INTRODUCTION

Medicine is an ever changing science. As new research and clinical

experience broaden our knowledge, changes in treatment and drug therapy

are required for a better patient care management.

Hypertension is defined by International Hypertension Societies and

World Health Organisation (WHO) and can be categorised into several

stages. An exact threshold value is difficult to establish and subject to change

over time, but currently, most guidelines have defined a BP of >140/90 mmHg

as requiring treatment. However this value is lower in patients with other risk

factors, for instance Diabetes Milletus and kidney disease (1).

Hypertension continues to be a major health issue, even among

already diagnosed patients. Only some patients with hypertension treatment

reach BP below the recommened values. However it bears an independent

relation with different indices of Cardiovascular (CV) diseases, including

stroke, myocardial infarction, heart failure, peripheral vascular artherosclerotic

disease and end stage renal disease.

As clearly stated in the lastest European Society Of Cardiology

guidelines for the management of arterial hypertension, the relationship

between the arterial blood pressure (BP) and CV morbidity and mortality could

be modified by the concomitance of other CV risk factors. Infact, metabolic

risk factors are more common in hypertensive subjects. Along this line, the

prevalence of hypertension and diabetes milletus are increasing in parallel in

the industrialised and developing countries, commonly coexsist, and patients

with both co-morbidities are particularly vulnerable to CV disease and death (2).

1
 It is not suprising that many patients suffer from CV events despite of

adequate control of hypertension, while on other hand upto 75% of specific

CV complications have been attributed to high BP in diabetic patients (3).

Under this prism, multiple CV risk factor intervention is required to maximize

the target organ protection and should be strongly encouraged wherever

possible.

The current Japanese Society of Hypertension Guidelines for the

Management of Hypertension(4) advocate the use of five classes of drugs as

first-line treatments for hypertension

 calcium channel blockers,

 angiotensin II (AII) receptor blockers (ARBs),

 angiotensin-converting enzyme (ACE) inhibitors,

 diuretics

 β-adrenoceptor blockers (β-blockers).

Among the recommended first-line agents, the ARBs are now widely

used as a key component of antihypertensive regimens because of their

favorable efficacy/tolerability profiles (5). In addition, clinical outcome trials have

shown that the ARBs reduce the proportion of hypertensive patients who

develop type 2 diabetes mellitus (6), and improve cardiovascular outcomes in

such conditions as high-risk hypertension (7)(8), heart failure(9)(10) and diabetic

kidney disease(11)(12) .

2
DRUG UTILIZATION STUDIES

The principle aim of drug utilization research is to facilitate the rational use of

drugs in population. These studies provide information on drug use from

consumers themselves(13) and are a source of data on many other

health–related issues(14). Drug utilization research may generate hypothesis

that set the agenda for prescribing pattern and for further investigations and

thus avoid prolonged irrational use of drugs.

Rational use of drugs play a vital role in cost minimization and optimal

utilization of available funds, as drug cost is a major concern for both health

care providers and the beneficiaries in the developing countries (15).Hence in

the present study, we will focus on the efficacy and safety profiles of

Azilsartan and Ramipril as well as on rational use of drugs.

3
 AIMS & OBJECTIVES

Aim of the study:

The aim of the study is to compare the efficacy of Azilsartan and Ramipril in the

management of hypertensive patients with coexisting type 2 Diabetes Mellitus.

Objectives of the study:

 To evaluate and compare the efficacy of Ramipril and Azilsartan on blood

pressure.

 To evaluate and compare the effect of Ramipril and Azilsartan on renal

parameters.

 To monitor the adverse drug reactions.

4
 REVIEW OF LITERATURE

Hypertension is a multifactorial disease affecting one billion people

worldwide. It is the most common, readily identifiable and a reversible risk

factor for myocardial infarction, stroke, heart failure, atrial fibrillation, aortic

dissection and peripheral arterial disease (16).

Currently, high blood pressure causes about 54% of stroke and 47% of

ischemic heart disease worldwide(17). Thus, high blood pressure remains the

leading cause of death worldwide and one of the world’s great public health

problems. As with smoking, diabetes, and dyslipidemia, hypertension is an

important risk factor for cardiovascular diseases, which are responsible for

roughly 30% of deaths worldwide(18).

