B4M1C1
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Lem obadLayers of the Artery Cardiac Muscle
● Independent of nervous stimulation
UNICA INTIMA
T
● Long and branching with end to end attachment
- Innermost layer made of:
(intercalated disc)
● Endothelium
● One nucleus at main segment
○ Contains rodlike inclusion bodies called
● Myofibrils in parallel bundles
Weibel Palade Bodieswhich contain a
● Fainter and closer cross striations
procoagulant factor
○ Layer of flattened cells Purkinje Fibers
● Specialized for conduction of impulses
● Subendothelial Layer ● Bigger but shorter, more sarcoplasm but fewer
○ Delicate fibroelastic tissue myofibrils
● Cross striations are fainter
● Internal elastic membrane ● Nuclei fewer, larger and paler
○ Marks the boundary between theTunica
IntimaandTunica Media Pericardium
○ Containsfenestrationsessential for the ● Is a serous membrane that covers the heart.
nutrition of the avascular Tunica Media.
TUNICA MEDIA
● Made up of smooth muscle and elastic fibers
TUNICA ADVENTITIA
● xternal elastic membrane- marks the boundary
E
between theTunica MediaandTunica Adventitia
● Fibroelastic Tissue
DEFINITION OF TERMS
ROSS AND HISTOLOGIC
G ● here is no dividing line between normal and
T
CHARACTERISTICS OF THE HEART higher blood pressure. Arbitrary levels have to be
LAYERS OF THE WALL OF THE HEART established to define persons who have an
● Endocardium increased risk of developing a morbid
○ Innermost Layer cardiovascular event and / or will benefit from
■ Endothelium- Layer of flattened medical therapy.
cells which form a long tube. ● Should take into account not only the level of
■ Sub-endothelium- contains diastolic pressure but also systolic pressure, age,
nerves and blood vessels, sex, race, and concomitant disease.
fibroblasts, collagen and elastic
fibers ssential
E levated arterial pressure
E
■ Sub-endocardial layer- main Hypertension withouta known cause.
mass of the endocardium, (Primary or
fibroelastic tissue, contains Idiopathic)
nerves, blood vessels, fat cells
econdary
S levated arterial pressure as a
E
Hypertension result ofknown or definable
● Myocardium
cause.
○ Middle and thickest layer made up of
cardiac muscles
ypertensive Heart
H vidence ofleft ventricular
E
Disease hypertrophy or left ventricular
● Epicardium
failurein the presence of
○ Outermost layer composed of
sustained arterial systolic and
mesothelium and areolar tissue.
diastolic hypertension.
○ Forms the visceral layer of the
pericardium
abile Hypertension
L rterial pressure that is
A
(Borderline sometimeswithin the
Hypertension) hypertensive range.
B4M1 Case 1 1of 25
PHILIPPINES
ccelerated
A significant recent increase over
A
Hypertension ● Filipino adults 20 years and above with
previous hypertensive levels
hypertension
associated with evidence of
○ 2012 - 21%
vascular damage on funduscopic
○ 2008 - 21%
examination but without
○ 2003 - 16%
papilledema.
Source: Philippines Society of Hypertension
alignant
M xtremely elevated systolic and
E
Hypertension diastolic arterial pressures,or
hypertension associated with
end-organ damage(p apilledema,
usually accompanied by retinal
hemorrhage, encephalopathy,
eclampsia, etc.) which must be
lowered in one hour.
Hypertensive Crisis ncontrolled hypertensionwhich
U
must be lowered in 24 hours. No
end organ damage as mentioned
in hypertensive emergencies.
Pseudohypertension Falsely elevated BPseen in:
● Elderly patients with
atherosclerotic
branchial arteries
● White coat
hypertension
● Mismatch in size of
pressure cuff and
patient’s arm
hite Coat
W nxious patientswho get
A
Hypertension elevated BP readings at the
doctor’s clinic.
PREVALENCE OF HYPERTENSION
INDUSTRIALIZED SOCIETIES
● lood pressure increases steadily duringthe first
B
two decades of life.
● Blood pressure is associated with growth and
development in children and adolescents.
● Duringearly adulthood, average systolic blood
pressure is higher for men than for women.
● Individuals aged 60 and older, the systolic blood
pressure is higher in women than in males.
UNITED STATES:
● 30% of adults have hypertension with blood
pressure of≥140/≥90
○ 33.5% in non-Hispanic blacks
○ 28.9% in non-Hispanic whites
○ 20.7% in Mexican Americans
B4M1 Case 1 2of 25
NATURAL HISTORY OF PATIENTS iologic and adoptive siblings, and adoption
b
ITH UNTREATED HYPERTENSION
W studies.
● Essential hypertensionis a heterogeneous ● Most studies support the concept that
disorder, variables other than the arterial inheritance is probably multifactorial or that a
pressure modify its course. number of different genetic defects each have an
● The probability of developing a morbid elevated blood pressure as one of their
cardiovascular event with a given arterial phenotypic expressions.
pressure may vary as much as 20-fold depending ● These include:
on whether associated risks factors are present ○ Gene defects in enzymes involved in
● ost untreated adults with hypertension will
M aldosterone metabolism(e.g. aldosterone
develop further increase in arterial pressure with synthase, II B - hydroxylase, 17 a -
time. hydroxylase).
○ Untreated hypertensionis associated with ■ These lead to an adaptive increase
shortening of life by 10 - 20 years, usually in secretion of aldosterone, increase
related to an acceleration of the salt and water resorption, plasma
atherosclerotic process. volume expansion, and ultimately
● Individuals who have relativelymild disease– i.e. hypertension
without evidence of end organ damage – that is ○ Mutations in proteins that affect sodium
left untreated for 7 - 10 years have a high risk of reabsorption.
developing significant complications. ■ For example, mutations in an
○ Nearly 30% will exhibit atherosclerotic epithelial sodium channel protein
complications lead to increased distal tubular
○ More than 50% will have an end organ reabsorption of sodium induced by
damage related to the hypertension itself, aldosterone, resulting in a
such as cardiomegaly, congestive heart moderately severe form of
failure, retinopathy, a cerebrovascular salt-sensitive hypertension called
accident, and / or renal insufficiency. Liddle syndrome.
ROLE OF THE FOLLOWING
IN THE GENESIS OF HYPERTENSION
GENETIC FACTORS
● enetic factorsclearly play a role in determining
G
blood pressure levels, as evidenced by studies
comparing pressure in monozygotic and
dizygotic twins, studies of familial aggregation of
hypertension comparing the blood pressure of
B4M1 Case 1 3of 25
NVIRONMENTAL FACTORS
E Low-Renin Essential Hypertension
● Salt intake, obesity, occupation, alcohol intake, ● Approximately20% of patients who have
family size and crowdinghave been implicated in essential hypertension have suppressed plasma
the development of hypertension. renin activity.
● These factors have all been assumed to be ● This is more common in individuals of African
important in the increase of blood pressure with descent than in white patients. The patients who
age in more affluent societies, in contrast to the have expanded extracellular fluid volumes.
decline in blood pressure with age in less affluent ● Hypothesis for the low plasma renin activity:
groups. ○ Sodium retention and renin suppression are
● Salt intakeis theenvironmental factor that has due toexcessive production of an
received the greatest attention. unidentified mineralocorticoid.
