Ministry of Health of the Republic of Moldova

Public Institution “Nicolae Testemiţanu” State University of Medicine and Pharmacy

of the Republic of Moldova

FACULTY OF MEDICINE

Department of Internal Medicine-Semiology

 
DIPLOMA THESIS
UP-TO-DATE APPROACH TO DIAGNOSTIC OF
ARTERIAL HYPERTENTION AND TREATMENT WITH
ANGIOTENSINEII RECEPTORS BLOCKERS
student AZBARGA LOCKMAN
VIyear, group M1245

scientific advisor CALIN GHENADIE

university asistant
INTRODUCTION
 Topicality and level of study of research topic
 Theoretical and practical importance of the report
 Definition, classification
 The incidence and prevalence
 Risk factors, risk stratification
 Natural evolution of disease
 Clinical picture
 Diagnosis
 Drug therapy
CONCLUSION
 INTRODUCTION
The hypertension is one of the most common cardiovascular pathologies, which is placed in
the top of the structure of the cardiovascular diseases and cardiovascular death rate, especially in
the less economically developed countries, and this fact was proved by the Framingham heart
study. HTN isn’t equally spread on the globe, being influenced by socioeconomic factors and by
the geographical environment etc. Thereby the rate of the morbidity in HTN varies between 5-
10% in the less developed countries and 10-30% in the industrialized countries.
Hypertension is a leading risk factor for cardiovascular disease and worldwide prevalence of
hypertension is increasing. In 2000 26% ofthe world’s adult population (over 1 billion people)
were considered tohave hypertension and in 2009 the WHO reported that hypertension had a
causative role in the deaths of over 7.5 million people [1,2]. Prevalence of hypertension in adults of
16 years or older in the UK was 31.5% in men and 29.0% in women in 2010
In the last decades, hypertension (HTN) has become a major problem of the public health,
leading to cardiovascular diseases and to a very high cardiovascular death rate. Analyzing the
statistic data offered by WHO, we can say that the morbidity in the HTN varies between 5 and
10% in the less economically developed countries and 20% in the industrialized countries. As the
time passes by, this problem grows so that more than a half of the 60-65 years old patients suffer
from this pathology and predicted that HTN would rise to 29% by 2025. By the age of 60, more
than one-half of adults in most regions of the world will be hypertensive.
The majority of hypertension is considered to be essential hypertension which develops due to
a complex interplay of genetic, lifestyle and environmental factors. Cardiovascular risk associated
with increasing blood pressure is continuous with 7% increase in mortality from ischaemic heart
disease and 10% increased risk of mortality from stroke for every 2 mmHg rise in population
blood pressure.
Definition

High blood pressure: blood pressure persistent equal

or higher than 140/90 mmHg in repose, have adults
taken under conditions in doctor’s office.
 ROLE OF VASCULAR OXIDATIVE STRESS IN HYPERTENSION
The occurrence of oxidative stress is due to an imbalance between ROS
generation and the antioxidant potential in the body, the latter being overwhelmed
by the increased ROS concentration in the steady state. It should be noted that
although ROS are mediators of normal biological effects related to vascular function
at the cell level, the increased levels of these species can give rise to pathological
changes, as those observed in cardiovascular disease. ROS behave as redox‐sensitive
blood pressure modulators .
Therefore, these data provide evidence of the involvement of vascular oxidative
stress in the mechanism of development of essential hypertension. Moreover, at the
cellular level, it has been reported that ROS production is enhanced in cultured
vascular smooth muscle cells (VSMC) isolated from both hypertensive rats and
isolated arteries of hypertensive human patients; these findings are associated with
amplified, redox‐dependent signaling and reduced antioxidant bioactivity .
These reports could support the view that the modulation of oxidative stress
could be expressed in blood pressure lowering in the case of known antihypertensive
agents, such as β‐adrenergic blockers, angiotensin‐converting enzyme (ACE)
inhibitors, angiotensin receptor antagonists, and calcium channel blockers.
VASCULAR ROS SOURCES
NADPH OXIDASE
In the vascular wall, as well as in the kidney, superoxide anion is mainly
produced enzymatically through NOX activity. The enhanced activity of NOX
in hypertension is achieved through mechanical and humoral signals, with AT‐
II being the most studied stimulus. However, it is important to remark that ET‐
1 and UT‐II cooperatively participate in NOX activation. In addition, NOX‐
derived superoxide anion is able to inactivate NO, thus producing
peroxynitrite anion. The latter induces downregulation of prostacyclin
synthase, further allowing the development of hypertension. Finally, oxidative
stress leads to eNOS uncoupling .

