A Triple Fixed Dose Combination of Olmesartan Medoxomil, Amlodipine and Hydrochlorothiazide To Treat Hypertension

A Triple Fixed Dose Combination of Olmesartan Medoxomil,
Amlodipine and Hydrochlorothiazide to Treat Hypertension
A dissertation submitted in the Department of Pharmaceutical Sciences, North South

University, in partial fulfillment of the requirements for the degree of Masters in Pharmacology
& Clinical Pharmacy.
Non-Thesis Report
Supervised by
Dr. Murad Hossain
Assistant Professor
Submitted by
Md. Fazlur Rahman
ID # 1612320072
Department of Pharmaceutical Sciences

North South University
A Triple Fixed Dose Combination of Antihypertensive drugs (olmesartan medoxomil, amlodipine

and hydrochlorothiazide) to Treat Hypertension Page 1
NON THESIS CERTIFICATE
This is to certified that the non-thesis entitled “A Triple Fixed Dose Combination of
Olmesartanmedoxomil, Amlodipine and Hydrochlorothiazide to treat Hypertension”
submitted to the department of pharmaceutical sciences, North South University in partial
fulfillment of the requirements for the award of the degree of masters in degree Pharmacology
and Clinical pharmacy is a complete record of original research work carried out by Md. Fazlur
Rahman, (ID#1612320072) during the period of 2018 of his non thesis report in the department
of pharmaceutical sciences at North south University, under my supervision and guidance.
Honorable supervisor
Dr. Murad Hossain

Assistant professor
Department of pharmaceutical sciences

Master of Pharmacy (Non-Thesis)
Approval
We, the members of the Non-Thesis Evaluation Committee have carefully evaluated the
following assignment and approved.
“A Triple Fixed Dose Combination of Olmesartanmedoxomil, Amlodipine and

Hydrochlorothiazide to treat Hypertension”
Submitted by Md. Fazlur Rahman, ID # 1612320072 for partial fulfillment of the requirements
of the degree of Master of Pharmacy.
………………………………………………………
Dr. Hasan Mahmud Reza
Chairman
……………………………………………………… ……………………………………………………
Dr. Murad Hossain Dr. Asim kumar Bepari
Assistant Professor Assistant Professor
Department of Pharmaceutical Sciences Department of Pharmaceutical Sciences
……………………………………………………… ……………………………………………………
Dr. Hasanuzzaman Shohag Dr. Nasrin Akhter
Assistant Professor Senior Lecturer
Department of Pharmaceutical Sciences Department of Pharmaceutical Sciences

Declaration
I do hereby declare that the non-thesis paper entitled “A Triple Fixed Dose Combination of
Olmesartanmedoxomil, Amlodipine and Hydrochlorothiazide to treat Hypertension”
presented to Department of Pharmaceutical Science, North South University, is the outcome of
the study performed by me under the supervision of Dr. Murad Hossain, Assistant Professor of
Department of Pharmaceutical Science of North South University. I also declare that no part of
this report has been or is being submitted elsewhere for the award of any degree.
Submitted by
Name: Md. Fazlur Rahman
ID: 1612320072

Acknowledgement
It was really a great experience to do this non-thesis work. Thanks to Almighty that he has given
me the opportunity to complete this work under the supervision of Dr. Murad Hossain, Assistant
Professor, Department of Pharmaceutical Sciences, and North South University.
I express my profound gratitude and deep respect to my supervisor Dr. Murad Hossain for his
expert and careful guidance, sincere help, constructive criticism, valuable time and honored
suggestion, who guided me in this assignment, without which I would not have been able to
complete this work.
I am grateful to Dr. Hasan Mahmud Reza, Professor & Chairman, Department of Pharmaceutical
Sciences, North South University for his cooperation and valuable suggestions. My gratefulness
and thanks to all of my respected teachers of the Department of Pharmaceutical Sciences, North
South University for their care and guidance.
Finally, I express my heartiest thanks to my family members, who are the inspiration of my
work, my friends and well-wishers for their nice co-operation that helped me to complete my
work.
Name: Md. Fazlur Rahman

ID: 1612320072
(Examinee)

Table of Contents
No. Title Page No.

1 1.1. Overview of Hypertenion 03
1.1.1. Ranges of blood pressure 04
1.1.2. Types of blood pressure 04
1.1.3. fast fact on hypertension 04-05
1.1.4. sign of hypertension 05
1.1.5. symptom of hypertension 05
1.1.6. hypertensive crisis 05
2 2.1. risk factor of hypertension 06
2.1.1. complications of hypertension 07-08
2.1.2. Pathophysiology of hypertension 08-09
2.2. diabetes and hypertension 09
2.2.1. hypertension in pregnancy and breast feeding 09
2.2.2. heart failure with hypertension 09
2.2.3. chronic renal failure with hypertension 10
3 3.1.Diagnosis of hypertension 10
3.1.1.Blood pressure measurement 10
3.1.2. Prognosis of hypertension 10
4 4.1. Treatment of hypertension 11-12
4.2. why combination drug therapy is needed 12
4.3. target combination therapy 13
5 5.1. treatment with Omdizide 13-26
5.1.1. introduction 14-16
5.1.2. M/A of omdizide 16-19
6 6.1. Methods 22-24
6.1.1. Results 24-30
6.1.5. safety 30-32
7 7.1. Warnings and precautions
32
7.2. Drug interaction 32-33
8 8.1. Discussion 33-34
9 9.1. Summery 35
10 10.1. Conclusion 36
11 11.1. Referances 36-39

List of Figures
List Name of figure Page

Figure 01 Causes of hypertension 06
Figure 02 Complications of hypertension 08
Figure 03 Mechanism of Action of Olmesartan medoxomil 17
Figure 04 Mechanism of Action of Amlodipine 18
Figure 05 Mechanism of Action of Hydrochlorothiazide 19
Figure 06 Study design for 12 week double blind treatment period. 23
Figure 07 Frequency distribution in Se-SBP at week 12 from baseline (last 25
observation carried forward) by treatment.
Figure 08 Mean baseline and week 12 Se-SBP (last observation carried forward) by 26
treatment.
Figure 09 Proportion of participants achieving a Se-SBP target of <140 mmHg at 27
week 12 (last observation carried forward).
Figure 10 Proportion of participants achieving a Se-BP target of <140/90 mmHg at 28
week 12 (last observation carried forward).
Figure 11 Mean Ambulatory Systolic Blood Pressure at Endpoint by Treatment and 29
Hour
Figure 12 Mean Ambulatory Diastolic Blood Pressure at Endpoint by Treatment 30
and Hour
List of Table
List Name of Table Page

Table 01 Ranges of blood pressure 05
Table 02 Tests involved in diagnosis of hypertension 10
Table 03 commonly available antihypertensive combination drugs 13
Table 04 Dosage form and strength of Omdizide 21
Table 05 Study participants with TEAEs by treatment and 31
categorical Se-SBP reduction