○ Even this factor illustrates the ○ Theadrenal cortex has an increased
heterogeneous nature of the essential sensitivity to angiotensin II- this could be
hypertensive population, in that the blood the cause of hypertension.
pressure is only approximately 60% of
hypertensive is particularly responsive to the High-Renin Essential Hypertension
level of sodium intake. ● Approximately15% of patients with essential
○ The cause of this special sensitivity to salt hypertension have plasma renin activity levels
varies, with primarily aldosteronism, bilateral above the normal range.
renal artery stenosis, renal parenchymal ● Has been suggested that plasma renin plays an
disease, and low-renin essential important role in the pathogenesis of the
hypertension accounting for about half the elevated arterial pressure in these patients.
patients. ● Postulated that the elevated renin levels and
● Other postulated contributing factors include blood pressure may both be secondary to an
chloride intake, calcium intake, a generalized increase in adrenergic system activity.
cellular membrane defect, insulin resistance and
“non modulation”. HORMONAL FACTORS (INSULIN RESISTANCE)
● Substantial fraction of the hypertensive
ROLE OF RENIN population hasinsulin resistance and
● eninis an enzyme secreted by the
R hyperinsulinemia.
juxtaglomerular cell of the kidney and linked with ● Insulin resistanceis common in patients with
aldosterone in a negative feedback loop. non-insulin-dependent diabetes mellitus (NIDDM)
● The primary factor that modifies its rate of or obesity.
secretion is thevolume status of the individual, ● Both obesity and NIDDM are more common in
particularly as related tochanges in dietary hypertensive than in normotensive individuals
sodium intake. ● Hyperinsulinemia and insulin resistance are
● The end product of the action of renin on its present even in lean hypertensive patients
substrate is the generation of the peptide without NIDDM.
angiotensin II. The response of target issues to ● Hyperinsulinemiacan increase arterial pressure
the peptide is uniquely determined by the prior by one or more of four mechanisms:
dietary electrolyte intake. ○ Hyperinsulinemia produces renal
● For example, sodium intake normally modulates sodium retention and increases
adrenal and renal vascular responses to sympathetic activity.
angiotensin II. ○ Vascular smooth muscle hypertrophy
● Withsodium restriction,adrenal responses are secondary to the mitogenic action of
enhanced and the renal vascular response insulin.
reduced. ○ Insulin modifies ion transport across the
● Sodium loadinghas the opposite effect. cell membrane, thereby potentially
● The range of plastic renin activities observed in increasing the cytosolic calcium levels
hypertensive subjects is broader than in of insulin-sensitive vascular or renal
normotensive individuals. tissue.
● Some hypertensive patients have been defined ○ Insulin resistance may be a marker for
as having low renin and others as having another pathologic process, e.g. non
high-renin essential hypertension. modulation, which could be the primary
mechanism increasing blood pressure.
B4M1 Case 1 4of 25
● ote: Some hypertensives are termed as
N TWO FORMS OF SMALL BLOOD VESSEL
non-modulatorsbecause of the absence of the DISEASE ASSOCIATED WITH HYPERTENSION
sodium-mediated modulation of target tissue HYALINE ARTERIOSCLEROSIS
responses to angiotensin Il. Have hypertension ● ncountered frequently inelderly patients,
E
that is salt sensitive because of a defect in the whether normotensive or hypertensive but is
kidney's ability to excrete sodium appropriately. more generalized and more severe in patients
EFFECTS OF HYPERTENSION with hypertension.
● Vascular lesion consists of ahomogenous, pink,
EART
H
hyaline thickening of the walls of arterioles with
● Concentric left ventricular hypertrophy
loss of underlying structural detail and with
characterized by an increase in wall thickness.
narrowing of the lumen.
● Dilatation of left ventricular cavity
○ The lesions reflect leakage of plasma
● Myocardial damage — ischemia or infarction
components across vascular
● P.E. findings:
endothelium and increasing
○ Heart is enlarged
extracellular matrix production by
○ Prominent left ventricular impulse
smooth muscle cells.
○ Sound of aortic closure is accentuated,
○ Presumably the chronic hemodynamic
and there maybe a faint murmur of
stress of hypertension or a metabolic
aortic regurgitation
stress in diabetes accentuates
○ Pre Systolic (atrial, fourth) heart sounds
endothelial injury, thus resulting in
are frequent
leakage and hyaline deposition.
○ Pre Diastolic (ventricular, third) heart
● The narrowing of the arteriolar lumens causes
sound or summation gallop rhythm may
impairment of the blood supply to affected
be present
organs, particularly in kidneys.
RETINA ● This is a major morphological characteristic of
● Retinal changes benign nephrosclerosis, in which the arteriolar
○ Focal spasm and progressive general narrowing causes diffuse renal ischemia and
narrowing arteriole symmetric shrinking of the kidneys.
○ Papilledema or hemorrhages of the
HYPERPLASTIC ARTERIOSCLEROSIS
macular area producing scotomata,
● enerally related to more acute or severe
G
blurred vision, and even blindness.
elevations of blood pressure and is therefore
CENTRAL NERVOUS SYSTEM characteristic but not limited to malignant
● erebral infarctionwhich is secondary to the
C hypertension
increased atherosclerosis. ● Characterized byonion-skin, concentric,
● Cerebral hemorrhagewhich is the result of both laminated thickening of the walls of the arteriole
the elevated arterial pressure and the with progressive narrowing of the lumensas
development of seen light microscope
● cerebral vascular microaneurysms. ● With an electron microscope, the laminations
● Prominent symptoms: consist of smooth muscle cells and thickened
○ Occipital headache and reduplicated basement membrane.
○ Dizziness ● These hyperplastic changes are accompanied
○ Light-headedness by deposits of fibrinoid and acute necrosis of the
vessel wall, referred to as necrotizing arteriolitis.
○ Vertigo
The arterioles in all tissues throughout the body
○ Tinnitus
may be affected but the favored site is the
○ Dimmed vision
kidney
○ Syncope
KIDNEYS
● rteriosclerotic lesions of the afferent and
A
efferent arterioles and the glomerular capillary
tufts
● Decreased glomerular filtration rate
● Tubular dysfunction
● Proteinuria and microscopic hematuria
● Renal failure
B4M1 Case 1 5of 25
EVALUATION OF PATIENTS WITH HYPERTENSION ○ izziness, palpitation, easy fatigability,
D
and impotence which may be related to
Evaluation of patients with hypertension has 3 objectives:
● To assess lifestyle and identify other elevated blood pressure.
cardiovascular risk factors or concomitant ● Referable to vascular diseases include epistaxis,
disorders that may affect prognosis and guide hematuria, blurring of vision owing to retinal
treatment changes, episodes of weakness or dizziness due
to transient cerebral ischemia, angina pectoris,
Table 3. Cardiovascular Risk Factors and dyspnea due to cardiac failure.
● A strong family history of hypertension favors the
Major Risk Factors
diagnosis of essential hypertension.
ypertension*
H ● A history of use of adrenal steroids or estrogen is
Cigarette Smoking of obvious significance.
Obesity (BMI>30 kg/m²) ● History of repeated urinary tract infection
Physical inactivity
Dyslipidemia* suggestschronic pyelonephritis;nocturia and
Diabetes mellitus* polydipsiasuggestrenal or endocrine disease.
Microalbuminuria or estimated GFR <60 mL/min ○ History of weight gain is compatible
Age (older than 55 for men, 65 for women)
with Cushing’s syndromeand one of
Family history of premature cardiovascular disease (men
under age 55, women under age 65) weight loss is compatible with
pheochromocytoma.
Target Organ Damage ● A number of aspects of the history aid in
determining whether vascular disease has
Heart
progressed to a dangerous stage. These include
● Left Ventricular Hypertrophy
● Angina or prior myocardial infarction angina pectoris and symptoms of
● Prior coronary revascularization cerebrovascular insufficiency, congestive heart
● Heart failure, and/or peripheral vascular insufficiency.
Brain
● Stroke or transient ischemic attack ● Other risk factors that should be asked about
Chronic Kidney Disease include smoking, diabetes mellitus, lipid
Retinopathy disorders, and a family history of early deaths
FR, glomerular filtration rate
G
due to cardiovascular disease.
*Components of the metabolic syndrome ● Aspects of the patient's lifestyle that could
contribute to hypertension or affect its treatment
● To reveal identifiable causes of high BP should be assessed including. diet, physical
activity, family status, work, and educational
Table 4. Identifiable causes of hypertension level.
leep apnea
S
Drug-induced or related causes PHYSICAL EXAMINATION
Chronic kidney disease
● eneral appearance-observe for facial
G
Primary aldosteronism
Renovascular disease expression and contours,andmuscular
Chronic steroid therapy and Cushing’s syndrome development in the upper extremities.