XANTHINE OXIDASE
This enzyme system provides an important endothelial source of superoxide in
the vascular wall . XO‐catalyzed reactions lead to oxygen reduction to produce
superoxide from purine metabolism. It has been reported that spontaneously
hypertensive rats demonstrate increased levels of both endothelial XO activity
and ROS production, together with increased arteriolar tone.
UNCOUPLED ENDOTHELIAL NO SYNTHASE
The vascular tone is modulated by vasoconstriction‐vasodilation
balance, and NO bioavailability constitutes an important component
of the latter process. Deficiency or oxidation of either will result in
decreased NO production. The initial ROS source is NOX‐dependent
superoxide generation. Furthermore, peroxynitrite is formed
through the reaction between NO and superoxide .The activity and
function of eNOS are changed due to the peroxidant ability
generated by peroxynitrite, and this enzyme produces more
superoxide instead of NO.
MITOCHONDRIAL DYSFUNCTION
The mitochondrion could behave as both a ROS source and target.
Superoxide is produced in the intermembrane space, but it is
rapidly carried to the cytoplasm .Either ubiquinol or coenzyme Q
could be a source of superoxide when these mitochondrial
components are partially reduced; In addition, it was found that
patients with hypertension show reduced activity of antioxidant
enzymes
 ROLE OF VASCULAR WALL COMPONENTS
In response to mechanical and hormonal stimuli, the endothelium
releases agents participating in the regulation of vasomotor tone.
Particularly relevant is the ability of endothelium to exert a
protective role through the generation of vasorelaxing factors. In
addition, pathophysiological conditions result in increased
released of endothelium‐derived vasoconstricting factors, such as
ET‐1, AT‐II, UT‐II, superoxide anions, vasoconstrictor
prostaglandins, and thromboxane A2, all of them capable of
producing vasoconstrictor effects. It should be mentioned that
VSMC contribute to modulating blood pressure not solely in short‐
term regulation of the blood vessel diameter, but also in the
structural remodeling occurring during long‐term adaptation,
both processes being mediated by ROS. It is of interest considering
that the adventitia can also participate in the development of
hypertension, which is achieved through ROS contribution in
either reduction of NO bioavailability or vascular remodeling
 ROLE OF VASCULAR HORMONES AND FACTORS
NITRIC OXIDE
It is involved in the physiological regulation responsible for the maintenance of the
health of vascular endothelium through processes such as inhibition of leukocyte‐
endothelial cell adhesion, VSMC proliferation and migration, and platelet
aggregation. The effect of decreased NO bioavailability is particularly relevant,
leading to reduction of vasodilatory capacity in the vasculature, there by providing a
mechanism of hypertension. It is of interest to mention that NO diffuses easily to
the adjacent VSMC, thus binding to receptors such as soluble guanylyl cyclase. The
numerous NO biological properties include not only vasorelaxing and
antiproliferative actions but also antagonizing the effects of AT‐II, endothelins and
ROS, among other vasoconstrictors. Though L‐arginine, a substrate for eNOS, could
be considered as a promising factor in preserving NO formation, it failed to prevent
blood pressure elevation and left ventricle remodeling in a model based on chronic
treatment with the methyl ester of N‐nitro‐L‐arginine (L‐NAME), an inhibitor of
eNOS It should be remarked that reduced NO levels can be the result of its
combination with superoxide to form peroxynitrite, a compound capable of
enhancing oxidative stress by oxidizing BH4, destabilizing eNOS, and producing
more superoxide The importance of the balance between NO and AT‐II in the
regulation of the sympathetic tone has been reported.
RENIN‐ANGIOTENSIN SYSTEM
There is cumulated evidence supporting that the renin‐angiotensin system (RAS)
contributes to the development of cardiovascular disease. The production of AT‐
II, a potent vasoactive peptide, occurs in vascular beds having important ACE
activity. Increased AT‐II production above normal levels is able to induce vascular
remodeling and endothelial dysfunction, as well as increases in levels of blood
pressure. At the cell level, AT‐II acts as a potent NOX activator, thus leading to
enhancement of ROS production . In addition, the effect of AT‐II is not only
confined to increasing NADPH oxidase activity but also upregulating SOD, likely
as a compensation mechanism against ROS increase.
Pharmacological inhibition of ACE by captopril and enalapril prevented blood
pressure rise in young spontaneously hypertensive rats. The hypotensive effect of
captopril is higher than that of enalapril, which could be due to the antioxidant role
of its thiol group.
ENDOTHELIN‐1
Vascular endothelium, among others vascular tissues, produces potent
vasoconstrictor isopeptides known as endothelins. ET‐1 is the major
endothelin generated by endothelial cells, and is probably the most
important in cardiovascular physiology and disease. It has been
demonstrated that large concentration of exogen ET‐1 acts as potent
vasoconstrictor capable of altering arterial pressure. ET‐1 mediates its effect
through two receptors, ETA and ETB. ETA exerts its effects via activation of
NOX, XO, lipoxygenase, uncoupled NOS, and mitochondrial respiratory
chain enzymes. ETB induces relaxation on endothelial cells [42]. The
vasoconstricting action of ET‐1 is counteracted by vasodilators such as
prostacyclin (PGI2) and/or NO, and it has been seen that many factors that
stimulate ET‐1 synthesis (e.g. thrombin, AT‐II) also cause the release of the
vasodilators above mentioned.
ACETYLCHOLINE
 The endothelium‐dependent vasodilation by acetylcholine (Ach) in
vascular vessels occurs mainly via NO production. NO rapidly diffuses to
the underlying VSMC, thereby inducing relaxation in these cells. Under
oxidative stress conditions, a diminution in NO bioavailability should be
expected, thus leading to significantly reduced ACh‐mediated vasodilation.
UROTENSIN‐II
UT‐II is the most potent vasoconstrictor identified .It acts through the activation
of NOX. UT receptors have been identified in several other organs besides
vascular bed, suggesting that vasoconstriction is not its only effect UT‐II has also
been shown to act as a potent vasodilator in some models

