinity to
the mineralocorticoid receptor)
o PRIMARY ALDOSTERONISM:
compelling example of
mineralocorticoid-mediated
hypertension.Aldosterone
and/or mineralocorticoid
receptor activation induces
structural and functional
alterations in the heart, kidney
and blood vessels, leading to
 ACADS: Hypertension
SLMC QC 2014-2015
MYOCARDIAL FIBROSIS,
NEPHROSCLEROSIS and
VASCULAR INFLAMMATION and
REMODELLING (amplified by
salt intake)
o HIGH ALDOSTERONE:
 Stimulate cardiac
fibrosis
(Spironolactone
prevents this)
 LVH
o CHF:
 Low-dose
spironolactone reduces
the risk of progressive
heart failure and
sudden death from
cardiac causes by 30%.
o PRIMARY
HYPERALDOSTERONISM:
 High levels of
aldosterone also may
cause glomerular
hyperfiltration and
albuminuria
 Increased activity of the RAAS is NOT
invariably associated with hypertension.
In response to a low NaCl diet or to
volume contraction, arterial pressure and
volume homeostasis may be maintained
by increased activity of the RAAS
 Secondary Hyperaldosteronism
(increased aldosterone from increased
renin) may also be observed in
edematous states such as CHF and liver
disease
VASCULAR MECHANISMS
 Important determinants of arterial
pressure:
o Vascular radius
o Compliance of resistance
arteries
 RESISTANCE to flow varies INVERSELY to
the 4th power of the radius, and
consequently, small decreases in lumen
size significantly increase resistance.
 REMODELING refers to geometric
alterations in the vessel wall without a
change in vessel volume.
o Hypertrophic (increased size
and deposition of intercellular
matrix)
o Eutrophic vascular remodeling
results in decreased lumen size
and hence contributes to
increased peripheral resistance
o Apoptosis, low grade
inflammation and vascular
fibrosis also contribute to
remodeling
o Lumen diameter is related to
elasticity
 Hypertensive patients have stiffer
arteries, and arteriosclerotic patients may
have particularly high SBP and wide pulse
pressures as a consequence of decreased
vascular compliance
 Some studies show that arterial stiffness
has INDEPENDENT predictive value for
cardiovascular events.
o UTZ and MRI: evaluate arterial
stiffness or compliance
 Ion transport by vascular smooth muscle
cells: contribute to HPN-associated
abnormalities of vascular tone and
vascular growth, both of which are
modulated by intracellular pH
 Three ion transports participate in the
regulation of pH:
o Na+-H+ exchange: increased
activity in HPN; causes
INCREASED vascular tone
 Increased Na
entryincreased
vascular tone by
activating Na-Ca
exchange, thereby
increasing intracellular
Ca
 Increased pH
(alkalotic) enhances
calcium sensitivity of
the contractile
apparatus, leading to
an increase in
contractility for a given
intracellular Ca
 Increased Na-H
exchange: STIMULATE
6 MIYADI: Transcription for Tuberculosis
growth of vascular
smooth muscle cells by
enhancing sensitivity to
MITOGENS
o Na+-dependent HCO3- - Cl-
exchange
o Cation-independent HCO3—Cl-
exchange
 Vascular endothelium synthesizes and
releases vasoactive substances (e.g. NO)
o Endothelium-dependent
vasodilation is impaired in
hypertensive patients
o Impairment is assessed by UTZ
BEFORE and AFTER the
hyperemic phase of repefusion
that follows 5 minutes of
forearm ischemia
o Can induce vasodilation by
infusion of endothelium-
dependent vasodilator (eg. ACh)
o ENDOTHELIN is a
VASOCONTRICTOR (endo-
THELIN:”endo-thin-lining”;
compresses vessels so
vasoconstrict)
 Produced by
endothelium
 Orally active
endothelin antagonists
may lower BP
 Currently, it is NOT known if the HPN-
related vascular abnormalities of ion
transport and endothelial function are
primary alterations or secondary
consequences of elevated arterial pressure.
 LIMITED EVIDENCE: aerobic exercise,
weight loss and antiHPN improve vascular
compliance and endothelium-dependent
vasodilation
PATHOLOGIC CONSEQUENCES of
HYPERTENSION
!!! HPN is an INDEPENDENT RISK FACTOR for:
1. Heart failure
2. CAD
3. Stroke
4. Renal disease
5. Peripheral arterial disease
HEART
 HEART DISEASE: MC cause of death in
HPN
 LVH can be diagnosed by ECG but ECHO is
more sensitive in measuring LV wall
thickness
 LVH patients are at increased risk for
o CHD
o Stroke
o CHF
o Sudden death
 Aggressive control of HPN can regress
LVH
 CHF: related to SYSTOLIC dysfunction,
DIASTOLIC or COMBINATION
 DIASTOLIC HEART FAILURE: Preserved
ejection fraction
 ~1/3 of patients with CHF have normal
SBP but ABNORMAL DBP
 Diastolic dysfunction: early consequence
of HPN-related heart disease and is