Pheochromocytoma ● Appropriate measurement of BP, with
Coarctation of the aorta verification in the contralateral arm.
Thyroid or parathyroid disease
● Examination of the optic fundi
● Calculation of body mass index (BMI)
● o assess the presence or absence of target
T ○ Measurement of the waist
organ damage and cardiovascular disease circumference also may be useful
EDICAL HISTORY
M ● Auscultation of carotid, abdominal, and femoral
● Most patients with hypertension have no specific bruits
symptoms referable to their blood pressure
● Palpation of the thyroid gland
elevation. ● Thorough examination of the heart and lungs
● Common complaintsare: ● Examination of the abdomen for enlarged
○ Headaches localized to the occipital kidney masses, and abnormal aortic pulsation.
region and are present when the patient ● Palpation of the lower extremities for edema
and pulses
awakens in the morning but subside
● Neurological assessment
spontaneously after several hours.
B4M1 Case 1 6of 25
LABORATORY TESTS AND OTHER DIAGNOSTIC NON-PHARMACOLOGIC TREATMENT
PROCEDURES ● General measures instituted
● Routine laboratory tests recommended before ○ Relief of stress
initiating therapy include: ○ Dietary management
○ Regular aerobic exercise
○ Weight reduction (if needed)
○ Control of other risk factors contributing
to the development of arteriosclerosis
● Lifestyle modifications
○ pecial studies to screen for secondary
S
hypertension
■ Renovascular disease—
angiotensin-converting enzyme inhibitor
radionuclide renal scan, renal duplex
Doppler flow studies, and MRI angiography
■ Pheochromocytoma— 24-hour urine assay
for creatinine, metanephrines, and
catecholamines
■ Cushing’s syndrome— overnight
dexamethasone suppression test or
24-hour urine cortisol & creatinine.
■ Primary aldosteronism— plasma
aldosterone:renin ratio
CONDITIONS NECESSITATING PROMPT PHARMACOLOGIC MANAGEMENT
REDUCTION OF BLOOD PRESSURE ● im of drug therapy— to use a drug
A
(HYPERTENSIVE URGENCIES AND EMERGENCIES)
alone or in combination, to return arterial
pressure to normal levels with minimal
ncephalopathy
E troke
S side effects
Myocardial infarction Head trauma
Unstable angina Life-threatening
Pulmonary edema arterial bleeding
Eclampsia Aortic dissection
MANAGEMENT OF HYPERTENSION
● he ultimate public health goal of
T
antihypertensive therapy is the reduction of
cardiovascular and renal morbidity and
mortality.
● For thegeneral patient population with
hypertension, the BP goal is<140 / 90 mmHg
(associated with a decrease in cardiovascular
disease (CVD) complications
● Lower BP goals for patients at higher risk of COMPELLING INDICATIONS:
CVD:patients with hypertension and diabetes ● Table above describes compelling indications
or renal disease, the BP goal is<130 / 80 that require certain antihypertensive drug classes
mmHg. for high-risk conditions.
B4M1 Case 1 7of 25
● he drug selections for these compelling
T ○ CEl — or ARB- based treatments
A
indications are based on favorable outcome data favorably affect the progression of
from clinical trials. diabetic nephropathy and reduce
● A combination of agents may be required. Other albuminuria andARBshave been shown
management considerations include medications to reduce progression to
already in use, tolerability, and desired BP targets. macroalbuminuria
In many cases, special consultation may be
indicated. ● Chronic Kidney Disease
○ Therapeutic goals are to slow
● Ischemic Heart Disease deterioration of renal function and
○ Ischemic heart disease (IHD)is the prevent CVD in people withchronic
most common form of target organ kidney disease (CKD),as defined by
damage associated with hypertension. either:
○ In patients with hypertension and stable ■ reduced excretory function
angina pectoris, the first drug of choice with an estimated GFR below
is usually a BB; alternatively, long-acting 60 ml/min per 1.73 m2
CCBs can be used. ● corresponding
○ In patients with acute coronary approximately to a
syndromes (unstable angina or creatinine of >1.5
myocardial infarction),hypertension mg/dL in men or >1.3
should be treated initially with BBs and mg/dL in women
ACEls, with addition of other drugs as ■ the presence of albuminuria
needed for BP control. ● >300 mg/day or 200
○ In patients with postmyocardial mg albumin/g
infarction,ACEls, BBs, and aldosterone creatinine)
antagonists have proven to be most ○ Hypertensionappears in the majority of
beneficial. Intensive lipid management these patients, and they should receive
and aspirin therapy are also indicated aggressive BP management, often with
three or more drugs to reach target BP
● Heart Failure values of <130 / 80 mmHg.
○ Heart failure (HF),in the form of ○ ACEls and ARBshave demonstrated
systolic or diastolic ventricular favorable effects on the progression of
dysfunction, results primarily from diabetic and nondiabetic renal disease.
systolic hypertension and IHD. ○ A limited rise in theserum creatinineof
○ Fastidious BPand cholesterol control as much as35 percent above baseline
are the primary preventive measures for with ACEls or ARBsis acceptable and is
those at high risk for HF. not a reason to withhold treatment
○ In asymptomatic individuals with unless hyperkalemia develops.
demonstrable ventricular dysfunction, ○ Withadvanced renal disease(estimated
ACEls and BBs are recommended. GFR <30ml/min 1.73 m2, corresponding
○ For those with symptomatic ventricular to a serum creatinine of 2.5-3 mg / dL),
dysfunction or end-stage heart disease, increasing doses of loop diureticsare
ACEls, BBs, ARBs, and aldosterone usually needed in combination with
blockers are recommended along with other drug classes
loop diuretics.
● Cerebrovascular Disease
● Diabetic Hypertension ○ The risks and benefits of acute lowering
○ Combinations of two or more drugsare of BP during an acute stroke are still
usually needed to achieve thetarget unclear;control of BP at intermediate
goal of <130 / 80 mmHg. levels (approximately160/100 mmHg)
○ Thiazide diuretics, BBs, ACEls, ARBs, is appropriate until the condition has
and CCBsare beneficial in reducing CVD stabilized or improved.
and stroke incidence in patients with ○ Recurrent stroke rates are lowered by
diabetes. the combination of anACEIand
thiazide-type diuretic.
B4M1 Case 1 8of 25
DIURETICS
● iureticsare drugs thatincrease the rate of urine
D
flow, also increase the rate of excretion of Na2+
(natriuresis) and of an accompanying anion,
usually CI
● NaClin the body is themajor determinant of
extracellular fluid volume, and most clinical
applications of diuretics are directed toward
reducing extracellular fluid volume by decreasing
total — body NaCl content.
● Diureticsnot only alter the excretion of Na2+, but
also maymodify renal handling of other cations
(K+, H+, Ca2+, and Mg2+), anions (CI-, HCO3-,
and H2PO4-), and uric acid.
B4M1 Case 1 9of 25
Inhibitors of Na+ - K+ - 2CI-
Symport
Acetazolamide Osmotic Diuretics
(Loop Diuretics; High-Ceiling
Diuretics)
prototype drug
● Osmotic diureticsare agents
● Inhibitors of Na+ - K+ - 2CI-
●
● The common molecular motif of that are freely filtered at the symport are a group of diuretics that
available carbonic anhydrase glomerulus, undergo limited have in common anability to block
inhibitors is an unsubstituted reabsorption by the renal the Na+ - K+ - 2CI- symporterin the
sulfonamide moiety. tubule, and are relatively inert thick ascending limbof the loop of
pharmacologically. Henle.
● Administered in large enough ● The efficacy of inhibitors of Na+ -
doses to increase significantly K+ - 2CI- symport in thethick
the osmolality of plasma and ascending limbof the loop of Henle
tubular fluid. is due to a combination of 2 factors.
