1. Describe the renin-angiotensin-aldosterone system (RAAS).

regulating blood volume and systemic vascular resistance, which together influence CO
and arterial pressure.
Renin, which is primarily released by the kidneys, stimulates the formation of
angiotensin in blood and tissues, which in turn stimulates the release of aldosterone
from the adrenal cortex.
Renin is a proteolytic enzyme that is released into the circulation primarily by the
kidneys. Its release is stimulated by: SANS activation (acting via 1-adrenoceptors),
renal artery hypotension (caused by systemic hypotension or renal artery stenosis),
decreased Na delivery to the distal tubules of the kidney.
JG cells associated with the afferent arteriole entering the renal glomerulus are the
primary site of renin storage and release in the body. A reduction in afferent
arteriole pressure causes the release of renin from the JG cells, whereas
increased pressure inhibits renin release.
Constricts resistance vessels (via AII [AT1] receptors) thereby ^systemic vascular
resistance and arterial pressure
Acts on the adrenal cortex to release aldosterone, which in turn acts on the kidneys to
increase sodium and fluid retention
Stimulates the release of vasopressin (antidiuretic hormone, ADH) from the posterior
pituitary, which increases fluid retention by the kidneys
Stimulates thirst centers within the brain
Facilitates NE release from SANS nerve endings and inhibits norepinephrine re-uptake by
nerve endings, thereby enhancing sympathetic adrenergic function
Stimulates cardiac hypertrophy and vascular hypertrophy
ACE inhibitors, AII receptor blockers and aldosterone receptor blockers, for example,
are used to decrease arterial pressure, ventricular afterload, blood volume and hence
ventricular preload, as well as inhibit and reverse cardiac and vascular hypertrophy.
2. Explain the pathophysiology of essential hypertension.
Primary (Essential) Hypertension
~90-95% of patients diagnosed with hypertension have primary hypertension.
No known cause = diagnosis made after excluding known causes that comprise
secondary HTN.
natural progression of this disease that suggests early elevations in blood volume and
CO might initiate subsequent changes in the systemic vasculature (increased
resistance) Inability of the kidneys to adequately handle sodium. Increased
sodium retention = increase in blood volume
chronic: blood volume and CO are often normal = HTN sustained by an elevation
in systemic vascular resistance rather than by an increase in CO
o increased resistance is caused by a thickening of the walls of resistance
vessels and by a reduction in lumen diameters.
o evidence for increased vascular tone mediated by enhanced SANS or by
increased circulating levels of ATII.
o evidence has suggested that changes in vascular endothelial function may
cause the increase in vascular tone. HTN: vascular endothelium produces less
nitric oxide and the vascular smooth muscle is less sensitive to the actions
of NO. There is also an increase in endothelin production, which can enhance
vasoconstrictor tone.
o evidence that hyperinsulinemia and hyperglycemia in type 2 diabetes (noninsulin dependent diabetes) causes endothelial dysfunction by enhanced
oxygen free radical mediated damage and decreased NO bioavailability.

3. Recognize risk factors for hypertension: race (blacks), heredity, Na intake, EtOH,
obesity, dyslipidemia, personality traits (hostile)
4. Discuss target organ damage in untreated hypertension including myocardial
hypertrophy and retinopathy.

Cardiovasc LVH: MC overall complication

ular
Acute MI: MC COD
Atherosclerosis
CNS

Intracerebral hematoma: due to rupture of Charcot-Bouchard aneurysms

Berry aneurysm: rupture produces a subarachnoid hemorrhage
Lacunar infarcts: small infarcts due to hyaline arteriolosclerosis

Renal

Benign nephrosclerosis: kidney disease of hypertension; due to hyaline

arteriolosclerosis; atrophy of tubules and sclerosis of glomeruli; progresses to
renal failure
Malignant hypertension: rapid increase in blood pressure accompanied by renal
failure and cerebral edema