1.1. Overview of Hypertension
Hypertension is another name for high blood pressure. It causes severe complications and
increases the risk of heart disease, stroke, and death.
Hypertension is the most general case in which the long-term force of the blood against artery
walls is enough high that it may ultimately lead to health problems, for example heart disease.
Recent analysis have displayed that in the year 2000, worldwide 972 million people living with
hypertension, and it is estimated that this number will expand to more than 1.56 billion in the
year of 2025.
Blood pressure is determined by the total amount of blood heart pumps and the amount of
resistance to blood flow in arteries. The more blood the heart pumps and the arteries narrow
more, ultimately increase blood pressure.
Blood pressure is exhibited by two measurements, the systolic and diastolic pressures that mean
the maximum and minimum pressures, respectively. In case of maximum adults, normal blood
pressure is within the range and that is 100–130 (mmHg) systolic pressures and 60–80 (mmHg)
diastolic pressure. In most of cases of adults, high blood pressure is exhibit if the resting blood
pressure is persistent at or over 130/90 or 140/90 (mmHg). Different things happen in case of
children. Ambulatory blood pressure monitoring over a 24-hour period shows more accurate than
office-based blood pressure measurement [1].
One can have high blood pressure (hypertension) for years without any sign and symptoms.
Although without symptoms, damage to blood vessels and heart continues that can be identified.
Unmanaged high blood pressure leads to risk of serious health problems, including stroke and
heart attack.
Hypertension generally develops for many years and it affects nearly everyone ultimately.
Blood pressure is the force exerted by the blood against the walls of the blood vessels. The
pressure depends on the work being done by the heart and the resistance of the blood vessels.
Hypertension is more general in men than women in the middle-age, around 45 years, with
women that cached up the age after 65. Worryingly, children’s are also becoming hypertensive
for many of the same causes like as adults – physical inactivity, unhealthy diet, and obesity.
Although it is general in the economically developed and developing countries and regions,
majority of people in developing countries can’t go diagnosed, and miss out on treatment.
Medical guidelines termed hypertension as a blood pressure higher than 130 over 80 (mmHg),
according to the American Heart Association (AHA) guidelines issued in November 2017 [2].

1.1.1. Ranges of Blood Pressure [3]
The following ranges of blood pressure define by The AHA 2017 guidelines:
Categories Systolic (mmHg) Diastolic (mmHg)

Normal blood Less than 120 Less than 80
pressure
Elevated Between 120 and 129 Less than 80
Stage 1 hypertension Between 130 and 139 Between 80 and 89
Stage 2 hypertension At least 140 At least 90
Hypertensive crisis Over 180 Over 120
Table 01: Ranges of blood pressure
1.1.2. Types of hypertension

Hypertension that isn’t caused by another case or disease is called primary or essential
hypertension. When it occurs as circumstances of another condition, it’s termed as secondary
hypertension.
1.1.2.1. Primary hypertension:
 Chronic high blood pressure without associated any other disease.

 Primary hypertension is the most general form of hypertension, approximately 90-95% of
cases is primary hypertension.
1.1.2.2. Secondary hypertension:
 Hypertension that may have specific additional signs and symptoms may recommend as
secondary hypertension, i.e. hypertension due to a traceable cause. For example,
 Cushing's syndrome.
 Obstructive sleep apnea.
 Kidney problems.
 Adrenal gland tumors.
 Thyroid problems.
 Certain defects, like born with (congenital) in blood vessels
 Certain medications, such as cold remedies, birth control pills, , decongestants,
over-the-counter pain relievers and some other prescription drugs [4]
1.1.3. Fast facts on hypertension:

Here are some key points about hypertension:
 Normal blood pressure is systolic 120 over diastolic (mmHg), but hypertension is defined
as higher than 130 (mmHg) over 80 (mmHg).

 High blood pressure has acute causes like stress, it also can happen on its own, or it
resulted from a core condition, for example kidney disease.
 Unmanaged hypertension can causes heart attack, stroke, and other problems.
 To address high blood pressure life style modification is the best way. [5]
1.1.4. Signs
 Having high blood pressure for a short time is a normal response to many situations.
Acute stress and intense exercise, for example, elevated blood pressure in a healthy
person.
That’s why; diagnosis of high blood pressure is required for a number of readings that
show high blood pressure over time.
 When the reading shows a hypertensive crisis in case of taking blood pressure, wait 2 or
3 minutes and after that repeating test.
 When the reading is the same or higher, that means a medical emergency.
 So, the person need immediate attention at the nearest hospital.[6]
1.1.5. Symptoms
 A person with hypertension may not notice any symptoms, even if blood pressure
readings reach dangerously high levels. Often hypertension is called the "silent killer."
While it remains undetected, it can cause severe complication like damage to the
cardiovascular system and some internal organs, such as the kidneys.
 Fewer people with hypertension may appear shortness of breath, headaches, or
nosebleeds.
 Hypertension may also produce anxiety, sweating, sleeping problems, and blushing.
Though, in many cases, there will absence of symptoms at all.
 When blood pressure reaches at the stage of a hypertensive crisis, a person may
experience headaches and nosebleeds.[7]
1.1.6. Hypertensive crisis
Severely raised blood pressure (equals to or higher than systolic 180 mmHg and diastolic 100
mmHg) is definite as a hypertensive crisis. Hypertensive urgency or hypertensive emergency are
two classification of Hypertensive crisis, in accordance with the presence or of end organ damage,
correspondingly.
In case of hypertensive urgency, the absence of end organ damage can cause elevated blood
pressure. In these cases, to lower the blood pressure gradually over 24 to 48 hours oral
medications are used.
In case of hypertensive emergency, there is one or more organs found to damage. The most
affected organs include the kidney, brain, heart and lungs, producing symptoms which may lead
chest pain, confusion, drowsiness, and breathlessness. In that case of hypertensive emergency,
the blood pressure must be controlled as soon as possible to prevent organ damage. [8]

2.1. Risk factors of hypertension
High blood pressure has many risk factors, including:
 Age: As increases as age the risk of hypertension is increases. Hypertension is more

general in men than women until at the age 64. After the age of 65 women are more
likely to develop hypertension.
 Race: Hypertension is more general in African heritage than others. Sometimes its
develop at earlier than happens in white. Severe complications included stroke, heart
attack and kidney failure which are also more general in African heritage people.
 Family history: Hypertension has tended to run in family members.
 Being overweight or obese: The more ones obese the more blood ones need to deliver
nutrients and oxygen to tissues. Thus the more the blood volume circulated through blood
vessels the more pressure observes on artery walls.
 Not being physically active: Inactive people tend to have higher heart rates. The higher
the heart rate, the harder the heart works in each contraction and the stronger the force on
ones arteries. Lack of physical activity also raises the risk hypertension.
Figure 01: Causes of hypertension
 Using tobacco: Smoking or chewing tobacco at once raises ones blood pressure
temporarily. The chemicals in tobacco can hamper the inside layer of one’s artery walls.
This causes ones arteries to narrow and also raises the risk of heart disease. Furthermore
secondhand smoke can also raise heart disease risk.
 Taking too much salt (sodium) in diet: Taking a lot of Na+ in the diet can cause to
retain fluid in the body, which increases the blood pressure.

 Taking to slight potassium in diet: Potassium helps balance the amount of Na+ in ones
cells. If enough potassium is not present in ones diet or retain enough potassium, it can
accumulate the amount of Na+ in their blood.
 Drinking large amount of alcohol: Too much, heavy drinking can damage ones heart.
Having too much drunk a day for women and men may affect ones blood pressure.
 Stress: Too much stress causes hypertension.
 Specific chronic conditions: Some chronic conditions also may raises the risk of
hypertension, that are kidney disease, diabetes and sleep apnea.[9]
Other factors that contributed include:
 Lack of activity.
 Taking salt-rich diet associated with fatty foods.
 Low quantity of potassium in the diet.
 Alcohol and tobacco using. [10]
2.1.1. Complications of hypertension

Hypertension may happen due to Too much pressure on artery walls that can harm blood vessels,
as well as organs in body. The more persistent the hypertension, it longer it goes to uncontrolled
and the damage go to greater.
Uncontrolled hypertension can lead to several complications, including:
 Heart attack or stroke: Hypertension can lead to hardening and thickening of the
arteries, which causes heart attack, stroke or other complications.
 Aneurysm: Hypertension can cause weak of blood vessel and bulge, formed an
aneurysm. It will be life threatening when aneurysm ruptures.
 Heart failure: The more the blood pump against the arteries, it will too hard for heart to
work. These causes thicken of the walls of the heart's pumping chamber (which called
left ventricular hypertrophy). Eventually, the thickened muscle to work harder to pump
enough blood to meet ones body's need that can cause to heart-failure.
 Weakening and narrowing of kidneys blood vessel: That can inhibit the organs from
normally functioning.
 Thickening, narrowing or torn of blood vessels in the eyes: This can causes in loss of
vision.