exacerbated by LVH and ischemia
 CARDIAC Catheterization: most accurate
assessment of diastolic function
BRAIN
 STROKE: 2nd MC cause of death in the
world
 5M deaths/year
 HYPERTENSION: STRONGEST RISK
FACTOR for stroke
 85% of strokes: due to INFARCTION
(remainder due to SAH or ICH)
 The incidence of stroke rises
progressively with increasing SBP
particularly in individuals >65 y/o
 HPN-related cognitive impairment and
dementia may be a consequence of a
single infarct due to occlusion of a
“STRATEGIC” larger vessel or multiple
infarcts due to occlusive small vessel
disease resulting in subcortical white
matter ischemia
 Cerebral blood flow: remains unchanged
over a wide range of arterial pressures
(MAP 50-150mmHg) because of
autoregulation
 Malignant Hypertension-
encephalopathy is related to failure of
 ACADS: Hypertension
SLMC QC 2014-2015
AUTOREGULATION of cerebral bood flow
at the upper pressure limit, resulting in
VASODILATION and HYPERPERFUSION
o S/Sx of HPN Encephalopathy:
 severe headache
 nausea and vomiting
(projectile)
 focal neurologic
deficits
 alterations in mental
status
 MAY PROGRESS to:
 Stupor, coma,
seizures,
death
 Other NEUROLOGIC Syndromes assoc
with HPN:
o Cerebral ischemia
o Hemorrhagic or thrombotic
stroke
o Seizure disorder
o Mass lesions
o Pseudotumor cerebri
o Delirium tremens
o Meningitis
o Acute intermittent porphyria
o Traumatic or chemical
KIDNEY
 Both TARGET and CAUSE of HPN
 PRIMARY RENAL DISEASE is the MC
etiology of secondary HPN, mechanisms:
o Diminished capacity to excrete
Na
o Excessive renin secretion in
relation to volume status
o Sympathetic nervous system
overactivity
 Renal disease more related to SBP than
DBP
 BLACKS have higher risk to develop ESRD
at every level of BP
 PROTEINURIA: reliable marker of the
severity of CKD; predictor of its
progression (Patients with high urine
protein excretion of more than 3g/24h
have a more rapid rate of progression than
do those with lower protein excretion
rates)
 GLOMERULAR injury from
HYPERPERFUSION
 Loss of autoregulation of renal blood flow
at the AFFERENT ARTERIOLE results in
transmission of elevated pressured to an
unprotected glomerulus
HYPERFILTRATION, HYPERTROPHY,
FSGS
 PROGRESSIVE RENAL INJURY: LOSS OF
AUTOREGULATION OF RBF and GFR
resulting in lower BP and renal damage
 Renal lesion associated with Malignant
Hypertension: FIBRINOID NECROSIS of
Afferent Arteriole
PERIPHERAL ARTERIES
 HPN + PAD of lower extremities:
increased risk for CVD
 Intermittent claudication: classic Sx of
PAD
o Aching pain in the calves or
buttocks while walking that is
relieved with rest
 Ankle-brachial index: ratio of
noninvasively assessed ankle to brachial
SBP
o <0.9- PAD; >50% stenosis in
atleast one major lower limb
vessel
o <0.8: assoc with elevated SBP
DEFINING HYPERTENSION
 EPIDEMIOLOGIC POV: No obvious level
of BP that defines HPN
 In adults, there is a continuous,
incremental risk of CVD, stroke and renal
disease across levels of both SBP and DBP
 META-ANALYSIS: IHD mortality, stroke
mortality and vascular mortality are
directly related to the height of the BP
beginning at 115/75, without evidence of
a threshold
 CVD risk DOUBLES for every 20mmHg
increase in SBP and 10mmHg increase in
DBP
 Among older individuals, SBP and Pulse
Pressure- more powerful predictors of
CVD compared to DBP.
 CLINICALLY: HPN is defined as level of BP
at which the institytion of therapy
8 MIYADI: Transcription for Tuberculosis
reduces bP-related morbidity and
mortality
o AVERAGE of 2 or more SEATED
BP during each of 2 or more
outpatient visits
 Children and adolescents: SBP and DBP
>95th percentile for age, sec and height;
between 90th and 95th percentile-PREHPN
and indicated to have lifestyle change
 Home BP and average 24H ambulatory
BO: generally lower than clinic BP
 BP tends to be higher in early morning
hourse, soon after waking that is why MI
and STROKE are more common in EARLY
MORNING HOURS
 Nighttime BP are generally 10-20% lower
than daytime BP, and an attenuated
nighttime BP “dip” is associated with
increased cardiovascular risk
 HPN:
o Awake BP > or equal to 135/85
o Asleep BP > or equal to 120/75
 Approximately 15-20% of patients with st
I HPN based on office BP have average
ambulatory readings <135/85 (White
coat HPN); Clinic BP >140/90
 Individuals with white coat HPN are also
at increased risk of developing
SUSTAINED HPN
CLINICAL DISORDERS of HPN
 80-95% of HPN have ESSENTIAL HPN
(Primary or Idiopathic HPN)
 5-20% are Secondary