Eyes

Hypertensive retinopathy: arteriovenous nicking, hemorrhage of retinal vessels,

exudates (increased vessel permeability, retinal infarction), papilledema

5. Discuss the evaluation of essential hypertension:

based on BP measurements taken in a standardized fashion: seated, feet on floor,
arm supported, after 5min rest, cuff bladder encircle 80% of the upper arm.
The average of the two is used for clinical decision-making, it is a good idea to
evaluate the BP in both arms to detect any difference from one limb to the
other. If there is a discrepancy, use the limb with the higher reading for diagnosis
and for subsequent readings.
HPI and PE must determine the risk for, and presence of, target organ damage.
o Does the PMI include heart disease, stroke or TIA, renal disease, DM, or PAD?
o In all patients with HTN, the retina should be examined for papilledema,
hemorrhages, and exudates. Hemorrhages can be shaped like blots, flames, or
lines (splinters). Exudates can be soft (also called cotton wool spots) or hard,
based on their edges. All of these findings suggest more severe HTN and in
themselves demand immediate attention, although a number of other conditions can
cause them. The retinal vessels should be examined for focal spasm,
arteriole-to-venule (AV) ratio, AV nicking, and abnormal arteriolar light
reflex. The normal AV ratio (ratio of widths of retinal arterioles and veins) is
somewhere between 2:3 and 4:5; but with HTN the ratio progressively
decreases. Ordinarily, veins appear to gradually taper throughout their course,
even where they cross the path of arteries, but with chronic HTN the vein becomes
depressed on either side of the artery (AV nicking). With advanced hypertensive
retinopathy, there can be dilation of the vein distal to the crossing point. The normal
artery is a thick red line with a fine yellow line centrally (the light reflex). With
arteriosclerosis, this light reflex gets progressively wider, eventually
merging with the red column to be an entirely orange (or copper)
structure, hence, this finding is called copper wiring. As the vessel wall gets

thicker, the red blood makes a smaller contribution and the artery is nearly
white, a finding that is called silver wiring.
o Does the medication list include drugs that may increase BP or suggest the
presence of another risk factor? Besides the standard Framingham
cardiovascular risk factors, obesity (BMI >30 kg/m2), physical inactivity,
and renal disease (microalbuminuria or glomerular filtration rate <60
mL/min) are associated with increased risks of HTN complications.
o social history must identify the presence of smoking (^risk of complications)
and alcohol (may cause HTN) use
o family history may give clues to secondary causes of HTN (i.e. polycystic
kidney disease, multiple endocrine neoplasia, or congenital heart disease)
or suggest that a patient is at increased risk for HTN complications, such as a
family history of stroke or heart disease. A family history of diabetes or
hyperlipidemia makes these comorbidities more likely but appropriate
laboratory tests must be obtained regardless of the family history.
ROS: manifestations of cardiovascular disease: dyspnea on exertion, orthopnea,
angina, or palpitations. Also important are signs of renal disease: nocturia, change
in urine color or quality, or signs of prostatism.
In patients with markedly elevated BP, the clinician should also search for clues of
HTN emergency including blurred vision, altered level of consciousness,
headache, nausea, vomiting, seizures, or focal neurologic signs. important to
know of baseline problems that might be exacerbated by side effects of a
specific drug.

1)
Hematocri
t

Anemia can increase cardiac work and blood pressure. Polycythemia can
suggest secondary causes of hypertension including renal artery
stenosis or pheochromocytoma.

2)
Creatinine
and/or
blood
urea
nitrogen

Both are signs of parenchymal renal disease, both a cause and

consequence of hypertension. An elevated creatinine is associated with
increased cardiac risk.

3)
Urinalysis

Active sediment or significant proteinuria suggest renal parenchymal

causes of hypertension. Proteinuria is also a marker for increased
cardiac risk.

4) Fasting
lipid
profile

Dyslipidemia increases the risk of renal and cardiac complications of

hypertension.

5) Fasting
blood

Diabetes mellitus increases the risk of complications of hypertension.

glucose

6) Thyroid
stimulatin
g
hormone

Screen for hyper- or hypothyroidism, both of which can contribute to

hypertension.

7)
Calcium

Screen for hyperparathyroidism, which is associated with hypertension.

Calcium levels may rise with thiazide diuretics.

8)
Potassium

Screen for mineralocorticoid excess, a cause of hypertension.

9)
Electrocar
diogram

Screen for left ventricular hypertrophy, an early sign of target organ

damage.