NOREPINEPHRINE
VSMC is innervated primarily by the sympathetic nervous system through three
types of adrenergic receptors: α1, α2 and β2. VSMC proliferation is stimulated by
norepinephrine.

PROSTAGLANDINS
PGI2 is considered one of the most important vasodilators depending on the
endothelium and relaxes the vascular musculature. A large amount of
substances that generate an increase in PGI2 release have been described, such
as thrombin, arachidonic acid, histamine, and serotonin. Prostaglandin H2 is
formed by the prostaglandin H2 synthase, which uses arachidonic acid as a
substrate. Then, prostaglandin H2 is converted to PGI2, a vasoactive molecule.
Oxidative stress‐related conditions, such as hypertension, impair the PGI2‐
mediated vasodilation.
HOMOCYSTEINE
 It has been proposed that homocysteine plays an important role
in the pathophysiology of primary hypertension . An increase in
homocysteinemia augments the proliferation of VSCM, thus
altering the elasticity of vascular wall; it generates an oxidative
stress state and diminishes NO bioavailability, thus impairing
vasodilation. All the mechanisms exposed contribute to elevated
blood pressure Homocysteine could also lead to endothelium
oxidative damage. The administration of vitamins B6, B12, and
folic acid has been proposed as a potential adjuvant treatment
in hypertension, probably by correcting the increased
homocysteinemia.
Classification
There are two types of high blood pressure.
Primary (essential) hypertension
For most adults, there's no identifiable cause of high blood
pressure. This type of high blood pressure, called primary
(essential) hypertension, tends to develop gradually over many
years.
Secondary (symptomatic) hypertension high blood pressure
caused by leading desease and increasing of blood pressure is
as symptome.
1. HTN due to kidney disease
2. HTN in endocrine affections
3. cardio-vasculur (haemodinamic)
4. CNS affections
5. exogene
6. pregnance
 Depending of regions and countries the
incidence of HNT is varios:
 Essential HTN 82-95.3%
 Symptomatic HTN 18-4.7%
HTN caused by/due to chronical kidney disease 2.4-
5.6%
Renovascular HTN 0.2-4.0%
HTN caused by coarctation of the aorta 0.1-1.0%
HTN caused by Primary Aldosteronism 0.1-0.5%
HTN caused by Cushing's syndrome 0.1-0.2%
HTN caused by Pheochromocytoma 0.1-0.2%
HTN caused by using of oral contraceptives 0.2-1.0%
Category Systolic Hg mm Diastolic Hg mm

Optimal <120 and <80

Normal 120–129 and/or 80–84

High normal 130–139 and/or 85–89

Grade 1 hypertension 140–159 and/or 90–99

Grade 2 hypertension 160–179 and/or 100–109

Grade 3 hypertension >/=180 and/or >/=110

Isolated systolic >/=140 and <90

hypertension

Definitions and Classification of Office Blood Pressure Levels (2013 ESH/ESC)