●Refer to Table 25-3. 1. Approximately 25% of the
filtered Na Load normally is
reabsorbed by thethick
ascending limb.
2. Nephron segments past the
thick ascending limbdo not
possess the reabsorption
capacity to rescue the flood
of rejects exiting thethick
ascending limb.
●Refer to Table 25-4.
echanism and Site of Action
M echanism and Site of Action
M hemistry
C
●Potently inhibits both the ● By extracting water from ●FUROSEMIDE, BUMETANIDE,
membrane-bound and intracellular compartments, AZOSEMIDE, PIRETANIDE,and
cytoplasmic forms of carbonic these agents expand the TRIPAMIDEall contain a
anhydrase, resulting in nearly extracellular fluid volume, sulfonamide moiety
complete abolition of NaHCOs decrease blood viscosity, and ●ETHACRYNIC ACIDis a
reabsorption in the proximal tubule. inhibit renin release. phenoxyacetic acid
● A high percentage of enzyme activity ● These effectsincrease renal derivative.
must be inhibited before an effect on blood flow (RBF), and the ●TORSEMIDEis a sulfonylurea.
electrolyte excretion is observed. increase in renal medullary
●The major site of actionis the blood flow removes NaCl and echanism and Site of Action
M
proximal tubulewhile thecollecting urea from the renal medulla, ●Bind to the Na+ - K+ - 2Cl-
duct systemis the2° site of action reducing medullary tonicity. symporterin thethick ascending
●Carbonic anhydraseis also ● Sites of action : limband block its function, bringing
involved in the secretion of titratable ● Loop of Henle - 1° site of salt transport in this segment of the
acid in the collecting duct system (a action nephron to a virtual standstill.
process that involves a proton pump) ● Proximal tubule ● Alsoinhibit Ca2+ and Mg2+
●Proximal tubular epithelial cellsare reabsorptionin thethick ascending
richly endowed with the zinc limbby abolishing the transepithelial
metalloenzyme carbonic anhydrase, potential difference that is the
which is found in the luminal and dominant driving force for
basolateral membranes(type IV reabsorption of these cations.
carbonic anhydrase, an enzyme
tethered to the membrane by a
glycosyl phosphatidylinositol linkage)
as well as in thecytoplasm(type Il
carbonic anhydrase)
● The actual reaction catalyzed by
⇆
carbonic anhydrase is OH + CO2
⇆
HCO3; however, H2O OH + H
⇆ and HCO3 + H H2CO3, so that
⇆
the net reaction is H2O + CO2
H2CO3.
B4M1 Case 1 10of 25
The primary site of action is the
●
thick ascending limb.
● In thethick ascending limb, flux of
Na+, K+, and Cl- from the lumen into
the epithelial cell is mediated by a
Na+ - K+ - 2Cl- symporter. This
symporter captures the free energy
in the Na+ electrochemical gradient
established by the basolateral Na+
pump and provide for “uphill”
transport of K+ and Cl- into the cell.
➢ K+ channels in the luminal
membrane (calledROMK)
provide a conductive pathway
for the apical recycling of this
cation and basolateral Cl-
channels (calledCLCN)
provide a basolateral exit
mechanism for CI-
● The luminal membranes of
epithelial cells in thethick ascending
limbhave conductive pathways
(channels) only for K+. Therefore the
apical membrane voltageis
determined by theequilibrium
potential for K+.
● The basolateral membrane has
channels for both K and Cl, so that
the basolateral membrane voltage is
less than Ek; i.e., conductance for CI-
depolarizes the basolateral
membrane.
ffects in Urinary Excretion
E ffects in Urinary Excretion
E ffects in Urinary Excretion
E
●Rapid rise in urinary HCO3 excretion ●Increase urinary excretionof ● Profound increase in the urinary
to approximately 35% of nearly all electrolytes, including excretion ofNa+ and CI-
filtered load. Na+, K+, Ca2+, Mg2+,Cl-, and ● Increase excretion ofCa2+ and
● Increase in urinarypH to HCO3-. Mg2+
approximately 8and the development ● Some(FUROSEMIDE)haveweak
of metabolic acidosis. Effects on Renal Hemodynamics carbonic anhydrase-inhibiting
● Increase excretion of K+ and ●Increases renal blood flow (RBF) activity→ increase urinary excretion
phosphate but have little or no effect by a variety of mechanisms. of HCO3 and phosphate.
on the excretion of Ca2+ or Mg2+. ➢ Dilatation of the afferent ● All increase the urinary excretion
arteriole increases the of K+ and titratable acid.
Effects on Renal Hemodynamics hydrostatic pressure in
the glomerular capillaries
B4M1 Case 1 11of 25
Increase delivery of solutes to the
● ( PGC) and dilute the ➢ T his effect is due in part to
macula densa triggers plasma which decreases increased delivery of Na+
tubuloglomerular feedback (TGF) → the mean colloidal to the distal tubule.
increase arteriolar resistance and osmotic pressure in the ● Acutely, these agents increase the
reduction in renal blood flow (RBF) and glomerular capillaries excretion of uric acid whereas
glomerular filtration rate (GFR). (TTGC) chronic administration results in
●Increase pressure in the reduced excretion of uric acid.
ther Actions
O proximal tubule (PT). ●Block the kidney's ability to
●Decreases the rate of formation of concentrate urine during hydropenia.
aqueous humorand consequently ●Impair the kidney’s abilityto
reduces intraocular pressure. excrete a dilute urine duringwater
●CNS effects:anticonvulsant action; diuresis.
somnolence, paresthesias
●Increase CO levels in expired gas. ffects on Renal Hemodynamics
E
● Reduce gastric acid secretion (large ●Increase total renal blood flow
doses)- no therapeutic applications. (RBF)and redistribute RBF to the
➢ Carbonic anhydrase is present mid cortex.
in a number of extrarenal ●Block tubuloglomerular feedback
tissues including the eye, (TGF) by inhibiting salt transport
gastric mucosa, pancreas, into the macula densa, so that the
CNS, and RBCs. macula densa no longer can “sense”
➢ Carbonic anhydrase in the NaCl concentrations in the tubular
ciliary processes of the eye fluid
mediates the formation of ●Powerful stimulators of renin
large amounts of HCO3 in release.
aqueous humor.
ther Actions
O
●Direct vascular effects
➢ Furosemide acutely
increases systemic venous
capacitance and thereby
decreases left ventricular
filling pressure.
●Inhibit electrolyte transport in
many tissues— this effect is
clinically important only in theinner
ear, where alterations in the
electrolyte composition of
endolymph may contribute to
drug-induced ototoxicity.
bsorption and Elimination
A bsorption and Elimination
A bsorption and Elimination
A
● These agents areavidly bound by ●Glycerin and Isosorbidecan be ●FUROSEMIDE, BUMETANIDE,
carbonic anhydraseand tissues rich in givenorally, whereasMANNITOL ETHACRYNIC ACID, TORSEMIDEare
this enzyme will have higher and UREAmust be administered extensively found in plasma
concentrations of these agents intravenously proteins.
following systemic administration. ●TORSEMIDEhas a longer half-life
than the other drugs
oxicity, Adverse Effects,
T oxicity, Adverse Effects,
T oxicity, Adverse Effects,
T
Contraindications, Drug Interaction Contraindications, Drug Contraindications, Drug Interaction
● Serious toxic reactions are infrequent. Interaction ● Most adverse effects are due to
● These drugs are sulfonamide 1. Frank pulmonary edema abnormalities of fluid and electrolyte
derivatives — in patients with heart balance.