Hypertension is an extremely common co-morbid condition in diabetes,

affecting 20-60% patients. The renin-angiotensin-aldosterone system (RAAS)

plays an important role in the pathogenesis of atherosclerosis and

pathophysiology of cardiovascular disease. Angiotensin converting enzyme

(ACE) inhibitors and angiotensin II receptor blockers (ARBs) have become

keystones of therapy for hypertension in diabetes because of their broadly

demonstrated favourable effects on diabetic nephropathy and cardiovascular

disease outcomes, as well as their modest favourable effects on measures of

glucose metabolism(19).

5
Figure 1 : Hypertension with coexisting Diabetes Milletus Risks

6
Normal Physiology of RAS:

The renin–angiotensin–aldosterone system (RAAS) is a critical

regulator of blood volume and systemic vascular resistance. While the

baroreceptor reflex responds in a short-term manner to decreased arterial

pressure, the RAAS is responsible for more chronic alterations. It is

composed of three major compounds:

 renin

 angiotensin II,

 aldosterone.

These three act to elevate arterial pressure in response to decreased renal

blood pressure, decreased salt delivery to the distal convoluted tubule, and/or

beta-agonism. Through these mechanisms, the body can elevate the blood

pressure in a prolonged manner. It does this by increasing sodium

reabsorption, water reabsorption, and vascular tone. The rennin-angiotensin-

aldosterone system (RAAS) plays a significant role in preserving

haemodynamic stability in response to the loss of blood volume, salt, and

water(20)(21).

7
Normal Function of the Renin-Angiotensin-Aldosterone System

The RAAS comprises a renin-triggered cascade of hormones with systemic effects

Figure 2 : Overview Of Normal Physiology Of RAAS

8
Epidemiology of Hypertension :

Despite advances in diagnostic and treatment modalities, hypertension

remains a prevalent medical condition, affecting over 26 % of the adult

population, a number expected to rise to nearly 30 % by the year 2025 (22).

Recent report of the WHO shows that one of three adults in the world is

affected by HT, more than 2 billion people, most of whom are not diagnosed.

In Africa, its prevalence exceeds 40% among adults in many countries often

undiagnosed(23).

HTN exhibits an iceberg phenomenon where unknown morbidity

exceeds the known morbidity. The prevalence of HTN is rapidly increasing in

developing countries and is said to be one of the leading causes of death and

disability among the elderly(24).

In non-diabetic individuals, the prevalence of HTN is higher in men as

compared to women until the age of 64 years when the gap closes and

prevalence in females reaches that of males (25). Interestingly, women with

impaired glucose tolerance (IGT) and DM have a higher incidence of HTN

than men with equivalent impairment in glucose homeostasis (26). Alarmingly,

diabetic women also have higher relative risk for death from CVD than

diabetic men(27).

Its prevalence is probably on the increase in developing countries

where adoption of western lifestyles and the stress of urbanization both of

which are expected to increase the morbidity associated with unhealthy

lifestyles unfortunately are not on the decline (28).

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 Genetic and environmental factors are also reported to play a key role

in HT, 90% of which are better classified as idiopathic. High blood pressure in

adults has a high impact on the economy and on the quality of life of

individuals with important implications for resource expenditures (29).

Several studies conducted in different ethnic groups show a close

association between HT and DM, where the prevalence of HT is significantly

higher in the patients with non insulin-dependent DM (NIDDM or type II DM).

Both systolic and diastolic HT has been reported, and conclusive evidence

indicates that the link between DM and essential HT is hyperinsulinemia (30).

The prevalence of HT is 1.5–2.0 times more in those with DM than in

those without DM, whereas almost one-third of the patients with HT develop

DM later(31).

The prevalence of HT has been increasing in India, both in rural and

urban regions. Prevalence rate of HT was found to be 25.2% in a study of

rural population in Tamil Nadu.

The prevalence of HT in the urban population of West Bengal,

representing eastern India, was reported to be 24.9%. The prevalence of HT

among the urban population of Trivandrum city in Kerala in the south western

India was reported to be 33.5% in the age groups between 45 and 64 years (32)
(33)
.