The incidence and prevalence

Predominans of age:
 it is found 5% increase of incidence at each 10 years
age interval exept the group of 65-74 years old people.
Predominance of sex:
age of 65 years M>W; in interval 65-74 years M<W[13].
 Risk factors
The risk factors of the disease that take part in the
development of the HTN:

The major risk factors:

Smoking
Dyslipidemia
The diabetes mellitus
The age above 60
Central Obesity
Sex (men or women in postmenopause)
A family history of cardiovascular diseases at women
under 65 and men under 55years
 Risk stratification

 Decisions about the management of patients with hypertension

should not be based on the level of bloodpressure alone, but also on
the presence of other risk factors, concomitant diseases such as
diabetes, target-organ damage and cardiovascular or renal disease,
aswell as other aspects of the patient's personal, medicaland social
situation.
 The estimates are based on age, gender, smoking, diabetes,
cholesterol, history of premature cardiovascular disease, the presence
of target-organ damage and history of cardiovascular or renal disease.
 Low-risk group
The low-risk group includes men below 55 and womenbelow 65 years of
age with grade 1 hypertension and noother risk factors. Among individuals
in this category,
the risk of a major cardiovascular event in the next 10years is typically less
than 15%. The risk will beparticularly low in patients with borderline hyper

Medium-risk group
This group includes patients with a wide range of bloodpressures and risk
factors for cardiovascular disease.Some have lower blood pressures and
multiple riskfactors, whereas others have higher blood pressures andno or
few other risk factors.

Very-high-risk group
Patients with grade 3 hypertension and one or more risk factors and all
patients with clinical cardiovasculardisease or renal disease carry the
highest risk of cardiovascular events, of the order of 30% or more over 10
years, and thus qualify for the most intensive and rapidly instituted
therapeutic regimes.
High-risk group
This group includes patients with grade 1 or grade 2hypertension who have
three or more risk factors listed
• Men 55 years
• Women 65 years
• Smoking
• Total cholesterol .6:5 mmol=l (250 mg=dl)
• Diabetes
• Family history of premature cardiovascular disease
Other factors adversely in¯uencing prognosis
• Reduced HDL cholesterol
• Raised LDL cholesterol
• Microalbuminuria in diabetes
• Impaired glucose tolerance
• Obesity
• Sedentary lifestyle
• Raised ®brinogen
• High-risk socioeconomic group
• High-risk ethnic group
• High-risk geographic region
 Target-organ
damage
• Left ventricular hypertrophy
(electrocardiogram,
echocardiogram or radiogram)
• Proteinuria and/or slight elevation
of plasma
creatinine concentration (1.2±2:0
mg=dl)
• Ultrasound or radiological
evidence of
atherosclerotic plaque (carotid, iliac
and
femoral arteries, aorta)
• Generalized or focal narrowing of
the retinal
arteries
Associated clinical conditions
Cerebrovascular disease
• Ischaemic stroke
• Cerebral haemorrhage
• Transient ischaemic attack
Cerebrovascular disease
• Ischaemic stroke
• Cerebral haemorrhage
• Transient ischaemic attack
Heart disease
• Myocardial infarction
• Angina
• Coronary revascularization
• Congestive heart failure
Renal disease
• Diabetic nephropathy
• Renal failure (plasma creatinine
concentration .2:0 mg=dl)
Vascular disease
• Dissecting aneurysm
• Symptomatic arterial disease
Advanced hypertensive retinopathy
• Haemorrhages or exudates
• Papilloedema
 The affection of the target organs:
The cardiac affectation;
The hypertrophy of the left ventricle;
The angina pectoris or the antecedents of the
myocardial infarction, an anterior revascularization, a
Heart failure;
The stroke (CVA) or the transient ischaemic attack;
Nephropathy;
The peripheral vascular disease;
Retinopathy;
 The group with low risk
This group comprises men under 55 and women under
65with HTN of 1 degree and without other risk factors. The
risk of the major cardiovascular event in the following 10
years is under 15% in this category. It is very low, especially
at the patients with borderline hypertension.
The group with medium risk
This group contains patients whose BP values are high and
who have associated cardiovascular risk factors. Some of the
HTN patients have lower values and more risk factors, and
others have higher BP values and less risk factors. At this
group of patients, the clinical exam will be able to influence
squarely the necessity and the moment of the establishment
of the antihypertensive treatment. The risk of the major
cardiovascular event at this group in the following 10 years is
of about 15-20%.
The group with high risk
This group includes the patients with HTN of 1-2 degree, who have three
or more associated risk factors, diabetes or the affection of the target
organs, as well as the patients with the HTN of 3 degree and without any
other risk factors. The risk of the major cardiovascular event in the
following 10 years is 20-30%.
The group of very high risk
This group comprises patients with the HTN of 3 degree and one or more
associated risk factors and all the patients with cardiovascular disease or
renal disease. These patients have the higher level of cardiovascular
events, of about 30% or higher, in the following 10 years, and it must e
established a rapid and intensive antihypertensive treatment.
 Clinical picture
Instalation of rapid HTN or of cardiac, cerebrovascular and renal
complications led to staging of WHO of HTN. Once the modern
antihypertensive treatment was introduced, the evolution of HTN is
modified, a part of HTN undergo the treatment and in this way the
prognostic of recovery is a little affected.

