Learning Objectives

2. Define high blood pressure

2. Calssify blood pressure into 4 categories and
list the systolic and diastolic pressures in each
3. Describe the ways to control and prevent
hypertension
4. Identify various groups of antihypertensive drugs
5. Describe the algorithm for treatment of hypertension
 Category Systolic (mmHg) Diastolic (mmHg)

Normal <120 <80

Pre-hypertension 120 – 139 80 – 89

Stage 1 hypertension 140 – 159 90 - 99

Stage 2 hypertension >160 >100

What is hypertension?

Abnormally chronic high blood pressure

(>140/90)
 LIFESTYLE MODIFICATIONS

)Not at Goal Blood Pressure )<140/90 mmHg

)mmHg for patients with diabetes or chronic kidney disease 130/80<(

INITIAL DRUG CHOICES

Without Compelling With Compelling

Indications Indications

Stage 1 Stage 2
Hypertension Drug)s( for the
Hypertension compelling indications
SBP 140-159 or DBP( )SBP >160 or DBP
)mmHg 100> )See table 8(
)mmHg 90-99
Two-drug combination for Other antihypertensive
Thiazide-type diuretics ,drugs )diuretics, ACEI
for most. May consider most )usually thiazide-type
diuretic and ACEI, or ARB, BB, CCB( as
,ACEI, ARB, BB, CCB .needed
.or combination .)ARB, or BB, or CCB

NOT AT GOAL BLOOD PRESSURE

Optimize dosages or add additional drugs until goal blood pressure is

.achieved. Consider consultation with hypertension specialists
Why should we treat hypertension?

Hypertension is called the

“SILENT KILLER”
General Treatment Goals

1. To reduce cardiovascular morbidity and

mortality
2. To prolong useful life
Treatment Goals
1. Normalization of pressure (below 140/90)

2. Prevention of complications: stroke,

heart failure, renal disease and coronary
events
How do anti-hypertensive
pharmacological agents work?

♣ In regulation of blood pressure, there are

factors that increase blood pressure and
factors that decrease blood pressure.
Anti-hypertensive agents are used:

1. To antagonize the actions of factors

that increase blood pressure.

2. To ‘potentiate’ the actions of factors

that decrease blood pressure
 1. Angiotensin-converting enzyme
inhibitors (ACEI)

Captopril, enalapril
Angiotensin II is a peptide that increases
blood pressure by causing vasoconstriction
and stimulation of aldosterone.
Mechanism of action

1. ACEI inhibit angiotensin-converting

enzyme and prevent the conversion of
angiotensin I to angiotensin II.
Mechanism of action (cont’d)
♣ Inhibition of synthesis of angiotensin II
results in decreased levels of
angiotensin II in the circulation,
and blood pressure decreases.
Mechanism of action (cont’d)
2. ACEI prevent the degradation
(inactivation) of bradykinin and
increase its levels.
Bradykinin causes vasodilation.
♣ ACEI are very effective as
monotherapy.

♣ BP decreases because of vasodilation

and reduction in peripheral resistance
♣ If an ACE inhibitor is used as
first-step monotherapy, small doses
should be prescribed initially.
♣ If target blood pressure is not achieved
with a minimal or moderate dose of
an ACE inhibitor, one can add a
small dose of another drug
like a diuretic.
♣ Side effects of the ACE inhibitors
are relatively uncommon,
except for cough.
 2. Angiotensin II Receptor
Blockers (ARB)

Losartan, valsartan
Mechanism of action:

1. Inhibit actions of angiotensin II by

blocking angiotensin type-1 receptors.
Mechanism of action (cont’d):

2. Reduce vascular resistance without

reducing cardiac output.
Renal blood flow is maintained.
♣ These medications are as effective
in lowering blood pressure as
the ACE inhibitors.

♣ These drugs have no major side effect.

