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PATHOPHYSIOLOGY OF
HYPERTENSION

A direct association exists between sodium and BP.

Patients with a high dietary sodium intake have a
greater prevalence of hypertension than those with a
low sodium intake.
Arterial blood pressure (BP) is the pressure in the
arterial wall measured in millimeters of mercury (mm
Hg).
The two typical arterial BP values are systolic BP(SBP)
and diastolic BP(DBP).

By
Jastria Pusmarani, S. Farm., M.Sc., Apt.

Patofisiologi & Interpretasi Data Klinik

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Jastria Pusmarani, M. Sc., Apt

Hypertension

Jastria Pusmarani, M. Sc., Apt

Patofisiologi & Interpretasi Data Klinik

Jastria Pusmarani, M. Sc., Apt

SBP is achieved during cardiac contraction

and represents the peak value.
DBP is achieved after contraction when the
cardiac chambers are filling, and represents
the nadir value.
The difference between SBP and DBP is a
measure of arterial wall tension.

Arterial blood pressure is mathematically

defined as the product of cardiac output and
total peripheral resistance according to the
following equation:
BP = cardiac output total peripheral
resistance
Cardiac Output= Stroke Volume/menit
Cardiac output is the major determinant of
SBP, whereas total peripheral resistance
largely determines DBP.
In turn, cardiac output is a function of stroke
volume, heart rate, and venous capacitance.
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Various neural and humoral factors are known

to influence and regulate BP.
Arterial BP also is regulated by the adrenergic
nervous system, which causes contraction and
relaxation of vascular smooth muscle.
the renin-angiotensin-aldosterone system
(RAAS)
regulates systemic and renal blood flow,
renal function and renal blood flow
influences fluid and electrolyte balance
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several hormonal factors

adrenal cortical hormones,
vasopressin,
thyroid hormone,
insulin,
and the vascular endothelium regulates release
of:
nitric oxide,
bradykinin,
prostacyclin,
endothelin
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The ReninAngiotensinAldosterone
System

Decreases in BP and renal blood flow,

volume depletion or decreased sodium concentration,
and
an activation of the sympathetic nervous system
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The kidney plays an important role in the regulation

of arterial pressure, especially through the Renin
angiotensin aldosteron (RAAS).
trigger an increased secretion of the enzyme renin
from the cells of the juxtaglomerular apparatus in
the kidney:

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The RAAS is a complex endogenous system

that is involved with most regulatory
components of arterial BP.
The renin-angiotensin-aldosterone system
contributes to the regulation of arterial
pressure primarily via the vasoconstrictor
properties of angiotensin II and the sodiumretaining properties of aldosterone.
Activation and regulation are primarily
governed by the kidney
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The RAAS regulates sodium, potassium,

and fluid balance.
Consequently, this system significantly
influences vascular tone and
sympathetic nervous system activity and
is the most influential contributor to the
homeostatic regulation of BP

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Renin
Renin is an aspartyl protease that is
synthesized as an enzymatically inactive
precursor, prorenin.
Renin is an enzyme that is stored in the
juxtaglomerular cells, which are located in
the afferent arterioles of the kidney.
Prorenin may be secreted directly into the
circulation or may be activated within
secretory cells and released as active renin.
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The release of renin is modulated by several

factors:
intrarenal factors
e.g.,
renal perfusion pressure,
catecholamines,
angiotensin II,
extrarenal factors
e.g.,
sodium,
chloride, and
potassium
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There are three primary stimuli for renin

secretion:
1. Decreased NaCl transport in the thick
ascending limb of the loop of Henle (macula
densa mechanism),
2. Decreased pressure or stretch within the
renal afferent arteriole (baroreceptor
mechanism), and
3. Sympathetic nervous system stimulation of
renin-secreting cells via 1 adrenoreceptors.
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The juxtaglomerular apparatus also includes

a group of specialized distal tubule cells
referred to collectively as the macula densa.
A decrease in sodium and chloride delivered
to the distal tubule stimulates renin release.
Catecholamines increase renin release
probably by directly stimulating sympathetic
nerves on the afferent arterioles that in turn
activate the juxtaglomerular cells.
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Renin secretion is inhibited by increased

NaCl transport in the thick ascending limb
of the loop of Henle, by increased stretch
within the renal afferent arteriole, and by 1
receptor blockade.
In addition, renin secretion may be
modulated by a number of humoral factors,
including angiotensin II.
Decreased renal artery pressure and kidney
blood flow is stimulate secretion of renin.
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Decreased serum potassium and/or

intracellular calcium are detected by the
juxtaglomerular cells resulting in renin
secretion.
Angiotensin I is then converted to angiotensin
II by angiotensin-converting enzyme (ACE).
NOTES

Renin catalyzes the conversion of

angiotensinogen to angiotensin I in the blood.