History. Once the diagnosis of hypertension is made, the clinician

should determine by history and physical examination whether the
patient has evidence suggesting secondary hypertension, as well as other
cardiovascular risk factors.
The history should focus on the following:
 Cardiovascular review of systems, including known duration of
hypertension
 Symptoms or previous personal/family history that helps to identify
secondary hypertension
 Presence or absence of other cardiovascular risk factors
 Psychosocial and environmental factors that may influence BP control
 Medications being taken
Physical examination
Based on expert opinion the JNC 7 recommendations for the physical
examination of hypertensive patients are:
• Two or more BP measurements separated by 2 minutes with the patient
either supine or seated
• Verification in the contralateral arm
• Body mass index (BMI), calculated by weight (kg)/[height (m)]2 (possibly
waist circumference)
• Funduscopic examination for arteriolar narrowing,nicking, hemorrhages,
exudates, etc.
• Neck examination for carotid bruits, distended veins, or enlarged thyroid
• Heart/lung examination
• Abdominal examination for enlarged kidneys, masses,distended bladder,
renal bruits, aortic aneurysm
• Extremity examination for pedal pulses and edema
• Neurological assessment, particularly for signs of cerebrovascular disease
Laboratory tests and diagnostic procedures.

Essential hypertension. Consider the following tests before

therapy is initiated. Screening for diabetes is particularly
important.
• Potassium • Urinalysis
• Blood glucose • Lipid panel
• Creatinine • EKG
• Calcium • Hematocrit
Treatment
Lifestyle for patients with essential hypertension consists
of the following activities:
- Quitting smoking and alcohol abuse. proved that the poisons
contained in cigarettes and alcohol.
- Limiting use of salt in food to 5 - 6 g per day.
- Proper nutrition. should be excluded from the diet of "harmful"
products - fast food, spicy, smoked, sharp, salty, fatty and fried
foods.It is recommended to increase the amount of food in fresh
fruits and vegetables, dairy products, cereals and cereal
products.For proper operation of the whole organism in food
should be taken at the same time, about 4 - 6 times a day.
- Proper organization of physical activity. To maintain good
condition of cardio - vascular system is not necessary to engage in
weight training, extreme sports or to spend every night in the
gym.It is enough to charge the morning and evening with a simple
set of exercises,
For