♣ The blood pressure-lowering effects
of the ARBs are greatly increased
when a diuretic is added.
 3. Calcium Channel Blockers (CCB)

Mechanism of action:

Lower blood pressure by inhibiting

the entry of calcium ions into
vascular smooth muscle cells, which
results in vasodilation, reduces
peripheral resistance, and decreases
blood pressure.
Types of calcium channel blockers:
1. The nondihydropyridines:

* vasodilation – decrease peripheral

resistance- decrease blood pressure

* coronary vasodilation

* decrease AV and SA nodal conduction

* verapamil, diltiazem
2. The dihydropyridine:

* vasodilation – decrease peripheral

resistance- decrease blood pressure
* coronary vasodilation

* do not affect cardiac function

* nifedepine, amlodipine, felodipine,

isradipine nicardipine
4. DIURETICS

Mechanism of action:

1. Initially, there is a decrease in plasma

volume with a short-term decrease
in cardiac output.
2. The long-term effect is one of
vasodilation and decreased vascular
resistance
Thiazide diuretics (hydrochlorothiazide)

Thiazide diuretics are one of the

preferred initial monotherapies.
♣ When used in combination with a
small dose of a beta-adrenergic
inhibitor, an ACEI, an ARB or a
calcium channel blocker(CCB),
response to normotensive levels is
approximately 80%.
Potassium Sparing agents (amiloride)

♣ Potassium-sparing diuretics are not

used by themselves because they
are weak diuretics and are relatively
ineffective in lowering blood pressure
when used alone.
♣ They are used to reduce excessive
potassium loss. Various combinations
of thiazides and potassium-sparing
agents can be used.
5. Beta-Adrenergic Receptor Blockers

Mechanism of action:

Lower blood pressure by decreasing

cardiac output, inhibiting the release
of renin, possibly reducing norepinephrine
release from sympathetic neurons, and
decreasing central vasomotor
activity (Figure 4).
There are several types of beta-blockers
available:
1. Beta-1 selective: atenolol and metoprolol
2. Non-selective: propranolol
Place in Therapy

Beta-Blockers are recommended

as one of the first-step drugs in the
management of hypertension.
♣ When beta-blockers are used as
monotherapy, about 40% to 50%
of patients will respond.
♣ In combination with small doses
of a diuretic, however, these agents
are highly effective in all patient
groups with relatively few side effects.
♣ A beta-blocker should be used in
almost every post-myocardial
infarction patient unless there
is a contraindication to it.
♣ Beta-Adrenergic inhibitors have been
shown to prevent a second myocardial
infarction in patients with known
ischemic heart disease and
to reduce mortality
6. Alpha-1 Adrenergic Inhibitors
Doxazosin, Prazosin, Terazosin
Mechanism of action:

♣ Block alpha1-receptors on vascular

smooth muscle. Vasoconstriction is reduced,
and peripheral vasodilation occurs without
major changes in cardiac output.
7. Combined Alpha-1 and Beta Blockers

Labetalol and carvedilol

Mechanism of action:

1. Their antihypertensive effect is due to their

combined alpha-1 and beta-adrenergic
blocking activity.
2. Blood pressure is reduced, mainly as
a result of a decrease in
peripheral resistance.
♣ Hemodynamically, unlike pure
beta-blockers, which reduce heart rate
and contractility, these compounds
reduce total peripheral
resistance, maintain cardiac output, and
preserve peripheral blood flow,
renal plasma flow and glomerular
filtration rate.
8. Central sympatholytics

alpha-Methyldopa, Clonidine,
Guanabenz, Guanfacine
Mechanism of action:

1. They stimulate alpha-2 receptors on the

adrenergic neurons located within the medulla,
which controls sympathetic outflow
2. Their effects include: decrease in
sympathetic activity, decrease in
peripheral resistance, and decrease
in blood pressure.
♣ They are particularly useful for
patients who have hypertension with
associated anxiety, especially that which
is manifested by sympathetic over activity.
♣ Methyldopa is used to treat
pregnancy-induced hypertension.
9. DIRECT VASODILATORS