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Loop Lengkung Henle

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Angiotensin I
and Angiotensin II

Angiotensin-converting enzyme (ACE)

converts angiotensin-1 to angiotensin-2
Angiotensin-2 is a potent vasoconstrictor
that acts directly on arteriolar smooth
muscle and also stimulates the production
of aldosterone by the adrenal glands.
Aldosterone causes sodium and water
retention and the excretion of potassium.
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The Angiotensin II receptor induces vasodilation,

sodium excretion, and inhibition of cell growth and
matrix formation.
A converting enzyme (ACE), converts angiotensin I
to the active octapeptide, angiotensin II, by
releasing the C-terminal histidyl-leucine dipeptide.
The same converting enzyme cleaves a number of
other peptides, including and thereby inactivating
the vasodilator bradykinin.
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Independent of its hemodynamic effects,

angiotensin II may play a role in the
pathogenesis of atherosclerosis through a
direct cellular action on the vessel wall.
Acting primarily through angiotensin II type
1 (AT1) receptors located on cell
membranes, angiotensin II is a potent
pressor substance, the primary trophic
factor for the secretion of aldosterone by
the adrenal zona glomerulosa,
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AT1 receptor blockade induces an

increase in AT2 receptor activity.
Experimental evidence suggests that the
AT2 receptor improves vascular
remodeling by stimulating smooth-muscle
cell apoptosis and contributes to the
regulation of glomerular filtration rate.
Currently, the AT2 receptor has a less well
defined functional role than the AT1
receptor.
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Angiotensin II directly inhibits renin secretion

due to angiotensin II type 1 receptors (AT1 ) on
juxtaglomerular cells, and renin secretion
increases in response to pharmacologic
blockade of either ACE or angiotensin II
receptors.
It is widely distributed in the kidney and has
the opposite functional effects of the AT1
receptor.
The AT 1 receptor is located in brain, kidney,
myocardium, peripheral vasculature, and the
adrenal glands.
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The AT 2 receptor is located in adrenal

medullary tissue, uterus, and brain.
Stimulation of the AT 2 receptor does not
influence BP regulation
After binding to specific receptors (classified as
either AT1 or AT2 subtypes), angiotensin II exerts
biologic effects in several tissues.
These receptors mediate most responses that
are critical to CV and kidney function.
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Circulating AT II can elevate BP through pressor

and volume effects.
Pressor effects include direct :
vasoconstriction,
stimulation of catecholamine release from
the adrenal medulla, and
centrally mediated increases in sympathetic
nervous system activity

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The heart and brain contain a local RAAS.

In the heart, angiotensin II is also generated by
a second enzyme, angiotensin I convertase
(human chymase).
Activation of the myocardial RAAS increases
cardiac contractility and stimulates cardiac
hypertrophy.
In the brain, angiotensin II modulates the
production and release of hypothalamic and
pituitary hormones, and enhances
sympathetic outflow from the medulla
oblongata
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AT II also stimulates aldosterone synthesis from the

adrenal cortex.
This leads to sodium and water reabsorption that
increases plasma volume, total peripheral resistance,
and ultimately BP.
Aldosterone also has a deleterious role in the
pathophysiology of other CV diseases (heart failure,
myocardial infarction [MI] and kidney disease) by
promoting tissue remodeling leading to myocardial
fibrosis and vascular dysfunction.
Clearly, any disturbance in the body that leads to
activation of the RAAS could explain chronic
hypertension.
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Some factor influence of Hypertension :

a. Natriuretic Hormone
b. Insulin Resistance
c. NEURONAL REGULATION
d. Baroreceptor reflex system
e. PERIPHERAL AUTOREGULATORY
COMPONENTS
f. VASCULAR ENDOTHELIAL MECHANISMS
g. Nitric oxide
h. ELECTROLYTES AND OTHER CHEMICALS
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Natriuretic Hormone