non-drug treatments include:
- auditory training
- psychotherapy
- acupuncture
- phytotherapy (valerian, St. John's wort, sage,
Motherwort, mint, lemon balm and other herbs.)
- electrosleep
Treatment Goal for Blood Pressure
Greater reductions in blood pressure have been shown
to be safe and beneficial.22,23 In the Hypertension Optimal
Treatment trial, the risk of major cardiovascular events was
lowest among patients whose blood pressure had been
reduced to 138.5/82.6 mm Hg. An additional reduction did
not further reduce the risk of events in nondiabetic
patients, but it was not harmful. Among diabetic
patients, the lowest rates of major cardiovascular events
and death from cardiovascular causes were achieved with
the lowest blood pressure. In patients over the age of 65
years, morbidity and mortality from cardiovascular disease
are reduced when systolic pressure is lowered to a level
below
160 mm Hg.24
Choice of Antihypertensive Drugs
Most antihypertensive drugs reduce blood pressure by 10 to 15 percent.
Monotherapy is effective in about 50 percent of unselected patients, and those
with stage 2 or 3 hypertension often need more than one.
Thus, the choice of therapy is based on a combined assessment of several
characteristics of the patient: coexisting conditions, age, race or ethnic group,
and the response to previously used drugs, including the presence or absence
of adverse reactions.
A critical issue is whether a drug reduces cardiovascular morbidity and
mortality. As compared with placebo, diuretics and beta-blockers reduce the
risk of stroke, coronary heart disease, and overall mortality from
cardiovascular disease in unselected patients with hypertension who do not
have preexisting coronary disease, diabetes, or proteinuria.
A meta-analysis of trials involving more than 26,000 patients showed that,
as compared with placebo, angiotensin-converting–enzyme (ACE) inhibitors
reduce the risk of stroke, coronary heart disease, major cardiovascular events,
death from cardiovascular causes, and death from any cause,26 Calcium-
channel antagonists, as compared with placebo, reduce the risk of stroke,
major cardiovascular events, and death from cardiovascular causes; however,
 A meta-analysis of clinical trials suggests that ACE inhibitors
are more effective than calcium-channel antagonists in reducing
the risk of heart failure but not in reducing the risk of stroke,
death from cardiovascular disease, or death from any cause.26
Losartan, an angiotensin-receptor antagonist, has recently been
shown to be more effective than atenolol in reducing the risk of
stroke.31 Another meta-analysis suggests that calcium-channel
antagonists may prevent stroke to a greater extent than diuretics
or beta-blockers but have not been shown to provide similar
protection against coronary heart disease.32 The
Antihypertensive and Lipid-Lowering Treatment to Prevent Heart
Attack Trial, the largest randomized trial comparing several
antihypertensive agents as initial therapy, demonstrated that in
patients older than 55 years (35 percent of whom were black and
19 percent of whom were Hispanic), diuretic-based therapy was as
effective as treatment with calcium-channel antagonists or
 On the basis of the available data,
diuretics or beta-blockers remain
appropriate for the initial treatment of
uncomplicated hypertension,
Alternative drugs are preferable for
patients with certain coexisting medical
conditions In particular, ACE inhibitors
and angiotensin-receptor antagonists are
appropriate initial therapy in patients
with diabetes mellitus, renal disease, or
congestive heart failure (though beta-
blockers and diuretics are also useful in
patients with heart failure);
ACE inhibitors can also be used in
patients with prior myocardial infarction
or coronary artery disease. Short-acting
calcium-channel antagonists cause a
rapid, acute drop in blood pressure,
which may precipitate coronary
ischemia, and long-acting calcium-
channel antagonists are therefore
preferred when this class of agent is
chosen.
Other Considerations in the Choice of Therapy
Age and race have been shown to be determinants of the response to specific
antihypertensive medications. The Department of Veterans Affairs Cooperative
Study reported that younger whites had a good response to ACE inhibitors and
beta-blockers, whereas older blacks had a better response to diuretics or
calcium-channel antagonists.

The magnitude of the blood-pressure response to monotherapy with a

diuretic or a calcium-channel antagonist may be greater than the response to
monotherapy with another agent, significant reductions occur with ACE
inhibitors, angiotensin-receptor antagonists, and beta-blockers when an
adequate dose is given.

Side effects differ according to the class of antihypertensive drug (Table 3).
Although adverse effects are reported by 10 to 20 percent of patients taking such
drugs, the quality of life improves when hypertension is treated. The Treatment
of Mild Hypertension Study and the Department of Veterans Affairs Cooperative
Study both demonstrated that among the five main classes of antihypertensive
drugs (diuretics, beta-blockers, calcium-channel antagonists, ACE inhibitors,
and alpha-blockers), no one drug is more acceptable than the others.
Combination Therapy
National and international groups hAve issued guidelines for the treatment of hypertension.
The main differences among these guidelines are the criteria for initiating drug therapy in low-
risk patients with stage 1 hypertension. Drug treatment is recommended for stage 1 or higher
hypertension if blood pressure does not decrease after a certain period of lifestyle-modification
counseling (6 to 12 months, according to the Joint National Committee guidelines).
The appropriate strategy for choosing the initial antihypertensive therapy is still unresolved.
Some have proposed that the choice of treatment should be based on renin levels, but this
approach is not widely used.
Persons who have stage 1 hypertension and are at low risk for cardiovascular disease can be
treated with lifestyle modifications for up to one year. Patients who have stage 1 hypertension
and other cardiovascular risk factors or a higher stage of hypertension should be treated with
drugs to reduce blood pressure to a level below 140/90 mm Hg, or to reduce pressure to 130/80
mm Hg or less if the patient has diabetes, renal disease, or both.
Diuretics and beta-blockers are
ACE inhibitors or angiotensin-receptor antagonists
Beta-blockers and ACE inhibitors
calcium-channel antagonists
Combination therapy provides more rapid control of blood pressure than does monotherapy
and is therefore an initial treatment option for patients with stage 2 or 3 hypertension.
Drug therapy