Figure 02: Complications of hypertension
 Metabolic syndrome: Metabolic syndrome is a huddle of body's metabolism disorders,

including waist circumference increased, high triglycerides, and high-density lipoprotein
(HDL) cholesterol also called good cholesterol, and high blood pressure and high insulin
levels. These conditions make ones more likely to develop heart disease, diabetes, and
stroke.
 Difficulty with memory or understanding: Uncontrolled hypertension may also affect
one’s capability to imagine, memorize and be taught. Difficulty with remembrance or
considerate something is more general in people with hypertension.
 Dementia: Narrowed arteries and arteries blocked decrease blood-flow to the brain,
causes to a certain type of dementia. A stroke that interrupts blood-flow to the brain also
causes to vascular dementia.[11]
2.1.2. Pathophysiology of hypertension
To characterize the effect of hypertension can be illustrated by determinants of mean arterial

pressure.
People who have established essential hypertension, blood flow resistance is increased which is
called total peripheral resistance or TPR. It is facts that those younger people have pre-
hypertension or 'borderline hypertension' may have high cardiac output, a prominent heart rate
and normal peripheral resistance. It is called hyperkinetic borderline hypertension. These

individuals develop some characteristic features of established essential hypertension in later life
as their cardiac output falls and peripheral resistance raises with age [12]. In establish
hypertension the increased peripheral resistance is mainly attributable to structural narrowing of
small arteries and arterioles, although the number or density of capillaries may also contribute is
decrease.
About 0.2% to 3% of newborns are suffered from hypertension. However, in case healthy
newborns hypertension is not measured routinely. In newborns there is a high risk of
hypertension. A variety of factors, such as gestational age, post-conception age and birth weight
needs to be aware when deciding if a blood pressure is normal in a newborn [13].
2.2. Diabetes and high blood pressure
About 25% of people of Type 1 diabetes and 80% of people of Type 2 diabetes have high blood
pressure. The American Diabetes Association's (ADA's 2016) standards of medical care in
diabetes indicate that a majority number of patients who have diabetes mellitus have
hypertension. In case of type 1 diabetes, nephropathy is often the cause of hypertension whereas
in type 2 diabetes, hypertension is one of a group of related cardio metabolic factors.
Hypertension is one of the major causes of congestive heart failure (CHF). To significantly
reduce the risk of death from CHF, antihypertensive therapy produces a greater extent of positive
result.
In case of diabetes raises the risk of heart disease, stroke, kidney disease and other health
problems. Having hypertension also increases this risk. If ones have diabetes and high blood
pressure both, this accumulates the health problems risk and even more.
People who have diabetes and high blood pressure are often taking ACE inhibitors or angiotensin
receptor blockers. [14]
2.2.1. Hypertension in Pregnancy and Breast feeding:
Hypertension complicates in all pregnancies about (5 to 7) %. In case of pregnant patient, the

antihypertensive treatment goal is to reduce the risk of maternal cardiovascular or
cerebrovascular proceedings. Hypertensive disorders categorized as preeclampsia, chronic
hypertension, gestational hypertension, chronic hypertension, and transient hypertension may
add to maternal, fetal, or neonatal morbidity and mortality, particularly in the 1st trimester and is
a marker for future cardiac and metabolic disease. [15]
2.2.2. Heart failure with hypertension:
Treatment of hypertension in patients with heart failure must take into account the type of heart
failure, systolic dysfunction or diastolic dysfunction, in which there is a condition to diastolic
filing and therefore in forward output due to raised ventricular stiffness. To managing
hypertension as well as heart failure, antihypertensive drugs are indicated to reduce morbidity
and mortality. [16]

2.2.3. Chronic renal failure with hypertension:
Hypertension can caused by chronic kidney disease but itself can worst the renal failure. The
guideline states that the hypertension management in CKD should focus on reduction of BP,
with some also emphasizing decreasing protein excretion. [17]
3.1. Diagnosis of Hypertension
Diagnosis: to diagnose hypertension should focus on persistently high resting blood pressure.
There are three measurements of separate resting sphygmomanometer at monthly intervals
suggested by The National Institute of Clinical Excellence. Three resting measurements on at
least two separate health care visits at least recommends by The AHA.
Typical tests performed[18]

System Tests
Kidney Protein in the urine, Microscopic Urinalysis, BUN and or Creatinine
Endocrine TSH, Serum Sodium, Calcium and Potassium,
Metabolic HDL, LDL, Fasting Blood Glucose, & Total Cholesterol, Triglycerides
Other Electrocardiogram, Hematocrit, , & Chest Radiograph
Table 02: Tests involved in diagnosis of hypertension
3.1.1. Blood pressure measurement
To diagnose hypertension there have two or three measurement that done two or three different
times.
 First of all patient should be seated in a chair about five minor more, feet on floor and
back supported.
 Secondly removal of cloth at the area of cuff placement and with the support of the limb
at the heart level.
 Third at least 30 minutes smoking, caffeine and exercise are prohibited.
For the first time visiting measurement of blood pressure done in both arms which gave the
higher reading.
The upper arms are tied by an appropriately sized BP cuff. This appropriately sized cuff bound
2/3rd of the biceps. 80% of the arm is surrounding by the bladder, and the width of bladder is
equals to 40% of the arm’s perimeter. That’s why large cuff is needed for obese patient. The cuff
is inflated above the estimated systolic pressure by the practitioner and after listening of brachial
artery the air should be gradually release. When the first heartbeat is heard due to pressure falls is
called systolic blood pressure. Diastolic blood pressure is identified when the sound is totally
vanished. The same methods are applied to measure blood pressure in a thigh and radial artery
(named as popliteal artery). Calibrated Mechanical devices should be used because sometimes
automated readers are gave wrong result.

BP measurement in both arms: when one arm have 15 (mmHg) higher BP than the others, is
connected to high mortality, in that case upper vasculature evaluation is required.
BP measurement in a thigh: In thigh BP is significantly lower than the arm.
When the blood pressure is found in stage 1 which means this is markedly labile, the
measurement of BP is desired. The measurements of BP may be at irregular intervals high before
hypertension goes too sustained; this occurrence is named for white coat hypertension, in which
at the physicians office the patients BP is elevated when measured but at home it runs out to
normal. Though, tremendous BP increasing alternated with normal readings is strange and
perhaps suggest pheochromocytoma, which means sleep disorder such as sleep apnea, or
unacknowledged drug use. [19]
3.1.2. Prognosis of hypertension
Prognosis means the worse, the more increase the blood pressure can cause the retinal changes
more and involvement of target organs. Systolic blood pressure is more harmful and risk of fatal
and nonfatal development than diastolic blood pressure. In case of retinal sclerosis, arteriolar
narrowing, hemorrhage and cotton wool exudates the 1 year survival rate without treatment is
less than 10 % and less than 5% in patients with the same cases plus papilledema. The main
reason for treated death hypertensive patient, Coronary Artery Disease (CAD) is the main. As a
result of inadequately treated hypertension ischemic or hemorrhagic stroke is occurring.
However, effective control of hypertension prevents most complications and prolongs life.
4.1. Treatment of hypertension
Treatment option for hypertension is Lifestyle modification and medication.