The initial diagnosis of HTN requires that elevated BP be documented on two

separate visits. However, because of the potential for damage with extreme elevations of
BP, one would likely consider treatment based on measures taken at a single visit if there
was evidence of ongoing target organ damage or if the BP was very high (greater than
180/110 mm Hg).
6. Recognize clinical features that suggest secondary hypertension: Most persons
do not require extensive testing for secondary causes of HTN. However, patient
characteristics that suggest secondary HTN (and therefore warrant a battery of screening
tests for secondary causes) include 1) pre-pubertal onset, 2) onset before the age of 30
years in a non-obese person without a family history of HTN, 3) evidence of severe
HTN (based on BP >180/110 mm Hg or fundoscopic abnormalities), or 4) new onset after
age 50 years in someone whose BP had been regularly measured and known to be
in the normal range.
Renovascular disease can be suggested by new-onset HTN in a young woman
(suggesting fibromuscular dysplasia) or by the new appearance or sudden
worsening of HTN in a person with evident atherosclerosis (suggesting
atherosclerotic renovascular stenosis). These individuals are prone to sudden
exacerbations of BP, which may precipitate flash pulmonary edema, and may develop
hypotension in response to initial treatment with angiotensin converting enzyme
(ACE) inhibitors. Physical examination may reveal renal bruits.
Coarctation of the aorta is typically asymptomatic except for the HTN, but can be
suspected with onset of HTN in childhood or young adulthood. Physical examination findings
can include delayed or reduced femoral pulses compared to brachial pulses, and an audible
(primarily) systolic murmur best heard in the posterior chest. A detailed examination will
detect a discrepancy in BP between arms and legs. There may be classic finding on chest
x-ray (rib notching from increased flow in the intercostal arteries, or a 3 sign in the

silhouette of the aorta). Most aortic coarctations are distal to the take off of the left
subclavian artery, so that BP is similar in the right and left arm, but as many as a third of
patients have coarctation that affects flow to the left subclavian artery, resulting in a lower BP
when measured using the left arm. radial femoral delay?
Pheochromocytoma is suggested by episodic rises and falls of BP. Other manifestations
include signs of adrenergic excess (e.g., arrhythmias) and episodic crises with
flushing, headache, sweating, palpitations, and/or a sense of apprehension.
Because of a chronically vasoconstricted state, these patients are more likely to have
significant orthostatic BP drops. Neurofibromatosis and cafe-au-lait spots may be
seen in patients with pheochromocytoma, particularly in the context of one of the
multiple endocrine neoplasia syndromes. Measuring metanephrine in a 24-hour
urine collection is one highly sensitive yet parsimonious approach.
Sleep apnea is sometimes not considered in the list of secondary causes of HTN because it
is associated so closely with obesity, another known contributor to HTN. However, HTN
can be seen even in non-obese persons with sleep apnea, so a careful sleep history should be
obtained in all hypertensive persons. If the history is suggestive, a sleep study serves as
both the screening and definitive diagnostic test.
Exogenous substances are among the most common secondary causes of HTN.
Adrenergic agents including appetite suppressants (dextroamphetamine, sibutramine) and
decongestants (pseudoephedrine, phenylephrine) can be associated with HTN. Although
effect on BP of these drugs is undetectable for most patients, they can raise BP substantially
in individual patients. Some herbal supplements also have adrenergic properties, including
ma huang and ephedra. Drugs of abuse including cocaine and amphetamines are potent
vasoconstrictors that can raise BP. Exogenous estrogens in the form of OCP or
postmenopausal HRT can also raise BP through fluid retention.
Mineralocorticoid excess is suggested by hypokalemia - neither sensitive nor
specific, one should have a low threshold to perform biochemical screening if BP is difficult to
control, or if there is a marked fall in potassium with use of thiazide diuretics. The ratio of
plasma aldosterone concentration to plasma renin activity is an appropriate
screening test that can effectively rule out the diagnosis, unless the pretest
probability is unusually high. It is best performed in the morning in an ambulatory
patient who has not received an aldosterone receptor antagonist during the last 6 weeks.
The MCC of mineralocorticoid excess are primary aldosteronism due to either adrenal
hyperplasia or an adrenocortical adenoma. Defects in synthetic enzymes are rare and
may be suspected by suppression of both renin and aldosterone. Primarily because it is a
question that commonly arises during attending rounds, it is important to know that
glycyrrhizinic acid, a natural licorice flavoring that has been used in both chewing
tobacco and candies, affects cortisol metabolism in a way that increases
mineralocorticoid activity.
Hypercalcemia (most often due to hyperparathyroidism) can be associated with HTN
prior to any clinical manifestations of the hypercalcemia. serum calcium level is typically
obtained during the initial evaluation of a person with HTN. If elevated, testing directed at
determining the etiology of the hypercalcemia should be performed.
7. List the causes of secondary hypertension
Secondary cause of hypertension
Renal parenchymal disease
Renovascular disease