Natriuretic hormone is potentially increased to

facilitate sodium and water excretion in response
to an increase in renal sodium retention and
extracellular fluid volume.
Natriuretic hormone might also cause an increase
in intracellular sodium and calcium, resulting in
increased vascular tone and hypertension.
Natriuretic hormone inhibits sodium and
potassium-adenosine triphosphatase
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Insulin Resistance

The increased intracellular sodium

concentration ultimately would increase
vascular tone and BP
The development of hypertension and
associated metabolic abnormalities is
referred to as the metabolic syndrome.
Hypothetically, increased insulin
concentrations may lead to hypertension
because of increased renal sodium retention
and enhanced sympathetic nervous system
activity.
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Inherited defects in the kidneys ability to

eliminate sodium can cause an increased
blood volume.
A compensatory increase in the
concentration of circulating natriuretic
hormone increase urinary excretion of
sodium and water.
However, this same hormone is also thought
to block the active transport of sodium out
of arteriolar smooth muscle cells.

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Insulin also may elevate BP by increasing

intracellular calcium, which leads to increased
vascular resistance.
The exact mechanism by which insulin resistance
However, this association is strong because many of
the criteria used to define this population (elevated
BP, abdominal obesity, dyslipidemia, and elevated
fasting glucose) are often present in patients with
hypertension.
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insulin resistance is responsible for the frequent

coexistence of diabetes, dyslipidemia, hypertension,
and abdominal obesity.
This is also referred to as the metabolic syndrome.
Although the exact role of insulin resistance in the
development of hypertension
The vascular epithelium is a dynamic system in which
vascular tone is regulated by numerous substances.
As noted previously, angiotensin-2 promotes
vasoconstriction of the vascular epithelium.
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the adrenergic nervous system

controls - and -receptors
Stimulation of -adrenergic receptors in
the central nervous system (CNS) results in
a reflex decrease in sympathetic outflow
causing a decrease in BP.
Stimulation of postsynaptic 1-receptors in
the periphery causes vasoconstriction.

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NEURONAL REGULATION

The purpose of these neuronal mechanisms is

to regulate BP and maintain homeostasis.
Pathologic disturbances in any of the four
major components :
autonomic nerve fibers,
adrenergic receptors,
baroreceptors, or
central nervous system

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Chronically
elevated BP.

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-receptors

Stimulation of presynaptic -receptors (2) exerts a

negative inhibition on norepinephrine release.
-Receptors are regulated by a negative feedback
system;
as norepinephrine is released into the synaptic
cleft and stimulates presynaptic 2-receptors,
further norepinephrine release is inhibited.
This negative feedback results in a balance
between vasoconstriction and vasodilatation.
Stimulation of postsynaptic -receptors (1) on
arterioles and venules results in vasoconstriction.
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-receptors

Stimulation of presynaptic -receptors facilitates

norepinephrine release.
There are two types of postsynaptic -receptors,
1and 2 Both are present in all tissue innervated
by the sympathetic nervous system.
However, in some tissues 1-receptors
predominate and in other tissues 2 -receptors
predominate.
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Baroreceptor reflex system

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The baroreceptor reflex system is the major negativefeedback mechanism that controls sympathetic activity.
Changes in arterial pressure rapidly activate
baroreceptors that then transmit impulses to the
brainstem
In this reflex system, a decrease in arterial BP stimulates
baroreceptors, causing reflex vasoconstriction and
increased heart rate and force of cardiac contraction.
These baroreceptor reflex mechanisms may be blunted
(less responsive to changes in BP) in the elderly and
those with diabetes.
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Stimulation of postsynaptic 1-receptors

located in the myocardium causes an:
increase in heart rate and contractility,
whereas stimulation of postsynaptic 2receptors in the arterioles and venules results
in vasodilation.