4.1.1. Lifestyle changes:
To prevent high blood pressure modification of life style must be change. And these are the
starting of hypertension management. The risk factors for cardiovascular disease is vary from
individual to individual with hypertension. That’s why more attention should pay the lifestyle
changes that favorably affect on blood pressure reduction. A very little reduction of blood
pressure incredibly affect in cardiovascular disease. Reduction for 2 mmHg of blood pressure
can reduce the risk of CAD about 6% and stroke by 15%. To check blood pressure, regular
health check up is necessary. Diet is the best way to regulate blood pressure before it reaches the
stage of hypertension. Here some treatment options are given below:
 Eat healthy foods.

 Decrease the salt intake in diet.
 Maintain a healthy weight.
 Increase physical activity.
 Limit alcohol.
 Manage stress.

4.1.2. Treatment with Medication:
Many different classes of drugs are used to treat high blood pressure. The most common are:
 Diuretics - these promote the production of urine, which removes excess fluid from the
bloodstream. Also reduces the volume of blood inthe circulatory system, and blood
pressure.
 Thiazide diuretics: chlorothiazide, hydrochloro thiazide

 Loop diuretics: frusemide, bumetanide
 Potassium sparing diuretics: spironolactone, eplerenone
 Carbonic anhydrase inhibitors: acetazolamide
 Osmotic diuretics: mannitol
 Beta-blockers – It causes heart beat slower and with less force, and your blood vessels
open up. It can reduce blood pressure, and improves blood flow. E.g. atenolol, carvedilol,
propranolol.
 Angiotensin-converting enzyme inhibitors, (ACE inhibitors) - these block the action

of angiotensin hormone that causes blood vessels to constrict and thickening and
stiffening the walls of blood vessels and heart, as well as triggering the release of another
hormone that increases the amount of sodium and water in body. Together, this has the
effect of blood pressure lowering. E.g. quinapril, ramipril, fosinopril, lisinopril
 Angiotensin II receptor blockers - It affects same biochemical pathways as ACE
inhibitors, for similar effects. E.g. valsartan, olmesartan.
 Alpha blockers - it blocks the action of hormones that trigger vasoconstriction of the
smaller arteries and veins, improving blood flow and lowering blood pressure. e.g.
prazosin, doxazosin
 Calcium channel blockers - these can relax and widen blood vessels by preventing
calcium from entering heart cells and the muscle cells within the blood vessel walls. E.g.
amlodipine, dilitazem, felodipine
 Combination of drug therapy. [20]
4.2. Why combination drug therapy is needed?

 Meticulous control of blood pressure is needed in hypertension to produce the maximum
reduction in clinical cardiovascular end points, especially in patients with co-morbidities
like diabetics mellitus, where more aggressive blood pressure lowering might be
beneficial. Recent clinical trials suggest that the approach of using mono-therapy for
control of hypertension is not likely to be successful in most patients. The first choice of
treating essential hypertension by monotherapy is effectively lower the blood pressure in
limited case. Thus, the combination therapy is to choose for both improve BP control and
reduce cardiovascular events. The combination of antihypertensive drugs can produce
different complementary mechanism to lower blood pressure. This is vital without
tolerability obtain additive BP-lowering effects [21].

Some of the commonly available combination of antihypertensive drugs is:
Combinations Fixed dose combination examples

Irbesartan/HCTZ
Losartan/HCTZ
ARB-Diuretic
Telmisartan/HCTZ
Valsartan/HCTZ
Metoprolol/HCTZ
Beta adrenoceptor antagonist- Diuretics Propanolol/HCTZ
Atenolol/Chlorotalidone
Captopril/HCTZ
ACEI-Diuretic Enalapril/HCTZ
Lisinopril/HCTZ
ACEI-CCB Benazepril/Amlodipine
Amlodipine/Olmesartanmedoxomil
ARB-CCB Amlodipine /Valsartan
Amlodipine/Telmisartan
ACEIs-ARB inhibitors Ramipril/Telmisaratan
Table 03: commonly available combination of antihypertensive drugs
4.3. Targeted combination therapy:
Historically, assessments of cardiovascular risk have focused on elevated diastolic BP (DBP).

However, DBP tends to reduce after 50 years age, whereas systolic BP (SBP) continuously
increases throughout life. In a recent analysis of data from the National Health and Nutrition
Examination Survey, the mean systolic BP (SBP) increased with advancing age from 115 mmHg
(ages 18–39 years) to 123 mmHg (ages 40–59 years) to 136 mmHg (age ≥60 years). In contrast,
mean DBP rose from 69 mmHg to 75 mmHg as increased age from 18–39 years to 40–59 years,
but then drop to 68 mmHg as age increase to ≥60 years. Thus, systolic hypertension increases in
prevalence with age, and it’s becoming the most common form of hypertension after 50 years
age.
In those cases, mono-therapy and double combination of treatment may not well control of
elevated hypertension. That’s why, a new combination form of triple combination of
antihypertensive drugs ( Olmesartanmedoxomil, Amlodipine and Hydrochlorothiazide ) is
preferred. [22]

5.1. Treatment with OMDIZIDE
A triple fixed combination of OlmesartamMedoxomil (OLM), Amlodipine (AML) &
Hydrochlorothiazide (HCTZ)
This product is tending to treat high blood pressure (hypertension). Lowering the blood pressure
helps to prevent heart disease, strokes, heart attacks, and kidney problems.
Omdizide contains 3 medications: olmesartan, amlodipine, and hydrochlorothiazide. Olmesartan

(OLM) is an angiotensin receptor blocker (ARB) and amlodipine is a calcium channel blocker
(CCB) & Hydrochlorothiazide (HCTZ) is a diuretic that directly promote the excreation of Na+
and Cl- in the kidney that may lead to reduction of intravascular volume. The three works by
relaxing blood vessels so blood can flow more easily.
5.1.1. Introduction
Hypertension or high blood pressure is one of the major causes of death worldwide. I the Recent
analysis of the year 2000, there was found 972 million people who living with hypertension
In the world, and it’s estimated that this number will escalate to over 1.56 billion this year 2025.
In Bangladesh approximately 20% of adult and 40% of elderly people suffer from hypertension.
According to NCD (Non Communicable Disease) risk factor survey, 1/3 of all Bangladeshi
population has never measured their blood pressure. Approximately 33% of adults in the United
States (representing 78 million adults) have hypertension, one of the most prevailing risk factors
for development of cardiovascular disease [23]. Here the risks of ischemic heart disease, heart
failure, stroke, and kidney disease have all been shown to interact directly with raising of blood
pressure (BP).
Historically, assessment of cardiovascular risk has paying attention on increase diastolic BP

(DBP) [24]. However, DBP have tendency to decrease after 50 years age, whereas systolic BP
(SBP) continuously increase throughout life [25].In a recent analysis of the NHNES (National
Health and Nutrition Examination Survey), shows that the mean SBP (systolic BP) increased
with advancing age from {115 mmHg (ages 18–39 years) to 123 mmHg (ages 40–59 years) to
136 mmHg (age ≥60 years)}. In difference, the mean DBP rose from 69 (mmHg) to 75 (mmHg)
as age increased from 18–39 years to 40–59 years, but after that it drops to 68 (mmHg) as age
further increased to more or equal to 60 years [26] .Thus, systolic hypertension increases in
prevalence with age, becoming the most common form of hypertension after 50 years age. [27]
Despite these data, systolic hypertension is frequently less well controlled than diastolic
hypertension. After 3 years of therapy in the antihypertensive and lipid-lowering treatment to
prevent heart attack trial, only 64% of patients had their SBP adequately controlled compared
with 90% who had controlled their DBP adequately. [28]