Essential Hypertension
 Essential HPN: prevalence increases with
age
 HPN patients: majority have
o Increased peripheral resistance
o CO is normal or decreased
 However, in younger patients with mild
or labile HPN, CO may be increased and
PR may be normal
 High renin patients may have a
vasoconstrictor form of HPN
 Low renin: volume-dependent HPN
 SPIRONOLACTONE: aldosterone
antagonist; may be a particularly effective
antiHPN agent for some patients with
essential HPN, including some patients
with “drug-resistant” HPN
Obesity and the Metabolic Syndrome
 OBESITY (BMI>30kg/m2) assoc with HPN
 Centrally located body fat is a more
important determinant of BP than
peripheral body fat
 60% of HPN adults are more than 20%
overweight.
 60-70% of HPN may be directly
attributable to adiposity
 HPN and dyslipidemia frequently occur
together and in association with
resistance to insulin-stimulated glucose
uptake
 METABOLIC SYNDROME:
o Insulin-resistance + abdominal
obesity + HPN + dyslipidemia
 As a group, 1st degree relatives of patients
with essential HPN are also insulin
resistant, and hyperinsulinemia (a
surrogate marker of insulin resistance)
may predict eventual development of
HPN and CVD.
 Insulin sensitivity INCREASES and BP
 ACADS: Hypertension
SLMC QC 2014-2015
DECREASES
Renal Parenchymal Diseases
 HPN is present in >80% of patients with
chronic renal failure
 HPN is MORE SEVERE in GLOMERULAR
DISEASES than in interstitial diseases
such as chronic pyelonephritis
 PROTEINURIA >1000mg/d and an active
urine sediment are indicative of Primary
Renal Disease.
Renovascular Hypertension
 HPN secondary to an occlusive lesion of a
renal artery
 Potentially curable form of HPN
 2 HIGH RISK GROUPS:
o older arteriosclerotic patients
who have plaque obstructing
renal artery
o fibromuscular dysplasia
(Fibromuscular dysplasia (FMD)
is an angiopathy that affects
medium-sized arteries
predominantly in young women
of childbearing age)
 lesions are usually
BILATERAL vs.
Atherosclerotic
renovascular disease
which tend to affect
more distal portions of
the renal artery
 Atherosclerosis accounts for the large
majority of patients with renovascular
hypertension.
 Fibromuscular dysplasia (histologic
variants):
o Lesions are usually bilateral
o Tend to affect more DISTAL
portions of the renal artery
o Medial fibroplasia
 MC variant; 2/3 of
patients
o Perimedial fibroplasia
o Medial hyperplasia
 MC variant
 2/3 of patients
o Intimal fibroplasia
 Although response to antiHPN therapy
does not exclude the diagnosis, severe or
refractory HPN, recent loss of HPN
control or recent onset of moderately
severe HPN and unexplained
deterioration of renal function or
deterioration of renal function associated
with ACEi should raise the possibility of
renovascular HPN.
 Approximately 50% of patients with
renovascular HPN have anABDOMINAL or
FLANK bruit, and the bruit is more likely
to be hemodynamically significant if it
lateralizes or extends throughout systole
into diastole.
 Patients with long-standing HPN,
advanced renal insufficiency or DM are
less likely to benefit from renal vascular
repair.
 ACEi and ARB: can decrease GFR in a
stenotic kidney owing to efferent renal
arteriolar dilation
o Not advisable for:
 B renal artery stenosis
 Solitary kidney with
RAS
 RENAL ARTERY STENOSIS:
o (PTRA) Percutaneous Renal
Angioplasty
o (stent) Placement of vascular
endoprosthesis
o Surgical renal revascularization
o Radionuclide [131I]-
orthoiodohippurate (OIH)
scan or [99mTc]-
diethylenetriamine
pentaacetic acid (DTPA)
BEFORE and AFTER a single
dose of CAPTOPRIL (or another
ACEi): to evaluate Renal Blood
Flow
 POSITIVE STUDY
 Decreased
relative
uptake by the
involved
kidney, which
contributes
<40% of total
renal function
 Delayed
1
0 MIYADI: Transcription for Tuberculosis
uptake of
affected side
 Delayed
washout on
the affected
side
o In patients with normal or
nearly normal renal function, a
NORMAL CAPTOPRIL renogram
essentially excludes functionally
significant RAS, however, its
usefulness is LIMITED in
patients with RENAL
INSUFFICIENCY
(CCr<20mL/min) or B RAS.
 Additional imaging
needed is scan is
POSITIVE
o GADOLINIUM-CONTRAST
MAGNETIC RESONANCE
ANGIOGRAPHY: offers clear
images of the PROXIMAL renal
artery but may miss DISTAL
lesions
o CONTRAST ARTERIOGRAPHY:
remains the “gold standard” for
evaluation and identification of
renal artery lesions.
o Functionally sifnificant lesions
generally occlude more than
70% of the lumen of the affected