➢ may cause bone marrow failure or pulmonary 1. Serious depletion of total
depression, skin toxicity, congestion body Na+→ hyponatremia
sulfonamide-like renal lesions 2. Hyponatremia— due to and/or extracellular fluid
and allergic reactions in extraction of water from volume depletion
patients hyper-sensitive to intracellular compartment associated with
sulfonamide. hypotension, reduced
B4M1 Case 1 12of 25
3. H
ypernatremia— due to lomerular filtration rate
g
Contraindications loss of water in excess of (GFR), circulatory collapse,
1. Patients with hepatic cirrhosis electrolytes. thromboembolic episodes,
— diversion of ammonia of and hepatic
renal origin from urine into the ● ommon adverse effects
C encephalopathy (patients
systemic circulation may — headache, nausea, with liver disease)
induce hepatic vomiting 2. Increase urinary excretion
encephalopathy. of K+ and H+→
2. Patients with hyperchloremic Contraindications hypochloremic alkalosis.
acidosisorsevere chronic 1. Anuria patientsdue to 3. Hypokalemia→ induce
obstructive pulmonary severe renal damage cardiac arrhythmias
disease. 2. Patients with impaired particularly in patients
liver function—UREA taking cardiac glycosides
3. Patients with active 4. Increase Mg2+ and Ca2+
cranial bleeding— excretion→
MANNITOLandUREA hypomagnesemiaand
hypocalcemia
● Ototoxicity — tinnitus, hearing
impairment, deafness, vertigo and
sense of fullness in the ears.
● Hyperuricemia and hyperglycemia
● Increase plasma levels of LDL
cholesterol and triglycerides.
● Decrease plasma levels of HDL
cholesterol
Contraindications
1. Severe Na+ and volume
depletion
2. Hypersensitivity to
sulfonamide
3. Anuriaunresponsive to a
trial dose of loop diuretic
Therapeutic Uses Therapeutic Uses Therapeutic Uses
● Open-angle glaucoma— 1. Jaundiced patients 1. Treatment ofacute
major indication undergoing surgery — pulmonary edema- major
● Secondary glaucoma and MANNITOL use
preoperatively in acute 2. Treatment of dialysis 2. Chronic congestive heart
angle-closure glaucoma to disequilibrium syndrome failure
lower ocular pressure before —MANNITOL 3. Hypertension
surgery. 3. To control intraocular 4. Edema of nephrotic
● Treatment of epilepsy — pressure during acute syndrome
Acetazolamide attacks of glaucoma and 5. Edema and ascites of liver
● Symptomatic relief in patients for short-term reductions cirrhosis.
with acute mountain sickness. in intraocular pressure, 6. Edema associated with
● Familial periodic paralysis both preoperatively and chronic renal insufficiency.
● Correcting a metabolic postoperatively. 7. Drug overdose — to induce
alkalosis, especially an 4. To reduce cerebral a forced diuresis to
alkalosis caused by edema and brain mass facilitate more rapid renal
diuretics-induced increases in before and after elimination of the offending
H' excretion. neurosurgery — drug.
MANNITOL 8. Hypercalcemia
9. Life-threatening
hyponatremia
B4M1 Case 1 13of 25
Inhibitors of Na+ - CI' Symport Antagonists of Mineralocorticoid
I nhibitors of Renal Epithelial Na+
(Thiazide and Thiazide-Like Receptors (Aldosterone Antagonists;
channels (K+ - Sparing Diuretics)
Diuretics) K+ - Sparing Diuretics)
● Refer to Table 25-5. ● MILORIDEis apyrazinyl
A Mineralocorticoids causeretention
●
guanidine derivative, and of salt and waterandincrease the
TRIAMTERENEis a excretion of K+ and H+by binding to
pteridine. Both drugs are specific mineralocorticoid receptors
organic bases and are (MR).
transported by the organic ●Refer to Table 29-7.
base secretory mechanism
in the proximal tubule.
● Refer to Table 29-6.
Mechanism and Site of Action Mechanism and Site of Action Mechanism and Site of Action
● Inhibit the Na - CI Symporter ● Blockade of Na+ channels ● Competitively inhibit the
perhaps by competing for in the luminal membrane of binding of aldosterone to
the CI- binding site. principal cells in the late the mineralocorticoid
● Sites of action: distal tubule and collecting receptor (MR).
○ Distal convoluted duct.
tubule (DCT)- 1° ● Sites of action:
site of action ○ Late distal tubule
○ Proximal tubule- ○ Collecting duct
2° site of action
B4M1 Case 1 14of 25
● s with the other nephron
A
segments, transport is
powered by aNa+ pumpin ● pithelial cellsin the late
E
thebasolateral membrane. ● rincipal cellsin the late
P
distal tubule and collecting
● The free energy in the distal tubule and collecting
ducthave in their luminal ductcontaining cytoplasmic
electrochemical gradient for MRs that have a high affinity
Na+ is harnessed by aNa+ - membranes aNa+ channel
that provide a conductive for aldosterone. This
CI symporter, in theluminal receptor is a member of the
membrane,which moves CI pathway for the entry of
superfamily of receptors for
into the epithelial cell Na+ into the cell down the
electrochemical gradient steroid hormones, thyroid
against its electrochemical hormones, vitamin D, and
gradient. Cl- then passively created by the basolateral
Na+ pump. retinoids.
exits the basolateral ● Aldosteroneenters the
membrane via CI- channel. ● The higher permeability of
epithelial cells from the
the luminal membrane for
Na+ depolarizes the luminal basolateral membrane and
membrane, but not the binds to MRs;
basolateral membrane, ● TheMR - aldosterone
creating alumen-negative complextranslocates to the
nucleus, where it binds to
transepithelial potential
difference. specific sequences ofDNA
● This transepithelial voltage (hormone-responsive
provides an important elements) and thereby
driving force for the regulates the expression of
secretion of K+ into the multiple gene products
lumenviaK+ channels calledaldosterone—induced
(ROMK)in the luminal proteins (AlPs)which have
membrane. the following effects:
○ activation of
“silent” Na+
channels and
“silent” Na+ pumps
that preexist in the
cell membrane;
○ alterations in the
cycling of Na+
channels and Na+
pumps between
the cytosol and cell
membrane so that
more channels and
pumps are located
in the membrane;
○ increase
expression of Na+
channels and Na+
pumps;
○ changes in the
B4M1 Case 1 15of 25
ermeability of the
p
tight junctions; and
increased activity
of enzymes in the
mitochondria that
are involved in ATP
production.
● The net effect of
aldosterone-induced
proteins (AIPs) is to
increase Na+ conductance
of the luminal membrane
andsodium pump activity
of the basolateral
membrane→
transepithelial NaCl
transport is enhanced and
the lumen-negative
transepithelial voltage is
increased.
● The MR - spironolactone
complex isnotable to
induce the synthesis of AlPs
Effects on Urinary Excretion ffects on Urinary Excretion
E Effects on Urinary Excretion
● Inhibit NaCl transport in the ● Mild increasein the ● Effects of
DCT→ increase Na+ and Cl- excretion rates ofNa+ and SPIRONOLACTONEon
excretion. СГ urinary excretion are very
● Increase HCO3- and ● Decreasethe excretion similarto those induced by
phosphate excretion→ rates ofK+, H+, Ca2+ and renal epithelial Na+ -
these agents have weak Mg2+ channel inhibitors.
inhibitors of carbonic ● Decreaseuric acid ● The clinical efficacy of this
anhydrase excretion - chronic drug is a function of
● Increase excretion of K+ administration endogenous levels of
and titratable acid→ due to aldosterone.
increased delivery of Na+ to Effects on Renal Hemodynamics ○ The higher the
the distal tubule. ● L ittle or no effect on renal levels of
● Increase uric acid excretion hemodynamics endogenous
→
acute administration. ● Do not alter aldosterone, the
● Reduced uric acid excretion tubuloglomerular feedback greater the effects
→
chronic administration (TGF) of this drug on
● Decrease Ca2+ excretion→ urinary excretion.
chronic administration Other Actions
● Mild magnesuria ● Blocks theNa+ - H+ and Effects on Renal Hemodynamics
● Alter the ability of the kidney Na+ - Ca2+antiporters ● Little or no effect on renal
to excrete a dilute urine ● InhibitNa+ pump hemodynamics
during water diuresis. ● Does not alter TGF.