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Stimulation of certain areas within the central

nervous system can either increase or decrease
BP.
For example, 2 -adrenergic stimulation within
the central nervous system decreases BP
through an inhibitory effect on the vasomotor
center.
However, angiotensin II increases sympathetic
outflow from the vasomotor center, which
increases BP.
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PERIPHERAL AUTOREGULATORY
COMPONENTS

Abnormalities in renal or tissue autoregulatory

systems could cause hypertension.
It is possible that a renal defect in sodium excretion
may first develop, which can then cause resetting of
tissue autoregulatory processes resulting in a higher
arterial BP.
The kidney usually maintains normal BP through a
volume-pressure adaptive mechanism.
When BP drops, the kidneys respond by increasing
retention of sodium and water.
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Intrinsic defects in these renal adaptive mechanisms

could lead to plasma volume expansion and increased
blood flow to peripheral tissues, even when BP is normal.
Local tissue autoregulatory processes that vasoconstrict
would then be activated to offset the increased blood
flow.
This effect would result in increased peripheral vascular
resistance, and if sustained, would also result in
thickening of the arteriolar walls.
This pathophysiologic component is plausible because
increased total peripheral resistance is a common
underlying finding in patients with essential
hypertension.
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Conversely, when BP rises above normal, renal

sodium and water excretion are increased to
reduce plasma volume and cardiac output.
When tissue oxygen demand is normal to low,
the local arteriolar bed remains relatively
vasoconstricted.
However, increases in metabolic demand
trigger arteriolar vasodilation that lowers
peripheral vascular resistance and increases
blood flow and oxygen delivery through
autoregulation.
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VASCULAR ENDOTHELIAL MECHANISMS

Vascular endothelium and smooth muscle play

important roles in regulating blood vessel tone and BP.
These regulating functions are ediated through
vasoactive substances that are synthesized by
endothelial cells.
It has been postulated that a deficiency in the local
synthesis of vasodilating substances (prostacyclin and
bradykinin) or excess vasoconstricting substances
(angiotensin II and endothelin I) contribute to essential
hypertension, atherosclerosis, and other CV diseases.
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Nitric oxide
Nitric oxide is produced in the endothelium,
relaxes the vascular epithelium, and is a very
potent vasodilator.
The nitric oxide system is an important
regulator of arterial BP.
Patients with hypertension may have an
intrinsic deficiency in nitric oxide, resulting in
inadequate vasodilation
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Nitric oxide (NO) is produced in the

endothelium and is a potent vasodilatory
chemical that relaxes the vascular epithelium.
The NO system has been firmly established as
an important regulator of arterial BP.
Hypothetically, some patients with
hypertension have an intrinsic deficiency in
NO release and inadequate vasodilation,
which could contribute to hypertension and
its vascular complications
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ELECTROLYTES AND OTHER

CHEMICALS

Altered calcium homeostasis also may play an

important role in the pathogenesis of hypertension.
A lack of dietary calcium hypothetically can disturb the
balance between intracellular and extracellular
calcium, resulting in an increased intracellular calcium
concentration.
This imbalance can alter vascular smooth muscle
function by increasing peripheral vascular resistance.
Some studies show that dietary calcium
supplementation results in a modest BP reduction in
patients with hypertension.
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A decrease in potassium has been associated

with an increase in peripheral vascular resistance.
It is important, however, that potassium
concentrations be maintained within the normal
range because hypokalemia increases the risk of
CV events, such as sudden death, and increases
the risk of metabolic side effects (hyperglycemia)
associated with diuretics.

The role of potassium fluctuations is also

inadequately understood.
Potassium depletion may increase peripheral
vascular resistance, but the clinical
significance of small serum potassium
concentration changes is unclear.
Furthermore, data demonstrating reduced CV
risk with dietary potassium supplementation
is very limited.
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Insulin resistance and hyperinsulinemia also have

been associated with hypertension.

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PUSTAKA

Dipiro, J.T., Robert, L.T., Gary, C.Y., Gary, R.M.,

Barbara, G.W., and L. Michael, P., 2008,
Pharmacotherapy A Pathophysiologic Approah,
Seventh Edition, Mc Graw Hill Medical.
Koda-Kimble, M.A., Lloyd, Y.Y., Brian, L.C., Robin,
L.C., Wayne, A.K., et al., Applied Therapeutics :
The Clinical Use of Drugs, Edisi 9 : Wolter Kluwer.
Larry, J.J., and Joseph, L., 2010, Nephrology and
acid Bacid Disorder, Horison: Mc Graw Hill.
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