renal artery
o Surgery may be the preferred
initial approach for younger
atherosclerotic patients without
comorbid conditions. However,
for most atherosclerotic
patients, depending on the
location of the lesion, the initial
approach may be PTRA and/or
stenting.
PRIMARY ALDOSTERONISM
 Increased aldosterone production is
INDEPENDENT of the renin-angiotensin
system, and the consequences are:
o Na retention
o Hypertension
o Hypokalemia
o Low PRA
 Prevalence: <2 to 15% of all HPN
 Age of Dx: 3rd to 5th decade
 HYPERTENSION: usually mild to
moderate but occasionally severe
 SHOULD BE CONSIDERED in patients
with REFRACTORY HPN
 Sx of Hypokalemic Alkalosis
o Polyuria
o Polydipsia
o Paresthesias
o Muscle weakness
 HPN + unprovoked hypokalemia, the
prevalence of primary aldosteronism
approaches 40-50%
 In patients on diuretic, serum K+
<3.1mmol/L (<3.1 meq/L) also raises the
possibility of primary aldosteronism
(However, serum K+ is an insensitive and
nonspecific screening test)
 K+ is NORMAL in ~25% of patients
subsequently found to have an
aldosterone-producing adenoma
 PRA (ratio of plasma ALDOSTERONE to
plasma RENIN) is a useful screening
test
o Taken in am: ambulatory pxs
o Ratio >30:1 with aldosterone
>555pmol/L (>20ng/dL)-
sensitivity of 90% and
specificity of 91% for
aldosterone-producing adenoma
o The cutoff for a “high” ratio is
laboratory- and assay-
dependent
o In patients with RENAL
INSUFFICIENCY, ratio may also
be elevated because of
DECREASED Aldosterone
Clearance
o In patients with an elevated
PA/PRA ratio, the diagnosis of
primary aldosteronism can be
confirmed by inability to
suppress plasma aldosterone to
<277 pmol/L (<10ng/dL) after
IV infusion of 2L of isotonic
ACADS: Hypertension
SLMC QC 2014-2015
saline over 4hours; post-saline
values of 138-277 pmol/L (5-
10ng/dL) are NOT determinant
 Alternative confirmatory tests- failure to
suppress aldosterone in response to
o Oral NaCl load
o Fludrocortisone
o Captopril
 60-70% of patients with Primary
Aldosteronism have ALDOSTERONE-
PRODUCING ADRENAL ADENOMA
o tumor: MC unilateral
o <3cm in diameter
 the remaining 30-40% of these patients
have BILATERAL ADRENOCORTICAL
HYPERPLASIA
 Rare: Primary aldosteronism secondary
to ADRENAL CA or an ECTOPIC
MALIGNANCY (ovarian arrhenoblastoma)
 Aldosterone biosynthesis:
o Is more responsive to ACTH:
ADENOMA (also tend to have
HIGHER ALDOSTERONE in am
that decreases in
pmDIURNAL)
o Is more responsive to
ANGIOTENSIN: HYPERPLASIA
(ALDOSTERONE INCREASE with
upright posture, reflecting the
normal postural response of
RAAS)
 ADRENAL CT: should be carried out in all
patients diagnosed with primary
aldosteronism
 HRCT: may define tumors as small as
0.3cm (positive for an adrenal tumor 90%
of the time)
 If CT is NOT DIAGNOSTIC, adenoma may
be detected by ADRENAL SCINTIGRAPHY
with 6 B[I131] iodomethyl-19-
norcholesterol (this technique has
DECREASED SENSITIVITY for adenomas
<1.5cm)
 BILATERAL ADRENAL VENOUS
SAMPLING: differentiates UNILATERAL
from BILATERAL forms of primary
aldosteronism
o Sens: 95%
o Spec: 100%
o Superior to adrenal CT
o An ipsilateral/ contralateral
aldosterone ratio >4, with
symmetric ACTH-stimulated
cortisol levels, is indicative of
unilateral aldosterone
production
 HYPERTENSION is RESPONSIVE to
SURGERY in patients with adenoma BUT
NOT in patients with BILATERAL
ADRENAL HYPERPLASIA
 Curative in 40-70% of pxs
 with adenoma: UNILATERAL
ADRENALECTOMY (but should be taken
once BP is controlled)
 Transient HYPOALDOSTERONISM may
occur up to 3months postoperatively,
resulting in hyperkalemia
o Monitor K!
o HyperK should be treated with
K-wasting diuretics and
fludrocortisone, if needed.
 Tx for BILATERAL ADRENAL
HYPERPLASIA: Aldosterone antagonist
+ K+-sparing diuretics
 Glucocorticoid-remediable
hyperaldosteronism is rare and
characterized by moderate to severe HPN
o May have a FHx of hemorrhagic
stroke at a young age
o Hypokalemia: mild or absent
 NORMAL:
o Angiotensin II stimulates
ALDOSTERONE production in the
zona glomerulosa
o ACTH stimulates CORTISOL
production in the zona
fasciculate
 In glucocorticoid-remediable
hyperaldosteronism: ACTH also regulates
aldosterone secretion (owing to chimeric
gene on chromosome 8)
CUSHING’S SYNDROME
 Related to excess cortisol production due
either to excess ACTH secretion (from a
pituitary tumor or an ectopic tumor) or to
ACTH-independent adrenal production of
cortisol.
 HPN occurs in 75-80% of patient’s with
Cushing’s syndrome
1
2 MIYADI: Transcription for Tuberculosis