Effects on Renal Hemodynamics Other Actions
● Variably reduceglomerular ● High concentrations of
filtration rate (GFR)due to SPIRONOLACTONE
increases in intratubular interfere with steroid
pressure. biosynthesis byinhibiting
● Do not affect therenal 11B- and 18-, 21-, and 17a-
blood flow (RBF). hydroxylase— have limited
● Little or no influence on clinical relevance.
tubuloglomerular feedback
(TGF).
Other Actions
● Inhibit phosphodiesterase,
mitochondrial oxygen
B4M1 Case 1 16of 25
onsumption, and renal
c
uptake of fatty acids — no
clinical significance
Absorption and Elimination Absorption and Elimination Absorption and Elimination
● Probenecidcan attenuate ● Amilorideis eliminated ● Spironolactoneis partially ~
the diuretic response to predominantly by urinary absorbed (approximately
thiazides by competing for excretion of the intact drug. 65%), extensively
transport into the proximal ● Triamterene is extensively metabolized, undergoes
tubule metabolized to an active enterohepatic recirculation,
metabolite, highly protein bound, and
4-hydroxytriamterene short half-life (1.6 hours)
sulfate, and this metabolite ● An active metabolite,
is excreted in the urine. canrenone, has ahalf-life of
approximately 16.5 hours,
which prolongs the
biological effect of
spironolactone
● Canrenoateis not active per
se but is converted to
canrenonein the body.
● MR antagonistsare the only
diuretics thatdo not require
access to the tubular lumen
to induce a diuresis.
oxicity, Adverse Effects,
T oxicity, Adverse Effects,
T oxicity, Adverse Effects,
T
Contraindications Contraindications Contraindications
● Sexual dysfunction (erection ● Hyperkalemia- most dangerous ●Life—threatening hyperkalemia
problems) adverse effect ● Inducemetabolic acidosisin
● Most serious adverse effects are ● Triamterene- reduce glucose cirrhotic patients
related to abnormalities offluid tolerance, induce ●Gynecomastia, impotence,
and electrolyte balance. photosensitization, interstitial decreased libido, hirsutism,
○ extracellular volume depletion nephritis, renal stone. deepening of the voice, and
○ Hypotension ○most common are nausea, menstrual irregularities— due to
○ Hypokalemia, hyponatremia, vomiting, leg cramps, dizziness its steroid structure
hypochloremia, ●Amiloride- most common ●Diarrhea, gastritis, gastric
hypomagnesemia are nausea, vomiting, bleeding, andpeptic ulcer
○ metabolic alkalosis diarrhea, and head-ache. ●CNS adverse effects—
○ hypercalcemia, hyperuricemia drowsiness, lethargy, ataxia,
● Decrease glucose tolerance Contraindications : confusion, and headache
●Increase plasma levels of LDL 1.Patients with hyperkalemia ●Skin rashes
cholesterol,total cholesterol, and 2.Patients at risk of developing
total triglycerides. hyperkalemia(patients with renal Contraindications :
failure, receiving other K+ - sparing 1.Patients with hyperkalemiaand
ontraindication
C diuretics, taking ACE inhibitors, or patients atincreased risk of
1.Hypersensitivity to sulfonamide K+ supplements) developing hyperkalemia
2.Patients with peptic ulcers
Therapeutic Uses Therapeutic Uses Therapeutic Uses
1. Congestive heart failure 1. Treatment of edema and 1. Coadministered with thiazide or
2. Treatment of edema associated hypertension loop diuretics in the treatment of
with hepatic cirrhosis, nephritic ● Seldom used as sole agents edema and Hypertension
syndrome, chronic renal failure, in these conditions but in 2. Primary hyperaldosteronism —
acute glomerulonephritis combination with other SPIRONOLACTONE.
● Most thiazide diuretics are diuretics. 3. Refractory edema associated with
ineffectivewhen theglomerular ● Coadministration of a 2° aldosteronism
filtration rate (GFR) is <30 —40 Na+- channel inhibitor 4. Hepatic cirrhosis —
ml/min.— exceptions are augments the diuretic and SPIRONOLACTONEis the diuretic
METOLAZONEandINDAPAMIDE antihypertensive response of choice
3.Calcium nephrolithiasis to thiazide or loop diuretics
andosteoporosis- these and tends to result in
B4M1 Case 1 17of 25
gents reduce urinary
a normal values of plasma K+
excretion of Ca2+ . Liddle syndrome
2
4. Nephrogenic diabetes insipidus 3. Cystic fibrosis- aerosolized
5. Management ofBr- intoxication AMILORIDEimproves mucociliary
clearance and augments hydration
of respiratory secretions.
4. Lithium-induced nephrogenic
diabetes insipidus -AMILORIDE
Angiotensin II - Receptor Antagonists or
Angiotensin-Converting Enzyme (ACE) Inhibitors
Blockers (ARB)
●ACE and kininase Ilare the same enzymes, which
catalyzes both the synthesis ofangiotensin II, apotent
pressure substance, and the destruction ofbradykinin,a
potent vasodilator.
echanism of Action
M echanism of Action
M
●ACE inhibitorsare specific competitive inhibitorsof Competitively inhibits angiotensin Il at its AT1
●
peptidyldipeptidase,the enzyme that converts angiotensinI receptor site
to angiotensin II.
○ Angiotensin Ilis apotent directvasoconstrictor—
these drugs inhibit vasoconstriction.
○ Angiotensin Ilstimulates the secretion of aldosterone,
whichpromotes salt and water retention —these drugs
inhibit salt and water retention and slightly increase
serum K+ levels.
● Because peptidyl dipeptidase is necessary to catalyze
the degradation of bradykinin, theACE inhibitorsmay
increase the concentration of bradykinin,which isa
potent vasodilator.
B4M1 Case 1 18of 25
harmacologic Effects
P harmacologic Effects
P
●Attenuate or abolishresponses to angiotensin Ibut ●ARBs potently and selectively inhibit,bothin vitro
not to angiotensin Il and in vivo, most of the biological effects of
●Increasebradykinin levels angiotensin I, including angiotensin induced:
●Increase by fivefoldthe circulating levels of ○ Contraction of vascular smooth muscle
the natural stem-cell ○ Rapid pressor responses
N-acetyl-seryl-aspartyl-lysyl-proline ○ Slow pressor responses
●Interfere with bothshort- and long-loop negative ○ Thirst
feedbacks on renin release— increase renin release ○ Vasopressin release
and the rate of formation of angiotensin I. ○ Aldosterone secretion
○ Release of adrenal catecholamines
emodynamics effect
H ○ Enhancement of noradrenergic
● Reduce afterload and systolic wall stress →↑ cardiac neurotransmission
output and cardiac index ○ Increases in sympathetic tone
● Decrease heart rate ○ Changes in renal function
● Decrease systemic blood pressure ○ Cellular hypertrophy and hyperplasia
● Decrease renovascular resistance —increase renal
blood flow ● ARBs differ from ACE inhibitors in several
● Reduced stimulus to secretion of aldosterone by aspects:
angiotensin I —natriuresis 1. ARBs reduce activation of AT receptors more
● Reduction of pulmonary arterial pressure, pulmonary effectively than do ACE inhibitors.
capillary wedge pressure, and left atrial and left 2. In contrast to ACE inhibitors, ARBs
ventricular filling volumes and pressures —diminish indirectly activate AT, receptors by
preload and diastolic wall stress. increasing angiotensin Il levels
3. ACE inhibitors may increase angiotensin (1-7)
levels more than do ARBs
4. ACE inhibitors increase the levels of a
number of ACE substrates, including
bradykinin, and Ac-SDKP
harmacokinetics
P
●Oral bioavailability is generally low (<50%);
exceptforIrbesartan (70%)
●Protein binding is high (>90%)
APTOPRIL
C ANDESARTAN CILEXETIL
C
○ A potent ACE inhibitorwith a Ki of 1.7 nM ○ An inactive ester prodrug that is completely
○ Rapidly absorbed when given orallyand has a hydrolyzed to the active form, candesartan,
bioavailabilityof about75% during absorption from the GIT.