The primary study results for the Triple Therapy with olmesartan medoxomil (OM) 40 mg,
amlodipine besylate (AML) 10 mg, and hydrochlorothiazide (HCTZ) 25 mg reduced both seated
DBP and seated SBP (Se-SBP) to a greater extent and enabled a larger proportion of study
participants to reach BP goal than all three component dual-combination treatments [29]. Here the
report of the unique results of a prespecified TRINITY analysis that evaluated categorical mean
reductions in Se-SBP with OM 40/AML 10/HCTZ 25 mg compared with each of the component
dual-combination treatments.
The active ingredient of omdizide, target three separate mechanisms is involving regulation of
blood pressure. Especially amlodipine blocks the contractile effect of calcium on cardiac and
vascular smooth muscle cell. Olmesartan medoxomil blocks the vasoconstriction and sodium
retaining effects of angiotensin 2 on cardiac, vascular smooth muscle, adrenal and renal cells and
Hydrochlorothiazide is called a "water pill" (diuretic), causes body to get rid of extra salt and
water by making more urine.
Olmesartanmedoxomoil:
The structural formula for olmesartanmedoxomil is:
Appearance : white to light yellowish-white powder or crystalline powder

Molecular Weight : 558.6
Amlodipine: The structural formula for amlodipine besylate is:
Appearance : white to off-white crystalline powder


Hydrochlorothiazide: The structural formula for hydrochlorothiazide is:
Appearance : white or practically white, crystalline powder

5.1.2. Mechanism of Action of OMDIZIDE

Omdizide contains olmesartan, amlodipine and hydrochlorothiazide that target three different
mechanismto regulates blood pressure. Amlodipine blocks the contractile effects of Ca2+ on
cardiac muscle cells and vascular smooth muscle cells. Olmesartan medoxomil acts on blocking
the vasoconstriction effect and sodium retaining effects of angiotensin II on cardiac muscle,
vascular smooth muscle, adrenal and renal cells. Hydrochlorothiazide promotes directly the
excretion of Na+ and Cl- in the kidney leading to reductions in intravascular volume.

Mechanism of action of Olmesartan medoxomil:
Angiotensinogen
Renin
Angiotensin 1
ACE
Angiotensin 2
OLM
AT1 receptor AT2 receptor
Vasodilation
BP
Figure 03: Mechanism of Action of Olmesartan medoxomil
Olmesartan medoxomil acts on blocking the vasoconstriction effect and sodium retaining effects
of angiotensin II on cardiac muscle, vascular smooth muscle, adrenal and renal cells.
Angiotensin II which is formed from angiotensin I by a reaction catalyzed ACE kininase II. This
Angiotensin II is the principal pressor agent of the renin-angiotensin system, which may effects
on vasoconstriction, stimulation of synthesis and release of aldosterone, stimulation of cardiac
muscle, and renal reabsorption of sodium. Olmesartan acts on At1 receptor by binding these
receptor it selectively blocking the binding site of angiotensine 2 in vascular muscle. [30]

Mechanism of action of Amlodipine:
Ca2+
CCB
L-Type Ca2+ Channel
Arterial Vasodilation
PVR Afterload
BP
Figure 04: Mechanism of Action of Amlodipine
Amlodipine is a dihydropyridine, calcium channel blocker that acts to inhibition of

transmembrane influx of Ca2+ in vascular muscle cells. Experimental data exhibit that
amlodipine bids with dihydrpyridine and non-dihydropyridine binding sites both. Amlodipine is
a calcium channel blocker that inhibits the calcium ions movement into vascular smooth muscle
cells and cardiac muscle cells and inhibition the contractile effect of of cardiac muscle and
vascular smooth muscle cells. Normally amlodipine directly inhibits Ca2+ ion influx across cell
membranes, and produce a great effect cells. Ultimately this causes vasodilation, reduction
peripheral vascular resistance, thus lowering blood pressure. It also effects on cardiac muscle to
prevent excessive constriction in the coronary arteries. [31]

Mechanism of action of Hydrochlorothiazide:
Na+/Cl-
HCTZ
Co-transport in DCT
Na+/Cl- excreation
BP
Figure 05: Mechanism of Action of Hydrochlorothiazide
Hydrochlorothiazide is a class thiazide diuretic. Thiazides diuretics act on the renal tubule and
produce electrolyte reabsorption, excretion of sodium and chloride increasingly in approximately
equivalent amounts. The action of hydrochlorothiazide is to reduce plasma volume and
consequent elavation in activity of plasma renin, aldosterone secreation increase, increases in
loss of urinary potassium, and decreases in serum potassium. [32]
5.2.1. Pharmacodynamics of Omdizide

Omdizide has been shown to be effective in BP lowering. Omdizide contains three componants
(olmesartan medoxomil, amlodipine, and hydrochlorothiazide) that lower the blood pressure
through complementary mechanisms, each componants working at a different site and blocking
different pathways. The pharmacodynamics of each individual component is described below.
Olmesartan medoxomil: The doses of olmesartan medoxomil are 2.5 to 40 mg, to inhibit the
pressor effects of angiotensin I infusion. The duration of the inhibitory effect was related to dose,
mmore than 90% inhibition can get at the dose of 40 mg
After administration of single and repeated dose of OLM increases plasma concentrations of
angiotensin I and angiotensin II and also increases plasma renin activity (PRA) to healthy
subjects and patients of hypertension. Repeated administration of up to 80 mg olmesartan
medoxomil had minimal influence on aldosterone levels and had no effect on serum potassium.
Amlodipine: Administration of following doses of amlodipine used to treat hypertension.

Amlodipine produces vasodilation effects, and as a result resulting reductionin blood pressure.

These decreases in blood pressure are not accompanied by a significant change in heart rate or
plasma catecholamine levels with chronic dosing.
Administration of once daily dose of amlodipine can manage blood pressure within 24 hours.. In
case of young and elder patient plasma concentration correlates. The height of pretreatment
elevation correlates with the degree of reduction in blood pressure with amlodipine. Thus,
individuals who have moderate hypertension diastolic pressure 105-114 (mmHg) had a great
response approximately 50% than mild hypertension patients with diastolic pressure (90-104
mmHg).
Amlodipine also decreases renal vascular resistance and thus increasing GFR (glomerular
filtration rate) and great effect on renal plasma flow without change of renal filtration rate or
proteinuria.
Amlodipine is also used to treat the hemodynamic measurements of cardiac function during
exercise in patients who have normal ventricular function which have generally a small increase
in cardiac index without significant influence on dP/dt or diastolic pressure or volume.
Amlodipine has not been producing a negative ionotropic effect in case hemodynamic, when
administered in intact animals and man in therapeutic dose range, same case happen when co-
administered with beta-blockers to man. Similar findings have been observed in normal or well-
compensated patients have heart failure with agents that produce significant negative inotropic
effects.
Hydrochlorothiazide: After oral administration of hydrochlorothiazide, its diuresis actions

begin within 2 hours and peak plasma obtained about 4 hours, and it lasts about 6 to 12 hours.
5.2.2. Pharmacokinetics of Omdizide

In case of healthy adults after oral administration of Omdizide, peak plasma concentrations of
olmesartan, amlodipine, and hydrochlorothiazide are obtained in about 1.5 to 3 hours, 6 to 8
hours and 1.5 to 2 hours. The rate and extent of absorption of olmesartan medoxomil,
amlodipine, and hydrochlorothiazide from Omdizide are the same as when administered as
individual dosage forms. There is no effect of food in the bioavailability of Omdizide.
Olmesartan medoxomil: Olmesartan medoxomil is a pro drug which can rapidly and completely
bioactivated by ester hydrolysis and form olmesartan during absorption from the GI tract.
Approximately 26% of bioavailability has appeared after oral administration of olmesartan
medoxomil. After 1 to 2 hours the peak plasma concentration of olmesartan medoxomil has
appeared. Food does not affect the bioavailability of olmesartan medoxomil.
Amlodipine: After oral administration of therapeutic dose of amlodipine the peak plasma
concentrations of amlodipine appears between 6 and 12 hours. Approximately 64% and 94% are
absolute bioavailability.