o Mechanism of HPN: related to obesity, HPN occurs in >50% of

stimulation of mineralocorticoid individuals with OSA)
receptor by CORTISOL and o SEVERITY of HPN = SEVERITY of
increased secretion of other OSA
adrenal steroids o 70% of patients with OSA are
 If clinically suspected, based on Obese
phenotypic characteristics, in patients not o OSA: confirmed by
taking exogenous glucocorticoids, Polysomnography
laboratory screening may be carried out o CPAP: effective tx for OSA
with measurement of 24H excretion  Coarctation of the Aorta
rates of urine free cortisol or an o MC CONGENITAL CAUSE of HPN
overnight dexamethasone-suppression o 35% of patients with Turner
test. syndrome
 Late night salivary cortisol is also a o PE:
sensitive and convenient screening test  Diminished and
delayed femoral pulses
PHEOCHROMOCYTOMA and a systolic pressure
 Catecholamine-secreting tumors are gradient between the
located in the ADRENAL MEDULLA right arm and the legs
(pheochromocytoma) or in EXTRA- and, depending on the
ADRENAL PARAGANGLION TISSUE location of the
(paraganglioma) and account for HPN in coarctation, between
~0.05% of patients the right and left arms.
 Clinical Manifestations:  Blowing systolic
o Related to increased murmur may be heard
catecholamines in the posterior left
o SMALL PERCENTAGE: interscapular areas
EPINEPHRINE-predominant  Dx: may be confirmed
catecholamine secreted by the by CXR and TEE
tumor; these patients may  Tx: surgical repair and
present with HYPOTENSION balloon angioplasty,
rather than HPN with or without
 20% are familial; Autosomal Dominant placement of an
 May be associated with MEN type 2A intravascular stent
(medullary CA of the thyroid,  Others:
pheochromocytoma, hyperparathyroidism o Thyroid diseases
and occasionally lichen amyloidosis) and  MILD Diastolic HPN-
type 2B (medullary thyroid CA and hypothyroidism
pheochromocytoma, multiple euromas and  SYSTOLIC HPN-
intestinal ganglioneuromas), von Hippel hyperthyroidism
Lindau and NF o Acromegaly
 Surgical excision is the DEFINITIVE tx of o Hypercalcemia
pheochromocytoma and results in cure of  Benign primary
~90% of patients. hyperparathyroidism