Hydralazine, minoxidil and

nitrates like sodium nitroprusside
(Figures 3 and 5)
Mechanism of action:

3. They act directly on the vascular

smooth muscle cell to cause vasodilation.
2. They cause dilation of arterioles with
a decrease in peripheral resistance
and blood pressure.
SUMMARY (Figure 6)
Problem Solution
Increased volume Diuretics

Increased sympathetic tone Alpha & Beta-blockers,

sympatholytics

Angiotensin ACEI, ARB

Excessive vasoconstriction CCB, direct vasodilators

APPROACH TO THERAPY

Stepped-care implies that if blood pressure is

not reduced to normal with one drug, it is
appropriate to add small doses of
another drug from another class.
The plan for initial medical therapy:

♣ A diuretic such as hydrochlorothiazide

can be given in small doses to most
patients unless there is a specific
contraindication to its use or a
specific indication for the use of another agent.
♣ A beta-blocker is also an acceptable
choice for initial therapy, although this
class of agents may not be the best choice
for elderly patients.
♣ If goal pressures of < 140/90 mm Hg are
not achieved with the diuretic alone, a
second drug such as a beta-adrenergic
inhibitor, an ACEI, an ARB, an
alpha1-beta-blocker, or, in some cases,
a long-acting CCB will be added.
♣ If a beta-blocker was used as initial therapy,
a diuretic should be added unless
there is a contraindication to its use.
♣ In the situation where a patient has been
started on an ACEI or a CCB,
a diuretic should also be added
if normalization of blood pressure
has not occurred.
♣ If no blood pressure-lowering effect is
noted with initial therapy or if
troublesome side effects occur,
the first medication should be stopped
and another agent substituted.
Multiple Drug Therapy

♣ Using small doses of two different classes

of drugs makes good sense, rather than
increasing the dosage of one drug to a
maximum level.
♣ Blood pressure response is generally better;
about 75% of patients will respond to a
combination of two different agents,
whereas only about 50% will respond
even to full doses of one drug.
♣ In addition, certain homeostatic
reflex mechanisms may be blocked
and side effects minimized by this
approach.
Combination Therapy

♣ Available combinations include diuretics

and beta-blockers, diuretics and
ACE inhibitors, diuretics and ARBs,
and ACE inhibitors and CCBs.
Important issues to remember:

1. Keep dosages of medication as low as possible

to minimize side effects.

2. Make all efforts to ensure that patients

follow instructions properly.
Patient education is very important in gaining
cooperation and helping patients to
understand the reasons for therapy
3. Treat to a goal of below 140/90mmHg.

4. Avoid overdosing.

5. Ensure 24 hour coverage.

 Algorithm for the Treatment of
Hypertension

 Begin life style modifications

(Stop smoking and alcohol intake, reduce
salt intake, exercise, etc)
Not at goal blood pressure (140/90 mmHg)

[Lower goals for patients with diabetes or

renal disease (lower than 130/85 mmHg)

]
 Initial Drug Choice
 Uncomplicated Hypertension: Diuretics,
Beta-blockers

 Diabetes mellitus (type 1) with

proteinuria: ACE inhibitors

 Heart failure: ACE inhibitors, diuretics

 Isolated systolic hypertension
(older patients): Diuretics (preferred),
long-acting dihydropyridine calcium
antagonists

 Myocardial infarction: Beta-blockers,

ACE inhibitors
 Not at goal blood pressure

 No response or troublesome side effects:

Substitute another drug (different class)

 Inadequate response but well tolerated:

Add a second agent (different class)

 Not at goal blood pressure

Continue adding agents from other classes

 Causes of Arterial
Hypertension

• Primary (Essential or idiopathic)