○ Half-life of approximately2 hours. ○ Plasma half-life is about9 hours.
○ Eliminated in urine, 40-50% as captopril, and the rest ○ Renal elimination (33%) and biliary excretion (67%)
as captopril disulfide dimers and captopril-cysteine ○ Oral dosage—4-32 mg daily- OD or BID
disulfide.
○ Oral dosage PROSARTAN
E
■ 6.25-50 mg2-3x daily ○ Plasma half-life ranges from11-15 hours.
■ 25 mgBID — for initiation of therapy for heartfailure ○ Cleared by renal elimination and biliary excretion
and hypertension ○ Plasma clearance isaffectedby both renal
○ Food reduces the oral bioavailability of this drug by insufficiency and hepatic insufficiency
25-30%, this drug should be given one hour before meals ○ Oral dosage—400-800 mg/day- OD or BID
NALAPRIL
E I RBESARTAN
○ Aprodrugthat is not highly active andmust be ○ Plasma half-life ranges from11-15 hours
B4M1 Case 1 19of 25
ydrolyzed byesterasesinthe liver to produce the active
h ○ Cleared by renal elimination (20%) and biliary
parent dicarboxylic acid,ENALAPRILAT excretion (80%).
○Rapidly absorbed when given orallyand has anoral ○ Plasma clearance isunaffectedby either renal
bioavailabilityof about60%(not reduced by food). or mild-to-moderate hepatic insufficiency
○ Half-life of only1.3 hours. ○ Oral dosage— 150-300 mg daily- OD
○ Nearly all of the drug is eliminated by the kidneys either
as intact enalapril or enalaprilat
OSARTAN
L
○ Oral dosage ○ Approximately14%of an oral dose is converted
■ 2.5-40 mg daily(single or divided dosage) to the5- carboxylic acidmetabolite, designated
■ 2.5 mg and 5 mg daily— for initiation of therapyfor EXP3174, which is more potent than losartan
heart failure and hypertension
as an AT1 receptor antagonist.
■ 2.5 mg daily— initial dose for hypertensive patients ○ Themetabolism of losartanto EXP3174 and
who are taking diuretics, are water— or Na+ -
to inactive metabolites is mediated by
depleted, or have heart failure
CYP2C9 and 3A4.
ISINOPRIL
L
○ Plasma half-lives are2.5 and 6-9 hours,
respectively.
○ A lysine analog of Enalaprilat. ○ Plasma clearance isaffectedby hepatic but
○ Slowly, variably, and incompletely (about 30%) absorbed notrenal insufficiency
after oral administration (not reduced by food).
○ Plasma half-life is about12 hours. ○ Oral dosage — 25-100 mg/day- OD or BID
○ Does not accumulate in tissues.
○ Oral dosage ELMISARTAN
T
■ 5-40 mg daily(single or divided dosage) ○ Plasma half-life is about24 hours
■ 5 mg and 10 mg daily— initiation therapy for heart ○ Cleared mainly by ciliary secretion of intact drug
failure and hypertension ○ Plasma clearance isaffectedby hepatic, but
■ 2.5 mg— recommended for patients with heart failure notrenal insufficiency
who are hyponatremic or have renal impairment. ○ Oral dosage— 40-80 mgonce daily
ENAZEPRIL
B ALSARTAN
V
○ Cleavage of the ester moiety by hepatic esterases ○ Plasma half-life is about9 hours.
transformsbenazepril hydrochloride, a prodrug, into ○ Food markedly decreases absorption.
Benazeprilat ○ Cleared from the circulation by the liver
○ Rapidly, yet incompletely (37%), absorbedafteroral (about70%of total clearance)
administration (only slightly reduced by food). ○ Plasma clearance isaffectedby hepatitis but
○ Nearly completely metabolized to Benazeprilat and to not renal insufficiency.
the glucuronide conjugates of benazepril and ○ Oral dosage— 80-320 mgonce daily
benazeprilat, which are excreted into both the urine and
bile.
○ Effectivehalf-life in plasma is about10-11 hours
○ With the exception of the lungs, it does not accumulate
in tissues.
○ Oral dosage — 5-80 mg daily(single or divided dosage)
OSINOPRIL
F
○ Cleavage of the ester moiety by hepatic esterases
transformsfosinopril, aprodrug, intoFOSINOPRILAT.
○ Slowly and incompletely (36%) absorbedafter oral
administration (rate but not extent reduced by food)
early completely metabolized to fosinopril (75%)
and to the glucuronide conjugate of fosinoprilat.
○ These are excreted in both the urine and bile.
○ Effective half-life in plasma is about11.5 hours,and its
clearance is not significantly altered by renal
impairment.
○ Oral dosage
■ 10-80 mg daily(single or divided dosage)
■ 5 mg daily— in patients with Na+ or water depletion
or renal failure.
B4M1 Case 1 20of 25
RANDOLAPRIL
T
○ Approximately10 % and 70%of an oral dose is
bioavailable (absorption rate but not extent is reduced
by food as trandolapril and trandolaprilat)
○ Trandolaprilatis about 8x more potent thantrandolapril
as an ACE inhibitor.
○ Metabolized to trandolapril and to inactive metabolites
and these are recovered in theurine(3 3%, mostly
trandolapril) andfeces(6 6%)
○ Trandolaprilat displays biphasic elimination kinetics with
an initial half-life of about10 hours(the major
component of elimination), followed by a more
prolonged half-life due to slow dissociation of
trandolapril from tissue ACE.
○ Oral dosage
■ 1-8 mg daily(single or divided dosage)
■ 0.5 mg— initial dose in patients who are taking
diuretics or who have renal impairment.
UINAPRIL
Q
○ Cleavage of the ester moiety by hepatic esterases
transformsquinapril hydrochloride, a prodrug, into
QUINAPRILAT
○ Rapidly absorbed(peak concentrations are achievedin 1
hour, but the peak may be delayed after food), and its
rate but not extent of oral absorption (60%) may be
reduced by food.
○ Metabolized to quinaprilat and to other minor
metabolites and quinaprilat is excreted in theurine
(61%)andfeces (37%)
○ Initial half-life of quinaprilatis about2 hours;a
prolonged terminal half-lifeof about25 hoursmaybe
due to high - affinity binding of the drug to tissue ACE.
○ Oral dosage — 5-80 mg daily(single or divided dosage)
AMIPRIL
R
○ Cleavage of the ester moiety by hepatic esterases
transformsramiprilintoRAMIPRILAT
○ Rapidly absorbedand the rate but not the extentof its
oral absorption (50-80%) is reduced by food.
○ Metabolized to ramiprilat and to inactive metabolites
and these are excreted predominantly by the kidneys.
○ Ramiprilat displaystriphasic elimination kineticswith
half-livesof2-4 hours, 9-18 hours, and greater than50
hours.
○ This triphasic elimination isdue to extensive distribution
to all tissues(initial half-life), clearance of freeramiprilat
from plasma (intermediate half-life), and dissociation
from tissue ACE (terminal half-life)
○ Oral dosage — 1.25-20 mg daily(single or divided
dosage)
OEXIPRIL
M
○ A prodrug whoseantihypertensive activityis almost
entirely due to its deesterified metabolite,MOEXIPRIL.
○ Incompletely absorbed, with bioavailability as moexipril
of about13%.
B4M1 Case 1 21of 25
○ Bioavailability is markedly decreased by food, so it
should be taken one hour before meals.
○ Eliminationhalf-lifevaries between2-12 hours.
○ Oral dosage — 7.5-30 mg dailyin one or two divided
doses.
○ Dosage range ishalvedin patients who are taking
diuretics or who have renal impairment.
ERINDOPRIL
P
○ A prodrug and 30-50% of systemically available
perindoprilis transformed toPERINDOPRILATby
hepatic esterases.