Hydrochlorothiazide: The plasma levels have been followed for at least 24 hours. The plasma
half-life of Hydrochlorothiazide has been observed to vary between 5.6 and 14.8 hours.
5.2.3. Dosage and Administration:

Once daily dose, Dosage may be increased in 2 weeks intervals, as needed. The maximum
recommended dose of Omdizide is 40/10/25 mg.
Dosage form and strength:
Omdizide Tablet is available in following combinations:
Medication 20/5/12.5 40/5/12.5 40/5/25 40/10/12.5 40/10/25

OmlesartanMedoxomil 20 40 40 40 40
Amlodipine 5 5 5 10 10
Hydrochlorothiazide 12.5 12.5 25 12.5 25
Table 04: Dosage form and strength of Omdizide

6.1. Methods
 Study population:
TRINITY was a 12-weeks, prospective, randomized, double-blind, and parallel-group evaluation
conducted on an outpatient basis. Individuals ≥18 years of age with a mean Se-BP ≥ 140/100
mmHg or ≥160/90 mmHg (off antihypertensive medication) were eligible for randomization
provided they did not have a recent (≤6 months) history of myocardial infarction, coronary
revascularization, or unstable angina.
 Study design:
The study design does for 3-week washout period for whom already taking antihypertensive
medications, followed by a 12-week double-blind treatment period (Figure 06) [33]. there were
taken randomized participants(stratified by age, race, and diabetes status) at the initial stage of
the study to treat a sequence that led to their final treatment assignment: either one of the three
component dual-combination treatments or the triple-combination treatment (OM 40 mg/AML
10 mg/HCTZ 25 mg [ fixed-dose combination], OM 40 mg/AML 10 mg [fixed-dose
combination], OM 40 mg/HCTZ 25 mg [fixed-dose combination], or AML 10 mg/HCTZ 25 mg
given separately). All participants received dual-combination treatment for 2 weeks, except for a
subset of 36 study participants who had not been taking antihypertensive medications for at least
3 weeks who received placebo for 2 weeks (to assess the study for non-treatment-associated BP
effects, some patients received placebo for 2 weeks). Until week 4 all participants are assigning
for dual combination treatment. Before assign to one of the three dual combination treatments for
2 to 4 weeks all participants must take placebo for 2 weeks. Participants were either maintained
on dual-combination treatment at 4 to week 12 or switched to triple-combination treatment with
OM 40 mg/AML 10 mg/HCTZ 25 mg until week 12. Participants were instructed to take all
medications at the same time (±2 hours) each day, and participants and investigators remained
blinded as to which drugs were being administered at any given time during the double-blind
treatment period.

Figure 06: Study design for 12 week double blind treatment period.
Efficacy assessments
The primary assessment for the present analysis was the distribution (or range) of Se-SBP
reductions at week 12 from baseline with triple-combination treatment compared with the
component dual-combination treatments. For this assessment, reductions in Se-SBP were
categorized as >50,>40 to ≤50,>30 to ≤40,>20 to ≤30,>10 to ≤20, and≤10 mmHg. Additional
assessments (post hoc analyses) included the least squares mean reduction in Se-SBP, the
proportion of participants achieving the Se-SBP target of <140 mmHg, and the proportion of
participants achieving the Se-BP target of <140/90 mmHg by treatment within each Se-SBP
reduction category.
Safety assessments
Safety was assessed at all visits. Safety parameters evaluated included adverse events, physical
examinations, twelve-lead electrocardiograms, and clinical laboratory tests. For this analysis,
safety parameters were categorized based on randomized treatment assignment and degree of Se-
SBP reduction (≤40 or >40 mmHg).
Statistical analysis
Efficacy was assessed in all study participants who had a baseline assessment of Se-BP, received
at least one dose of study medication, and had at least one post dose assessment of Se-BP. Safety

was assessed in all participants who received at least one dose of study medication at or beyond
the week 4 visit (i.e., the first time at which participants could receive triple-combination
treatment). Both efficacy and safety were categorized on the basis of the degree of Se-SBP
reduction at week 12.
Changes in Se-BP at week 12 were evaluated with an analysis of covariance model with baseline
Se-BP as a covariate and final randomized treatment, subgroup, and final randomized treatment
by subgroup interaction as fixed effects. Least squares mean differences and standard errors,
derived from this model, were used to calculate baseline changes in Se-BP; 2-sided P-values
were used to test the significance of these changes for study participants receiving triple-
combination treatment versus each dual-combination treatment.
6.1.1. Results
Study population
Of the 6724 individuals who were screened, 2492 were randomized and entered the double-blind
treatment period, and 2116 completed the trial. The safety population included 2302 participants.
The demographic and clinical characteristics at baseline by treatment assignment were similar
for randomized study participants. Overall, 52.9% of participants were male, 66.8% were white,
30.4% were black, 9.1% had chronic cardiovascular disease, 15.5% had diabetes, and 4.1% had
chronic kidney disease. Mean age (standard deviation [SD]) was 55.1 (10.9) years (18.9% ≥65
years), and mean body mass index (SD) was 33.1 (7.1) kg/m2 (62.4% ≥30 kg/m2). The mean
(SD) duration of hypertension was 9.9 (9.6) years, and mean baseline Se-BP was 168.5/100.9
mmHg. [34]
Efficacy
Triple-combination treatment resulted in greater Se-SBP reductions than the dual-combination

treatments (Figure 07). Se-SBP reductions of >50 mmHg were seen in 24.4% of participants
receiving OM 40 mg/AML 10 mg/HCTZ 25 mg, but in only 8.1%, 9.5%, and 15.8% of
participants receiving AML 10 mg/HCTZ 25 mg, OM 40 mg/AML 10 mg, and OM 40
mg/HCTZ 25 mg, respectively. Se-SBP reductions of >40 mmHg to ≤50 mmHg were seen in
23.0% of participants receiving triple-combination treatment compared with 14.2%–17.6% of
participants receiving dual-combination treatments. Se-SBP reductions of ≤20 mmHg were seen
in only 12.9% of participants receiving triple-combination treatment compared with 21.8%–
28.3% of participants receiving dual-combination treatments. As a result, the overall least
squares mean reduction in Se-SBP was significantly greater (−37.1 mmHg versus −27.5 mmHg
to −30.0 mmHg, respectively; P< 0.0001) [35],and the overall mean Se-BP was significantly
lower (129.8/79.4 mmHg versus 137.0/83.2 mmHg and 140.0/86.4 mmHg, respectively; P<

0.0001) at week 12 in participants receiving triple-combination treatment than in those receiving
dual-combination treatment.
Figure 07: Frequency distribution in Se-SBP at week 12 from baseline (last observation carried forward)
by treatment.
For a given categorical Se-SBP reduction, the baseline and week 12 Se-SBP levels were similar
across treatment groups (Figure 08). In general, the degree of Se-SBP reduction correlated with
baseline pressure (ie, the higher the Se-SBP at baseline, the greater the reduction at week 12).
The study participants who had the highest mean Se-SBP levels at baseline (176–188 mmHg,
depending on treatment) experienced the greatest therapeutic effect (lowest mean Se-SBP levels)
at week 12 (116–129 mmHg, depending on treatment).