MISCELLANEOUS CAUSES of HYPERTENSION

 OSA
o HPN due to OSA (Independent of
 ACADS: Hypertension
SLMC QC 2014-2015

MONOGENIC HYPERTENSION  SALT-RETAINING

 Several inherited defects in adrenal adrenogenital syndrome
steroid biosynthesis and metabolism  Decreased CORTISOL
result in mineralocorticoid-induced HPN synthesis
and hypokalemia.  Increased
 17a-hydroxylase deficiency: MINERALOCORTICOI
o synthesis of sex hormones and Ds
cortisol is decreased  Shunting of steroid
o do not mature sexually biosynthesis into the
androgen pathway
o MALE: pseudohermaphroditism
o SEVERE form:
o FEMALES: primary amenorrhea
 EARLY in life:
o Absent secondary sexual
 virilization
characteristics
and
o Because cortisol-induced negative
ambiguous
feedback on pituitary ACTH
genitalis
production is diminished, ACTH-
(female)
stimulated adrenal steroid
 penile
synthesis proximal to the
enlargement
enzymatic block is increased.
(male)
Hypertension and hypokalemia are
 OLDER children
consequences of increased
 PRECOCIOUS
synthesis of mineralocorticoids
puberty
proximal to the enzymatic block,
particularly desoxycorticosterone.  SHORT
Increased steroid production and, stature
hence, hypertension may be  ADOLESCENT
treated with low-dose  Acne,
glucocorticoids. hirsutism,
o Results in: menstrual
irregularities
1
4 MIYADI: Transcription for Tuberculosis
o HPN is less common in the late-
onset forms
o IMPAIRED capacity to
metabolize CORTISOL to its
inactive metabolite, CORTISONE
o HPN is related to activation of
mineralocorticoid receptors by
Cortisol
 This defect may be
inherited or
ACQUIRED (licorice-
containing glycyrrhizin
acid)
 Liddle syndrome
o Constitutive activation of
amiloride-sensitive epithelial Na
channels on the DISTAL RENAL
TUBULE results in excess Na
reabsorption
o Ameliorated by AMILORIDE
 Pregnancy
o HPN exacerbated in pregnancy
is due to activation of the
mineralocorticoid receptor by
PROGESTERONE
HOW BP should be taken
 Sit individual with feet on the floor for
atleast 5mins in a private, quiet setting
with a comfortable room temperature
 Atleast 2 measurements should be made
 Center of cuff: HEART LEVEL
 Atleast 2 measurement should be taken
 Width of the bladder cuff: atleast 40% of
arm circumference
 Length of bladder cuff: enough to encircle
atleast 80% of the arm circumference
 Cuff deflation: 2mmHg/s
 SBP: first of atleast 2 regular “tapping”
Korotkoff sounds
 DBP: point at which the last regular
Korotkoff sound is heard
 24H ambulatory BP monitoring more
reliably predicts cardiovascular disease
risk than do office measurements
PHYSICAL EXAMINATION
 Even if femoral pulse is normal to
palpation, arterial pressure SHOULD be
MEASURED at least ONCE in the lower
extremity in patients in whom HPN is
discovered BEFORE age 30.
 HPN have an INCREASED PREVALENCE of
Atrial fibrillation
 Examination of the heart may reveal a
loud second heart sounds due to closure
of the aortic valve and an S4 gallop
attributed to atrial contraction against a
noncompliant LV
 An ABDOMINAL BRUIT that lateralizes
and extends throughout systole and
diastole, raises the possibility
TREATMENT
 Lifestyle Interventions
o Weight loss and reduction of
dietary NaCl have been shown to
prevent the development of HPN
ACADS: Hypertension
SLMC QC 2014-2015
o Other dietary modifications that 140/90.
lower HPN: o The degree of benefit from
 Increased K intake antiHPN depends on the
 Moderation of alcohol magnitude in the reduction of
consumption BP
 Overall healthy dietary  Lowering the SBP by
pattern 10-12mmHg and
o Even modest weight loss can diastolic by 5-6mmHg
lead to reduction of BP and an confers relative risk
increase in insulin sensitivity reductions of 35-40%
o Ave reduction in BP 6.3/3.1 for stroke and 12-16%
mmHg have been observed with for CHD within 5 years
a reduction in mean body of the initiation of
weight of 9.2kg treatment.
o BP may be lowered by 30min of o Risk of CHF is reduced by >50%
moderately intense physical o HPN control is the single most
activity, such as brisk walking, effective intervention for
6-7 days a week, or by more slowing the rate of progression
intense, less frequent workouts of HPN-related CKD
o Lower NaCl intake to 4.4-7.4g
(75-125 meq): results in BP
reductions of 3.7-4.9/0.9-2.9
mmHg
o K and Ca supplementation have
inconsistent, modest antiHPN
effects and independent of BP, K
supplementation may be
associated with reduced stroke
mortality
o Alcohol use in persons
consuming 3 or more drinks per
day (a std drink contains ~14g
ethanol) is associated with
 Diuretic
higher BP and a reduction of
o Low dose thiazide diuretics:
alcohol consumption is
associated with reduction of BP  1st line agents alone or
o DASH (Dietary Approaches to in combination with
Stop Hypertension) trial: other antiHPN
demonstrated that over an 8-  inhibit NaCl pump in
week period a diet high in the DCT and hence,
FRUITS, VEGETABLES, LOW FAT increase Na excretion
DAIRY PRODUCTS lowers BP in  may also act as
individuals with high normal BP VASODILATORs
or mild HPN  safe, efficacious,
o Reduction of daily NaCl intake to inexpensive
 DIURETIC + CCB: less
<6g (100meq) augmented the
effective than
effect of this diet on BP
DIURETIC + BB or ACEi
 Pharmacologic Therapy
or ARB
o Drug therapy is recommended
 Usual dosage of HCTZ
for individuals with BP > or =
6.25-50mg/d
1
6 MIYADI: Transcription for Tuberculosis