○ Oral bioavailability ofperindopril (75%)is notaffected
by food butperindoprilat'sbioavailability is reducedby
approximately35%
○ Metabolized to perindoprilat and to inactive metabolites
and these are excreted predominantly by the kidneys.
○ Perindoprilatdisplaysbiphasic elimination kineticswith
half-livesof3-10 hours( the major component of
elimination) and30-120 hours(due to slow dissociation
of perindoprilat from tissue ACE)
○ Oral dosage — 2-16 mg daily(single or divided dosage)
Therapeutic Uses herapeutic Uses
T
1. Hypertension 1.Treatment of hypertension— the
● Lower blood pressure except when high blood only approved therapeutic
pressure is due indication
toprimary aldosteronism. 2.Reserve for treatment of heart
● Inhibition of ACE lowers systemic vascular failurein patients who cannot
resistance and tolerate or have an unsatisfactory
mean, diastolic, and systolic blood pressures in response to ACE inhibitors.
various 3.Treatment of partial hypertensionin patients with
dysfunction. cirrhosis and portal hypertension without
2. Left ventricular systolic dysfunction compromising renal function — Losartan
● These drugs should be given to all patients
with impaired left
ventricular systolic function whether or not
they are
experiencing symptoms of overt heart failure.
3. Acute myocardial infarction
● These agents reduce overall mortality when
treatment is
begun during theperiinfarction period.
● Unless contraindicated (eg. cardiogenic shock
or severe
hypotension), these agents should be started
immediately
during the acute phase of MI and can be
administered along
with thrombolytics, aspirin, and B-adrenergic
receptor
antagonists.
4. Patients who are at high risk of cardiovascular
events
● These agents tilt the fibrinolytic balance toward
a profibrinolytic
state by reducing plasma levels of
plasminogen activator
inhibitor - 1 and improve the endothelial
B4M1 Case 1 22of 25
vasomotor dysfunction
in patients with coronary artery disease.
5. Chronic renal failure
● These agentsprevents or delay the
progression of renal diseasein patients with
type I diabetes mellitusanddiabetic
nephropathy● Maydecrease retinopathy
progressionintype I diabetics
6. Scleroderma renal crisis
Adverse Effects dverse Effects
A
1. Hypotension 1.Angioneurotic edema—incidence islesser
○ A steep fall in blood pressure may occur compared to ACE inhibitors
following thefirst doseof an ACE inhibitor in 2. Fetopathic potential
patients with elevated PRA (plasma renin activity) ○ Should bediscontinued before the 2nd
○ Treatment should be initiated withvery small trimester of pregnancy.
dosesof these agents, orsalt intake should be 3.Hyperkalemiain patients with renal disease or
increasedanddiuretics withdrawnbefore in patients taking K+ supplement or K - sparing
beginning therapy. drugs.
2. Cough
○ Induce a bothersome,dry coughin 5-20% of
patients.
○ Usually not dose-related, occurs more frequently
inwomenthan in men.
○ Usually develops between1 week and 6 months
afterinitiation of therapy, and sometimes require
cessation of therapy.
○ May be mediated by the accumulation in
the lungs of bradykinin, substance P,
and/or prostaglandins
3. Hyperkalemia
○ Seen in patients withrenal insufficiencyor in
patients taking K+, sparingdiuretics, K supplement,
B - adrenergic receptor blockers, or NSAIDs.
4. Acute renal failure
○ Can induce acute renal insufficiencyin patients
with bilateral renal artery stenosis, stenosis of
the artery to a single remaining kidney, heart
failure, or dehydration due to diarrhea or
diuretics.
○ Older patients with congestive heart failureare
particularlysusceptible to ACE
inhibitor-induced acute renal failure.
5. Fetopathic Potential
○ Continued administration of these agents
during the 2nd and 3rd trimesterscan cause
oligohydramnios fetal calvarial hypoplasia,
fetal pulmonary hypoplasia, fetal growth
retardation, fetal death, neonatal anuria, and
neonatal death.
○ ACE inhibitorsare not contraindicated in
women of reproductive age, once pregnancy
is diagnosed, it is imperative that ACE
inhibitors be discontinued as soon as
possible.
○ Thefetusisnot at risk of ACE
inhibitor-induced pathology if ACE
inhibitors are discontinuedduring the 1%
B4M1 Case 1 23of 25
trimester of pregnancy.
6. Proteinuria
○ Proteinuria ofmore than 1 gm/day
○ In general, proteinuria is not a contraindication for
ACE inhibitors.
7. Angioneurotic edema
○ Induce a rapid swelling of the nose, throat,
mouth, glottis, larynx, lips, and/or tongue.
○ Not dose-related and nearly always develops
within thefirst week of therapy, usually
within thefirst few hoursafter the initial
dose.
○ Mechanism is unknown, it may involve the
accumulation of bradykinin, induction of
tissue-specific autoantibodies,orinhibitionof
complement 1- esterase inactivator.
○ Disappears within hours once these agents are
stopped.
○ If necessary, administerEpinephrine, an
antihistamine, and/or acorticosteroid.
8. Dysgeusia
○ Alteration in or loss of tastemay occur more
frequently with captopril. ○ Is reversible.
9. Neutropenia
○ Rare but serious side effects.
○ Occurs predominantly in hypertensive patients
with collagen-vascular orrenal parenchymal
disease
10. Glycosuria
○ Exceedingly rare and reversible
11. Hepatotoxicity
○ Exceedingly rare and reversible
○ Usually of the cholestatic variety.
B4M1 Case 1 24of 25
CAUSES OF RESISTANT HYPERTENSION ● Weight
● reasons for poor therapeutic response in - A gain in weight is associated with an
patients with hypertension increased frequency of hypertension in persons
1. Improper BP measurement with normal blood pressure and weight loss in
obese persons with hypertension lowers their
2. Volume overload and pseudotolerance arterial pressure
a. Excess sodium intake
b. Volume retention from kidney disease RISK FACTORS FOR AN ADVERSE
c. Inadequate diuretic therapy
PROGNOSIS IN HYPERTENSION
3. Drug-induced or other causes .
1 Black Race
a. Nonadherence 2. Youth
b. Inadequate doses 3. Male sex
c. Inappropriate combinations 4. Persistent diastolic pressure >115 mmHg
d. Nonsteroidal anti-inflammatory drugs; 5. Smoking
cyclooxygenase 2 inhibitors 6. Diabetes mellitus
e. Cocaine, amphetamines, other illicit drugs
7. Hypercholesterolemia
f. Sympathomimetics (decongestants,
anorectics) g. Oral contraceptives 8. Obesity
h. Adrenal steroids 9. Excess alcohol intake
i. Cyclosporine and tacrolimus 10. Evidence of end organ damage
j. Erythropoietin a. Cardiac
k. Licorice (including some chewing tobacco) I. Cardiac enlargement
l. Selected over the counter dietary ii. Electrocardiographic signs of
supplements and medicine (e.g. ephedra, ma
ischemia or left ventricular strain
huang, bitter orange)
iii. Myocardial infarction
4. Associated conditions iv. Congestive heart failure
a. Obesity b. Eyes
b. Excess alcohol intake i. Retinal exudates and hemorrhages
ii. Papilledema
c. Renal: Impaired Renal Function
FACTORS THAT AFFECT THE d. Nervous system: Cerebrovascular
PROGNOSIS OF HYPERTENSION accident.
● Age
- The younger the patient is first noted, the
greater is the reduction in life expectancy if the
hypertension is left untreated
● Race
- Urban blacks have about twice the prevalence
of hypertension as whites and more than four
times the h ion-i morbidity rate.
● Sex
- At all ages, 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
● Smoking
● Alcohol intake
● Elevated serum cholesterol
● Glucose intolerance
- Elevated serum cholesterol, glucose
intolerance, and / or cigarette smoking
significantly enhance the effect of
hypertension on mortality rate regardless of
age, sex, or race
B4M1 Case 1 25of 25
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