Figure 08: Mean baseline and week 12 Se-SBP (last observation carried forward) by treatment.
Notes: Mean baseline and week 12 Se-SBP (last observation carried forward) by treatment
among participants with (A) ≤10 mmHg; (B) >10 mmHg and ≤20 mmHg; (C) >20 mmHg and
≤30 mmHg; (D) >30 mmHg and ≤40 mmHg; (E) >40 mmHg and ≤50 mmHg; and (F)>50

mmHg Se-SBP reduction from baseline. In (Figure 06) for the number of participants in each
category. Error bars depict the standard deviati on. *P< 0.05 for the least squares mean reduction
in Se-SBP, OM/AML/HCTZ versus dual-combination treatment.
Overall, triple-combination treatment was significantly more effective than the dual-combination
treatments in achieving the Se-SBP target of <140 mmHg (73.6% versus 51.3%–58.8%,
respectively) and the Se-BP target of <140/90 mmHg (69.9% versus 41.1%–53.4%, respectively)
at week 12 (P< 0.001 for all triple- versus dual-combination comparisons) [36] .The higher the
categorical Se-SBP reduction, the more the observed differentiation based on treatment potency,
and as a result, more participants with higher baseline BP had greater achievement of BP targets
(Figures 09 and Figures 10) particularly with Se-SBP reductions >30 mmHg.
Figure 09: Proportion of participants achieving a Se-SBP target of <140 mmHg at week 12 (last
observation carried forward).

Notes: Proportion of participants achieving a Se-SBP target of <140 mmHg at week 12 (last
observation carried forward) with a (A) ≤10 mmHg; (B) >10 mmHg and ≤20 mmHg; (C) >20
mmHg and ≤30 mmHg; (D) >30 mmHg and ≤40 mmHg; (E) >40 mmHg and ≤50 mmHg; and
(F) >50 mmHg Se-SBP reduction from baseline in (Figure 06) or the number of participants in
each category. *P< 0.05; †P ≤ 0.01; ‡P ≤ 0.001, OM/AML/HCTZ versus dual-combination
treatment.
Figure 10: Proportion of participants achieving a Se-BP target of <140/90 mmHg at week 12 (last
observation carried forward).

Notes: Proportion of participants achieving a Se-BP target of <140/90 mmHg at week 12 (last
observation carried forward) among participants with a (A) ≤10 mmHg; (B) >10 mmHg and ≤20
mmHg; (C) >20 mmHg and ≤30 mmHg; (D) >30 mmHg and ≤40 mmHg; (E) >40 mmHg and
≤50 mmHg; and (F) >50 mmHg Se-SBP reduction from baseline. In Figure 06 for the number of
participants in each category. *P< 0.05; †P< 0.0001; ‡P ≤ 0.01; §P ≤ 0.001, OM/AML/HCTZ
versus dual-combination treatment.
 Ambulatory Blood Pressure Monitoring:

A total of 440 patients participated in the ambulatory blood pressure monitoring portion of the
study. Over the 24-hour period, there was a greater reduction in systolic and diastolic ambulatory
blood pressure for olmesartan medoxomil/amlodipine/hydrochlorothiazide 40/10/25 mg
compared to each of the dual combination therapies[37] (given Figure 11 and Figure 12).
Figure 11: Mean Ambulatory Systolic Blood Pressure at Endpoint by Treatment and Hour

Figure 12: Mean Ambulatory Diastolic Blood Pressure at Endpoint by Treatment and Hour
6.1.2. Safety
The safety concerns of triple combination and dual combination treatment were identified. In that
case treatment emergent adverse event (TEAE) observes in total 1287/2302 study participants
and percentage about (55.9%) and drug-related TEAE observes in 585 participants (25.4%). In
severity most of the TEAE were mild to moderate. The prevalence and severity of adverse events
did not appear to be related to either treatment or the degree of categorical Se-SBP reduction [38]
(Table 05).

Table 05
Study participants with TEAEs by treatment and categorical Se-SBP reduction
Category OM40 mg/AML OM 40 AML 10 OM 40 mg/AML

10 mg mg/HCTZ 25 mg mg/HCTZ 25 mg 10 mg/HCTZ 25
mg
Se-SBP Se-SBP Se-SBP Se-SBP

reduction reduction reduction reduction
≤40 >40 ≤40 >40 ≤40 >40 ≤40 >40

mmHg mmHg mmHg mmHg mmHg mmHg mmHg mmHg
(n = (n = (n = (n = (n = (n = (n = (n =
435) 161) 392) 188) 426) 126) 288) 286)
All TEAEs* 226 82 213 106 251 74 162 173
(52.0) (50.9) (54.3) (56.4) (58.9) (58.7) (56.3) (60.5)
Severe 18 (4.1) 6 (3.7) 11 (2.8) 6 (3.2) 14 (3.3) 4 (3.2) 11 (3.8) 13 (4.5)
TEAEs
Drug-related 99 39 81 40 126 38 76 86
†
TEAEs (22.8) (24.2) (20.7) (21.3) (29.6) (30.2) (26.4) (30.1)
Drug-related 1 (0.2) 0 0 0 0 0 0 0
serious
adverse
events
Discontinuations
TEAEs 6 (1.4) 0 11 (2.8) 1 (0.5) 10 (2.3) 1 (0.8) 16 (5.6) 7 (2.4)
Drug-related 4 (0.9) 0 4 (1.0) 1 (0.5) 5 (1.2) 0 11 (3.8) 7 (2.4)
TEAEs
TEAEs that occurred in ≥5% of any group
Dizziness 32 (7.4) 7 (4.3) 25 (6.4) 24 26 (6.1) 5 (4.0) 19 (6.6) 35
(12.8) (12.2)
Headache 22 (5.1) 10 (6.2) 34 (8.7) 13 (6.9) 12 (2.8) 7 (5.6) 22 (7.6) 18 (6.3)
Upper 18 (4.1) 8 (5.0) 8 (2.0) 10 (5.3) 10 (2.3) 4 (3.2) 7 (2.4) 9 (3.1)
respiratory
tract infection
Fatigue 23 (5.3) 11 (6.8) 16 (4.1) 15 (8.0) 26 (6.1) 10 (7.9) 9 (3.1) 15 (5.2)
Peripheral 30 (6.9) 12 (7.5) 5 (1.3) 1 (0.5) 35 (8.2) 11 (8.7) 18 (6.3) 26 (9.1)
edema
Nausea 4 (0.9) 8 (5.0) 13 (3.3) 9 (4.8) 9 (2.1) 3 (2.4) 9 (3.1) 8 (2.8)
Hypokalemia 1 (0.2) 1 (0.6) 2 (0.5) 1 (0.5) 16 (3.8) 9 (7.1) 2 (0.7) 2 (0.7)
Hypotension 0 0 2 (0.5) 1 (0.5) 0 0 4 (1.4) 4 (1.4)

Notes: Values are n (%).
TEAEs were defined as adverse events that emerged during treatment (started on or after the first
dose of double-blind medication) or that worsened relative to the pretreatment state.
Drug-related TEAEs were considered definitely, probably, or possibly related to randomized

study medication.
TEAEs with triple-combination treatment OM 40 mg/AML 10 mg/HCTZ 25 mg occurred in