Hypertension is a chronic disease. Thus,the choice of which medication(s) to

prescribe has longterm implications. In according of ESH/ESC 2013 guideline of
mamagement of arterial hypertension we can us different combinations of drugs,
depending of particularities of clinical case.
Drug selection

Moderate-to-high dose thiazide diuretics (chlorthalidone 25mg/day) are as good as any

other class of agents in reducing cardiovascular adverse outcomes, and superior in
secondary outcomes such as stroke and CHF.
The choice of additional or alternative medication should be individualized to
achieve the target BP and the following goals:
• Once daily administration
• Reduction in CV complications demonstrated in clinical trials
• Choice of agent(s) that also treat concurrent conditions
• Least potential disruptive side-effects based on concurrent conditions or lifestyles
• Least expensive (both in pharmaceutical and laboratory monitoring costs)
• Fixed combination therapy can be more cost-effective and may improve compliance.
Diuretics.
Thiazide diuretics have traditionally been the initial treatment for
most patients with hypertension. Higher dosages of thiazide diuretics
have shown only minimal improvement in BP control. Consequently,
the maximum suggested dosage of thiazide diuretics has been lowered
in order to avoid metabolic side-effects. The range of
hydrochlorthiazide is 12.5mg to 50 mg each morning.
Side effects. Thiazide diuretics increase the frequency of sexual
dysfunction in men and women and initially may cause interruptions
in daily routine for micturition.
Thiazides cause a short-term increase in LDL cholesterol; however,
long-term trials have shown minimal change and outcome studies
show no clinical impact. Thiazides slightly increase risk for diabetes
(ALLHAT).
Loop diuretics. These diuretics are preferred for individuals with renal
impairment (serum creatinine ≥ 2.5mg/dl) and individuals allergic to
thiazide diuretics. Loop diuretics are useful for reducing preload,
which contributes to hypertension in renal-impaired individuals.
Angiotensin converting enzyme (ACE) inhibitors.
As a class, ACE-inhibitors have similar actions and side effects, with the only
major difference being duration of action. ACE inhibitors reduce BP with
generally few side effects and slow the decline of renal function in most
diseases.
The renoprotective effect may be augmented when combined with
angiotensin receptor blocker. Ramipril was shown in a randomized controlled
trial to decrease cardiovascular events in hypertensive and normotensive
individuals with systolic heart failure over placebo. However, newer trials have
not shown renin-angiotensin blockade to be superior to other medications in
decreasing morbidity and mortality. Onset of diabetes was not prevented by
ramipril in a study directly addressing this issue.
Side effects. Angioedema is a rare side effect (0.1-0.7%), which may be life-
threatening and may occur at any point in the treatment. The incidence may
be higher in AfricanAmericans. Although renal artery stenosis per se is not a
contraindication for ACE therapy, renal impairment may occur in patients
with bilateral renal artery stenosis or unilateral renal artery stenosis with a
single kidney. All in this class induce cough equally, which may be disabling
enough with some patients to result in the need to discontinue the drug;
cough occurs more often in women.
This class is contraindicated in pregnancy.
Angiotensin II receptor antagonists (ARB) displace
angiotensin II (AII) from its type 1 receptors
Losartan and irbesartan have been shown in randomized,
double-blind trials in diabetics with microalbuminuria or
azotemia to decrease the development of frank proteinuria or
progression to renal failure requiring dialysis ortransplantation.
In patients who have systolic heart failure and are intolerant to
an ACEI because of cough, ARBs are recommended.
Side effects. Angioedema has been rarely reported with Losartan,
but has occurred in patients with prior angioedema on ACE
inhibitors. Losartan has a uricosuric effect (i.e. increases
excretion of uric acid, lowering concentration in blood) that is
unique compared to others in this class. Losartan may be less
efficacious compared to others in this group at lowering BP and
should be used twice a day.
This class is contraindicated in pregnancy.
Calcium channel blocking (CCB) agents. There arethree classes of calcium channel
blocking agents based ondifferent calcium channel receptors, all with differentphysiological
effects and side effects: verapamil, diltiazem, and dihydropyridines. All long acting DHP
CCB’s have been shown to reduce blood pressure and cardiovascular events. (e.g. amlodipine,
felodipine, nislodipine) make single daily dosing possible. These drugs provide the most
reliable and significant blood pressure reduction in most patient subtypes. They are
particularly effective in stroke reduction and have been shown to reduce overall CVD risk.