 HCTZ: side effects- the adverse

hypokalemia, insulin effects of
resistance, diuretics on
hypercholesterolemia) glucose
 K sparing diuretics metabolism
(Amiloride and  combi of
Triamterene): inhibit ACEi and
epithelial Na channels ARB: LESS
in the distal nephron EFFECTIVE in
o LOOP DIURETICS: lowering BP
 Generally reserved for than is the
HPN patients with case when
reduced GFR (reflected either is used
in serum CREA >220 in combi with
micromol/L other agents
(2.5mg/dL)), CHF, Na and is
retention and edema associated
for some other reason, with HIGHER
such as treatment with ADVERSE
a potent vasodilator EVENTS
(eg Minoxidil) especially in
o Blockers of the RAS those with
 ACEi decrease the vascular
production of diseases.
Angiotensin II, increase  VALSARTAN:
bradykinin levels and has been
reduce sympathetic shown to
nervous system reduce the
activity risk of
 ARBs selectively block developing
AT1 receptors, and the DIABETES in
effect of angiotensin II high-risk
on unblocked AT2 HPN patients
receptors may  In HPN patients with
augment their proteinuria,
hypotensive effect. preliminary data
 Both ARB and ACEi: suggest that reduction
 may be used of proteinuria with
in ACEi/ARB combination
combination treatment may be
with more effective than
diuretics, treatment with either
CCBs and agent alone.
Alpha  Side effects of ACEi and
antagonists ARB: functional renal
 improve insufficiency due to
INSULIN efferent renal
action and arteriolar dilation in a
ameliorate kidney with stenotic
ACADS: Hypertension
SLMC QC 2014-2015
lesion of the renal addition to
artery. conventional
 Dry cough occurs in therapy with
~15% of patient and ACEi, digoxin
angioedema occurse in and loop
<1% of patients taking diuretics
ACEi  Particularly effective in
 HYPOKALEMIA due to patients with LOW
hypoaldosteronism is RENIN ESSENTIAL
an occasional side HPN, resistant to HPN,
effect of both ACEi and and primary
ARBs aldosteronism
 Blockade of the RAS is  SIDE effects:
MORE COMPLETE with gynecomastia,
renin inhibitors. impotence, menstrual
 ALISKIREN: 1st class of abnormalities
oral, nonpeptide  EPLERENONE: elective
competitive inhibitors aldosterone antagonist
of the enzymatic o Beta Blockers
activity of renin; as  Lower BP by
effective as ACEi or decreasing Cardiac
ARB in lowering BO; Output, due to a
further blood reduction in HR and
reductions may be contractility
achieved when  Particularly effective in
aliskiren is used in HPN + tachycardia
combination with a  Hypotensive potency is
thiazide diuretic, an enhanced by diuretics
ACEi, an ARB or CCB;  In CHF patients, B
NOT a first-line blockers reduce the
antiHPN risks of hospitalization
o Aldosterone antagonists and mortality
 Spironolactone:  Have both alpha and
 nonselective beta blocking
aldosterone properties: Carvedilol
antagonist and Labetalol
that may be o Alpha Blockers
used alone or  Post-synaptic, selective
in alpha blockers lowers
combination BP by peripheral
with a vascular resistance
thiazide  In clinical trials, it has
diuretic not been shown to
 low dose reduce CV morbidity
reduced and mortality or to
mortality and provide as much
hospitalizatio protection against CHF
ns for heart as other classes of
failure when antiHPN
given in  Effective in treating
1
8 MIYADI: Transcription for Tuberculosis
lower urinary tract
symptoms in men with
BPH
 Nonselective alpha
blockers bind to
postsynaptic and
presynaptic receptors
and are used primarily
for the mgt of patients
with
pheochromocytoma
o Sympatholytic agents
 Centrally acting alpha2
agonists: decrease
peripheral resistance
by inhibiting
SYMPATHETIC
OUTFLOW.
 Useful in patients with
autonomic neuropathy o Comparisons of antiHPN:
who have wide
variations in BP due to
baroreceptor
denervation.
 SE: somnolence, dry
mouth, rebound
hypertension on
withdrawal,
orthostatic
hypotension, sexual
dysfunction
 Decrease peripheral
resistance and venous
constriction by
depleting nerve
terminal
norepinephrine
o Drug Vasodilators
 Decrease peripheral
resistance and
concomitantly active
mechanisms that
defend arterial
pressure, notably the
sympathetic nervous
system, the RAAS and
Na retention.
 NOT 1st lines
 Effective in combi with
B blocker and diuretic
 HYDRALAZINE: potent
direct vasodilator with
antioxidant and NO-
enhancing actions;
may induce Lupus-like
syndrome
 MINOXIDIL: potent
agent; particularly
useful in those with
RENAL
INSUFFICIENCY who
are refractory to all
other drugs.
 Side effects:
hypertrichosi
s and
pericardial
effusion
 6 Major Classes
equivalent BP lowering
effects when used as
monotherapy:
 Thiazide
 Beta blockers
 ACEi
 ARBs
 CCBs
 Alpha
blockers
 On average, standard
doses lower BP by 8-
10/4-7 mmHg
 YOUNGER: more
responsive to Beta
blockers and ACEi
 Patients over 50
years: more
responsive to
DIURETICs and CCBs
 Limited relationship
between plasma renin
and BP response
 HIGH RENIN
HPN: more
responsive to
ACEi and
ACADS: Hypertension
SLMC QC 2014-2015
ARBs than to + CCB
other classes (Amlodipine)
of agents was superior
 ALLHAT (ANtiHPN and treatment
Lipid-Lowering to with ACEi +
prevent Heart Attack diuretic
Trial) (HCTZ)
 Occurrence of  After a stroke,
coronary combination therapy
heart disease with ACEi and diuretic,
death and but not with ARB,
nonfatal MI, reduces the rate of
as well as recurrent stroke
overall o BP GOALS of ANTIHPN TX
mortality,  Max protection against
was virtually combined
identical in cardiovascular
HPN treated endpoints is achieved
with either with BP <135-140/80-
ACEi 85
(Lisinopril),  Treatment
diuretic has not
(chlorthalido reduced
ne), CCB cardiovascula
(amlodipine) r disease risk
 Independent of BP, this to the level in
is the only antiHPN nonHPN
drug that attenuates individuals
the development of  Target <130/80:
LVH, improve  DM
symptomatology and  CHD
risk of death from CHF  CKD
and reduces morbidity  Additional
and mortality rates cardiovascula
post MI: r disease risk
 ACEi factors
 ACCOMPLISH Trial:  Target SBP<120
 [Rationale  Proteinuria
and Design of (>1g/d) since
the Avoiding decline of
Cardiovascul GFR in these
ar Events patients is
through particularly
combination BP-
Therapy in dependent
Patients  To achieve
Living with recommended BP
Systolic HPN] goals, the majority of
 ACEi individuals with HPN
(benazepril) will require treatment
2
0 MIYADI: Transcription for Tuberculosis