56.3% and 60.5% of participants with Se-SBP reductions of ≤40 mmHg and >40 mmHg,
respectively. Drug-related TEAEs occurred in 26.4% and 30.1% of participants with Se-SBP
reductions of ≤40 mmHg and >40 mmHg, respectively. For the total study population, 2.3% of
participants discontinued study participation because of a TEAE, and 1.4% of participants
discontinued study participation because of a drug-related TEAE. [39] In case of triple-
combination treatment discontinuations related to adverse events were more prevalent,
particularly in participants with a ≤40 mmHg reduction in Se-SBP across treatment groups
(Table 03).
7.1. Warnings and precautions

 Fetal toxicity in Pregnancy Category D
 Hypotension in Volume or Salt-Depleted Patients
 Increased Angina and/or Myocardial Infarction
 Impaired Renal Function
 Patients with Hepatic Impairment
 Electrolyte and Metabolic Imbalances
 Postsympathectomy Patients
 Acute Myopia and Secondary Angle-Closure Glaucoma
7.2. Drug interactions
Drug Interactions with Olmesartan Medoxomil:
 Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2

Inhibitors (COX-2 Inhibitors)
 Dual Blockade of the Renin-Angiotensin System (RAS)
 Colesevelam Hydrochloride
 Lithium
Drug Interactions with Amlodipine:
 Simvastatin
 Immunosuppressants e.g. cyclosporine
 CYP3A Inhibitors

 CYP3A Inducers
Drug Interactions with Hydrochlorothiazide:
 Antidiabetic Drugs
 Cholestyramine and Colestipol.
8.1. Discussion
Here the pre specified analysis done from a large, multicenter, and randomized, parallel-group
trial established the efficacy of triple combination therapy with OML 40mg/AML
10mg/HCTZ25mg in lowering of elevated blood pressure. For getting these treatment 50% of
patients randomized to achieved more than 40 (mmHg) and 25% of patient achieved more than
50 (mmHg) reduction in Se-SBP. As a result, the triple combination receiving participants
achieved the Se-SBP target of less than <140 mmHg. Furthermore, triple-combination treatment
has well tolerability.
Similarly, improvements in cardiovascular outcomes have been shown to be more closely related
to reductions in SBP than DBP. From a Meta analysis data of 10 hypertensive trials, shows that
the active treatment reduce 21.3/13.7 (mmHg) and significantly reduce cardiovascular disease
like CAD (coronary artery disease), stroke and fatal or non fatal vascular disease [40].
Various data that collect from numerous clinical trials shows the better effects of reducing BP on
cardiovascular and renal disorder, and some of the trials show the beneficial effects of reducing
elevated blood pressure on cardiovascular and renal endpoints. In a meta analysis data from
participating of 2,00,000 patients getting 31 clinical trials which found 11.9% reduction of
cardiovascular events that means 95% of confidence interval [CI]: 5.3% to 18% in individualise
less than 65 years of age and 9.1% reduction of cardiovascular events in individuals more than
65 years age for each 5(mmHg) reduction systolic blood pressure[41]. As a result, the guideline of
current US suggested to reducing systolic blood pressure less than 140 (mmHg) and less than 30
(mmHg) in patients with concomitant diabetes or CKD.
For BP control adherence of treatment is necessary. A recent analysis shows that using of
Medication Event Monitoring System caps to evaluate adherence found that mean SBP and DBP,
respectively, were 11.6 mmHg and 7.7 mmHg higher (both P< 0.001) in patients after 7 days of
poor (<60%) versus excellent (100%) adherence [42]. Using of multiple antihypertensive agents to
get desirable BP range that may adversely affect on adherence and produce poor BP control. This
is especially relevant to that patient who requires two more agents to get desirable BP target and
that is about 25% of patients who require two or more agents. From a retrospective evaluation of
data found about 85,000 patients through Kaiser Permanente produce inverse correlation

between the number of antihypertensive medications prescribed and adherence. [43] Consistent
with this, several evaluations have shown that the use of fixed-dose combination therapy to
simplify the therapeutic regimen and reduce pill burden significantly improves adherence
relative to free-dose combination therapy [44].
The patient whom age is more than 50 years old easily reached the goal of diastolic blood
pressure if systolic blood pressure goal once reached. That’s why the main focus should be to
manage systolic blood pressure. Systolic blood pressure targets are more difficult to target than
diastolic blood pressure managing; SBP is more correlated with cardiovascular risk than diastolic
blood pressure. Thus patient adherence may increase in single pill combination therapy to
managing SBP target. As shown in the above study it is concluded that, OM 40 mg/AML 10
mg/HCTZ 25 mg may be a safe and effective option in hypertensive patients [45].
8.2. Prevention of Hypertension
A comprehensive strategy for reduction of mortality and morbidity associated with hypertension
must include prevention strategies, earlier detection, and adequate treatment. In an ideal world,
to lower the blood pressure in the community a population strategy should be used. In case of
high risk population group, to lower the blood pressure more intensive efforts are required,
which individuals have a family history of high blood pressure, obesity, black ancestry,
excessive sodium consumption, physical inactivity, and/or alcohol consumption. That’s a
minimum reduction of BP may produce a greater reduction of SBP. 2 (mmHg) reduction of DBP
produce 15% reduction risk of stroke and 6% reduction risk of coronary artery disease.
Prevention of hypertension may be achieved by the following interventions:
 Weight control
 Increased physical activity
 Moderated sodium and alcohol intake
 Increased potassium intake
 A diet rich in fruits and vegetables and low-fat meat, fish, and dairy products. [46]

9.1. Summary
I case stage 2 hypertensive patient the Three-drug single-pill fixed-dose combinations expand the
options for effectively treating hypertension who have not getting goal BPs with two drugs.
From clinical trials we found that reduction of systolic and diastolic blood pressure is almost
similar. Thus these 3-drugs combination fixed dose therapy are very much effective equally to
reducing blood pressure toward if not to recommended goals in both sexes, in African Americans
and Hispanic or Latino minorities, in the elderly, in diabetics, and in obese or overweight
patients with metabolic syndrome with minimal adverse effects. Extrapolation of data shows that
the fixed dose combination of drug is better in case of adherence and persistence than with the
ICs taken as separate medications, although this has yet to be thoroughly evaluated. An
unanswered question is whether major adverse clinical events will be reduced when FDC rather
than IC are prescribed.
10.1. Conclusion
Hypertension is one of the most complex syndromes of cardiac and vascular structure changes
and function. All of the recent guidelines suggest that to effectively reduce cardiovascular risk in
most patients more than one hypertensive agent is requires. When mono therapy encountered
bottlenecks in treating hypertension, fixed-dose combinations were recommended as an effective
and safe regimen for initiating therapy especially for the patients with complications. The perfect
combination of each drug will exert its best effect with low side effect. Each drug in perfect
combination will exert its best effectiveness with fewer side effects. Additionally, fixed-dose
combinations also brought economical benefits for patients with fewer medications compared
with several drugs administered separately. Based on the clinical practice and market research,
fixed-dose formulations are becoming a promising choice for hypertensive patients gradually.

11.1. Referances
1. Roger VL,Go AS,Lloyd-Jones DM, et al. Heart disease and stroke statistics – 2012
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A Triple Fixed Dose Combination of Olmesartan Medoxomil, Amlodipine and Hydrochlorothiazide To Treat Hypertension

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A Triple Fixed Dose Combination of Olmesartan Medoxomil, Amlodipine and Hydrochlorothiazide To Treat Hypertension

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A dissertation submitted in the Department of Pharmaceutical Sciences, North South

Department of Pharmaceutical Sciences

A Triple Fixed Dose Combination of Antihypertensive drugs (olmesartan medoxomil, amlodipine

Dr. Murad Hossain

A Triple Fixed Dose Combination of Antihypertensive drugs (olmesartan medoxomil, amlodipine