The short-acting agents are not indicated for hypertension. Some effects with specific
diseases include:
• Acute coronary syndrome. Short-acting dihydropyridines should be avoided in the first 24-48
hours of an acute coronary syndrome.
• Chronic kidney disease. Dihydropyridines should be avoided as a single agent for patients
with microalbuminuria, as they will worsen protein loss and renal function, but may be used
in combination with ARB or ACE inhibitors.
• Chronic CAD. Verapamil has shown to be as effective as a beta-blocker in patients with CAD
or remote history of MI. All CCB’s can be used in hypertensive patients with chronic CAD to
reduce anginal episodes.
 Aortic regurgitation. Nifedipine may be useful in hypertensive patients with aortic
regurgitation.
Side effects. Edema may occur and is more pronounced with the dihydropyridine agents.
Bradycardia is a side effect of verapamil and diltiezem, but renders them useful agents in the
treatment of atrial fibrillation/SVT). Verapamil has more pronounced bradycardia effects
and often results in constipation.
Aldosterone inhibitors
 Spironolactone and eplerenone are used in certain
conditions associated with hypertension, such as
resistant hypertension, hyperaldosteronism, and
potassium wasting. However, when used in patients
with chronic kidney disease, or concurrently with
potassium sparing agents (ACEI, ARB, triamterene),
they carrysignificant risk for life-threatening
hyperkalemia.
Combination therapy is generally restricted to patients
with systolic heart failure, and requires close follow-up.
Gynecomastia and breast pain are common side effects
with spironolactone, causing discontinuation in about
10%.
Beta blockers have been shown to reduce cardiovascular morbidity and
mortality in controlled clinical trials for both diastolic and isolated systolic
hypertension.
However, one study showed that diuretics are superior to beta-blockers for stroke
reduction. Atenolol has poorer outcomes when compared to other beta-blockers
(an excess stroke riskof 17%). Beta blockers are indicated for patients with coronary
disease or CHF unless specific contraindications or documented intolerance exists.
Discussion regarding other properties of beta blockers, such as B1 selectivity and
lipid solubility, are beyond the scope of this guideline.
Side effects. Occasionally fatigue and uncommonly impotence are side effects at the
recommended low doses. Beta-1 blockers produce the same dramatic reduction in
Angiotensin II levels as ACE inhibitors, and the two agents together have an
additive effect. Though beta blockers may raise triglycerides and lower HDL
cholesterol, these effects have not been found to be clinically significant in
outcome studies. Renin inhibitors are a novel way of blocking the
reninangiotensin-aldosterone system (RAAS). The first drug in this class is
aliskiren. The drug has been shown to lower blood pressure alone or in
combination with other antihypertensives, but its effects on clinical outcomes is
unknown.
Side Effects. As with other RAAS agents, aliskiren cancause an increase in serum
creatinine and potassium especially is used in combination with an ACE inhibitor
or ARB. This class is contraindicated in pregnancy.
Peripheral alpha blockers.
Side effects: Alpha blockers may cause first dose syncope, so are generally started
at bedtime and slowly titrated up in dose. They may cause fluid retention and
edema. The ALLHAT study showed a 25% increase in cardiac events in the
doxazosin vs. chlorthalidone group. Centrally-acting alpha-2 agonists are less
often used due to their side-effects. They have no evidence of outcome benefit.
Methyldopa remains a first line agent in pregnancy.
Direct vasodilators. Direct vasodilators induce reflex tachycardia and thus
should be combined with a beta blocker or non-dihydropyridine calcium
channel blocker. Due to increased fluid retention, they should also be
combined with a diuretic.
Hydralazine may produce a lupus erythematosus-like syndrome; the syndrome
is extremely rare when the daily dose is less than 200 mg. Side effects include
headache, palpitations, anorexia, and nausea. At least twice daily dosing
requirements limit the usefulness of this drug. Hydralazine has shown benefit
in CHF when combined with a nitrate.
Minoxidil is effective in treating the severest forms of hypertension, although
it is used less frequently today because ACE inhibitors and calcium channel
blockers may be as effective. Side effects include hypertrichosis and fluid
accumulation in serous cavities, including the pericardium.
 The main complications of HTN:
- Coronary heart disease caused by atherosclerosis and/or
impairment of coronary microcirculation
- Heart failure caused by Diastolic and/or systolic dysfunction
Cerebrovascular impairment:
- Hemorrhagic stroke
- Atheroembolic (thrombotic) stroke
-Lacunar Infarct
- Hypertensive encephalopathy
Kidney impairment:
- Nephroangiosclerosis
- Kidney failure
The great vessels impairment:
-Dissection
- Aneurysm
- Atherothrombotic accidents