Hypertension- ~80-90%
 Unknown cause
2. Secondary Hypertension- ~10-20%
 Renal disease, vascular disease, adrenal
disease, other causes
 Prognosis of Untreated
Hypertension

 There is an inverse relationship between

blood pressure and longevity
 Blood pressure regulation
Factors that increase BP Factors that decrease BP
Increased volume (Diuretics) Bradykinin (ACEI)

Increased sympathetic tone

Histamine
Norepinephrine (Beta blockers)

Angiotensin (ACEI, ARB)

Prostaglandins (ACEI)
vasopressin, endothelin

Increased vascular reactivity Nitric oxide (dilators, ACEI)

(CCB, dilators)
Increased baroreflex sensitivity
 Case #1
A 76 year old female comes to her family
doctor complaining of constipation and
epigastric pain as well as weakness and
painful cramps (due to hypokalemia).
History: She has a history of hypertension,
for which she has been taking propranolol
and hydrochlorothiazide for the past
several months.

Observation: Mild hypertension

(BP 145/90);
Treatment: Potassium rich foods
(chickpeas, bananas, papaya), potassium
supplement, or switch to
potassium-sparing diuretics such as
spironolactone or triamterene.
 Case #2

A 62 year old female is referred to a

pulmonary specialist by her family
physician because of a chronic dry cough
that has been unresponsive to medications.
History: On careful questioning the
specialist discovers that she had been
taking captopril for hypertension for three
years.

Observation: Normal BP
Treatment: Consider alternate
antihypertensive agents.

Losartan would be a good choice.

 Case #3

A 45 year old female news reporter is

brought to the emergency room from work
after she was found to be disoriented; she
also complained of a splitting headache and
ringing in the ears.
Observation: hypertension (BP 190/120).

Treatment: Nitroprusside; do not attempt

to lower BP>30% in the first hour due to
possible coma or MI.
Discussion: Nitroprusside (a potent
arteriolar and venular vasodilator) reduces
preload and afterload and has very rapid
onset and end of action (easy titration in
case of hypertensive emergencies), making
it the first drug of choice.
 Angiotensinogen
Renin low BP
Angiotensin I
ACE
Angiotensin II

AT1 AT2

 BP  BP
Alternative Enzymatic Pathways The Renin-Angiotensin System

Angiotensinogen (α2 globulin)

Non-Renin
(tonin Renin
cathepsin) Bradykinin
Angiotensin I decapeptide
Non-ACE
ACE
(chymase)
Angiotensin II octapeptide Inactive peptides

AT1 receptors AT2 receptors

Angiotensinases

Ang heptapeptide, hexapeptide, others

 Angiotensin I
non ACE
ACE
Angiotensin II

AT1 AT2

 BP  BP
 Pathways for Angiotensin II (AII) and Targets for Inhibition

* Biologically active
 Angiotensin II
AT1 Receptors

Adrenal Vascular
Kidney Gland Smooth Muscle CNS Myocardium

 BP
Factors involved in blood pressure control. Determinants of blood
pressure are cardiac output, determined by heart rate and stroke volume
Renin-angiotensin-aldosterone system
The relationship between cerebral blood flow (CBF) and mean arterial
pressure (MAP)
Number of antihypertensive prescriptions in the US, 1984-1989
Dose-response relationship for thiazide antihypertensive agents and blood
Pressure (antihypertensive action) and as a diuretic (shown here as effect
on K+ excretion, the kaliuretic action)
Antagonism at postsynaptic α1 adrenoceptors
β Adrenoceptor antagonists classified according to cardioselectivity and
partial agonist activity
Presynaptic α2 agonism
α2 Agonism decreases sympathetic activity and consequently reduces
blood pressure
Metabolism of α methyldopa to α methylnorepinephrine
Effects of angiotensin-converting enzyme (ACE) inhibitors
Changes of chronic hypertension in the blood vessel wall
Changes of accelerated hypertension in the blood vessel wall