with more than one nonadherenc

drug. e, identifiable
 Three or more drugs causes of
frequently are needed HPN (Obesity
in patients with DM and excessive
and renal insufficiency alcohol
 For most agents, intake), use
reduction of BP at half- of non-
standard doses is only prescription
~20% less than at and
standard doses prescription
 A small drugs
nonprogressive  Rarely, in older
increase in the serum patients, pseudoHPN
CREA with BP may be related to
reduction may occur in INABILITY TO
patients with Chronic MEASURE BP
Renal Insufficiency ACCURATELY in
 Individuals >80 years: SEVERELY SCLEROTIC
 Gradual BP ARTERIES
reduction to  If radial pulse
less REMAINS
aggressive PALPABLE
target levels despite
of control occlusion of
may be the brachial
appropriate artery by the
 RESISTANT HPN: cuff (OSLER
 Patients with Maneuver)
BP >140/90 o HYPERTENSIVE EMERGENCIES
despite taking  Precipitous lowering of
3 or more BP may be associated
antiHPN, with significant
including a morbidity
diuretic, in a  The key to successful
reasonable management of severe
combination HPN is to differentiate
and at full HPN crises from HPN
doses. urgencies
 MC in px >60  The degree of target
years than in organ damage rather
younger than the level of BP
 May be alone, determines the
related to rapidity with which BP
“pseudoresist should be lowered
ance” (high  MALIGNANT HPN:
office BP and syndrome associated
low Home with an abrupt
BP), increase of BP in a
ACADS: Hypertension
SLMC QC 2014-2015
patient with o Progressive
underlying HPN or retinopathy
related to the sudden (arteriolar
onset of HPN in a spasms,
previously hemorrhages,
normotensive exudates and
individual. papilledema)
 The absolute o Deteriorating
level of BP is renal function
not as with proteinuria
important as o Microangiopathic
its rate of hemolytic anemia
rise. o encephalopathy
 Associated
with DIFFUSE
NECROTIZIN
G
VASCULITIS,
ARTERIAL
THROMBI
and FIBRIN
DEPOSITION
in arteriolar
walls
 FIBRINOID
NECROSIS:
observed in
arterioles of
kidney, brain,
retina and
other organs

 Initial goal of therapy:

reduce mean arterial BP by
no more than 25% within
minutes to 2h or to a BP in
the range of 160/100-110
 May be given: IV
nitroprusside, short-acting
vasodilator with a rapid
onset of action that allows
minute-to-minute control of
BP, parenteral labetalol,
nicardipine
 In pxs with malignant HPN
without encephalopathy, it
is preferable to reduce BP
over hours or longer than
 Manifestations: minutes give frequent
2
2 MIYADI: Transcription for Tuberculosis

doses of short acting oral

agents: captopril, clonidine
and labetalol
 For patients with
CEREBRAL INFARCTION
who are NOT CANDIDATES
for thrombolytic therapy,
one recommended
guideline is to institute
antiHPN only for those with
SBP>220 or DBP>130
 If thrombolytic tx is to be
used, recommended goal
SBP if <185 or DBP <110
 In patients with
HEMORRHAGIC STROKE,
suggested guidelines for
initiation antiHPN are
SBP>180 or DBP>130
 Management of HPN after
subarachnoid hemorrhage
is controversial
 Cautious reduction of BP is
indicated if MAP is >130
 ADRENERGIC CRISIS:
o Related to cocaine
or amphetamine
overdose
o Clonidine
withdrawal
o Acute spinal cord
injuries
o Interaction of
tyramine-
containing
compounds with
MAOIs
o Tx: nitroprusside
or phentolamine

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