Frequency among patients with

hypertension in a primary care practice
2% - 3%

Atherosclerotic renal artery stenosis

Fibromuscular dysplasia
Endocrine causes
Pheochromocytoma
Cushing's syndrome (excess production or
consumption of glucocorticoids)
Mineralocorticoid excess
Primary hyperaldosteronism
17-alpha hydroxylase defects
11-beta hydroxylase defects
Excess consumption of licorice
Acromegaly (excessive growth hormone)
Hypothyroidism
Hyperthyroidism
Hypercalcemia (hyperparathyroidism)
Miscellaneous
Coarctation of the aorta
Exogenous vasoconstrictor drugs
Chronic alcohol use in high doses
Sleep apnea syndrome
Exogenous estrogens

1% - 2%
0.1%
<0.1%
<0.1%
0.3%
Most common cause of this syndrome
Rare
Rare
Rare
<0.1%
10% - 12% (most not related to the
hypertension)
1% - 2% (most not related to the
hypertension)
1% (most not related to the hypertension)
<0.1%
<0.1%
3% - 5%
10% (treatment usually does not resolve
hypertension)
0.5% - 1%

11) Major groups of antihypertensives and side effects

Class of
drug
Diuretics

Commonly
Contraindicati
used agents
ons
Thiazide-type
Gout
diuretics
Hydrochlorothiazi
de
Chlorthalidone
Indapamide
Potassiumsparing diuretics
Triamterene
Amiloride
Spironolactone

Selected side effects and comments

Thiazide and thiazide-like diuretics: More
likely to cause impotence at starting doses
Hypokalemia, except indapamide
Potassium-sparing Agents: Hyperkalemia
Triamterene raises creatinine without
decreasing glomerular filtration rate
Spironolactone can cause gynecomastia
Furosemide: Less effective than thiazides, but
it is effective even in presence of markedly
reduced creatinine clearance

Loop diuretics
Furosemide
BetaAtenolol
blockers
Metoprolol
Propranolol
Bisoprolol
Combined alphaand betablockers
Labetolol
Carvedilol
Calcium
Verapamil
antagonists Diltiazem
Dihydropyridinetype
Nifedipine
Amlodipine
Felodipine
Angiotensin- Captopril
converting Enalapril
enzyme
Lisinopril
(ACE)
Ramipril
inhibitors
Fosinopril
Angiotensin- Valsartan
receptor
Losartan
blockers
Telmisartan
Irbesartan
AlphaDoxazosin
blockers
Terazosin

Direct
Hydralazine
vasodilators Minoxidil
Centrally
acting
sympathetic
inhibitors

Clonidine
Alpha-methyldopa
Reserpine

Reactive
Bronchospasm, Impotence
airways(Asthma) Bradycardia, Depression
Heart block
May be more likely to cause fatigue than
Peripheral
alternatives
vascular disease Withdrawal hypertension if at high doses
Athletes and
Combined alpha- and beta-blockers may be
physically active more likely to cause postural hypotension,
patients
less likely to cause fatigue
Heart block,
Nondihydropyridines: Conduction defects
congestive heart Constipation
failure
Dihydropyridines: Ankle edema
(nondihydropyri Headache
dine)
Avoid short-acting formulations
Pregnancy
Hyperkalemia
Bilateral renal
artery stenosis
Pregnancy
Bilateral renal
artery stenosis
Hyperkalemia
Pregnancy
Orthostatic
hypotension

Significant cough in up to 10%

Angioedema
Hyperkalemia
fetal loss if given in second or third
trimester
Similar to ACE inhibitors but do not cause
cough and rarely cause angioedema
Orthostatic hypotension common with first
dose
Effective therapy for benign prostatic
hypertrophy
Inferior to diuretics as first-line therapy to
prevent cardiovascular events
Common: headaches, fluid retention,
tachycardia, hypertrichosis (with minoxidil)
Rare: lupus-like syndrome with hydralazine
Sedation
Dry mouth
Withdrawal hypertension, primarily seen at
high doses