10
CLASSIFICATION OF HYPERTENSION :

Figure 3 : Diagnostic Criteria For Hypertension According to JNC 7

CAUSES & PATHOPHYSIOLOGY: Converging pathways in coexisting

HTN and DM

DM and HTN share several pathophysiologic mechanisms including:

inappropriate activation of the renin angiotensin aldosterone system (RAAS),

oxidative stress secondary to excessive production of reactive oxygen species

(ROS), inflammation, impaired insulin-mediated vasodilatation, increased

sympathetic nervous system (SNS) activation, dysfunctional innate and

adaptive immune responses and abnormal renal handling of sodium.

Obesity and increased visceral adiposity are key pathogenic factors

behind the coexistence of both DM and HTN. Chronic low-grade inflammation

and oxidative stress in the adipose tissue lead to increased production of

angiotensinogen (AGT) and angiotensin II (Ang II) which consequent tissue

11
RAAS activation(34). Further, overexpression of AGT in the white adipose

tissue results in elevated BP. Hence, AGT and Ang II have local as well as

systemic effects on BP regulation. Ang II exerts many of its detrimental effects

via activation of the Ang II type 1 receptor (AT1R).

Activation of AT1R in non-adrenal tissues results in multiple

intracellular events, including production of ROS, reduced insulin metabolic

signaling, and proliferative and inflammatory vascular responses resulting in

endothelial dysfunction, insulin resistance and HTN (35). Thus, there is often an

activated RAAS in coexistent DM and HTN.

Increased aldosterone production and augmented signaling through

the mineralocorticoid receptor (MR) are also key events in the pathogenesis

of HTN.

Corticosteroids may also contribute to CVD in DM patients via actions

mediated in part through activation of the MR. Adipose tissue is known to

produce a lipid-soluble factor that stimulates aldosterone production from the

adrenal zona glomerulosa(36).

Complement-C1q TNF-related protein 1 (CTRP1) is a novel adipokine

that promotes aldosterone production in a rodent model of obesity and insulin

resistance. Aldosterone activation of the MR in the renal distal tubule and

collecting duct increases sodium retention leading to expansion of plasma

volume and increased BP. In addition, aldosterone exerts non-genomic

actions also likely through MR activation, which contribute to HTN by altering

cellular redox state, signaling and endothelial-mediated vascular relaxation (37).

12
Thus, adipose tissue contributes to systemic elevations in BP, in part, through

local production of components of the RAAS

Role of oxidative stress

Increased oxidative stress is a key pathogenic factor in the

development of insulin resistance, DM and HTN (38). ROS can be produced in

different vascular cell types, including endothelial cells (ECs) and vascular

smooth muscle cells (VSMCs) through activation of xanthine oxidase (XO),

nitric oxide (NO) synthase, the mitochondrial respiratory chain.

In turn, ROS can lead to impaired endothelial function by direct tissue

injury, reduction of bioavailable NO, and impaired NO-mediated vasodilation.

One important additional source of ROS and endothelial dysfunction is

endothelial nitric oxide synthase (eNOS) uncoupling.

Under conditions of decreased availability of tetrahydrobiopterin (BH4,

a cofactor in NO production) or the substrate L-arginine, eNOS switches from

this coupled state to an uncoupled state resulting in production of superoxide

(O2−)(39). Mitochondrial and XO mediated oxidative stress also contribute to

this excess generation of ROS in coexistent DM and HTN. XO is also

expressed in vascular endothelial and VSMC, and is another source of

vascular oxidative stress, which generates O2− by catalyzing hypoxanthine

and xanthine to uric acid.

A major source of ROS is the membrane bound vascular-derived

nicotinamide adenine dinucleotide phosphate-oxidase (NADPH), a protein

enzyme composed of several subunits, including the membrane-bound

subunits p22phox and Nox2, the cytosolic regulatory subunits p47phox,

p67phox, p40phox and the small GTP-binding protein Rac1/Rac2.

13
 Increased ROS production in turn results in cell as well as tissue

damage by activating inflammatory pathways such as the NF-kB

inflammation is characterized by increased activity of adhesion molecules,

pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α),

interleukin (IL) 1 and 6, as well as acute phase reactants such as C Reactive

Protein and molecules that promote fibrosis and remodeling, such as

transforming growth factor beta (TGF-β) and plasminogen activator inhibitor 1

(PAI-1)(40).

Interestingly, mechanical stretch (a characteristic phenomenon in HTN)

can lead to membrane translocation and activation of p47phox and Rac1, thus

leading to NADPH oxidase activation. Ang II and aldosterone can also directly

activate NADPH oxidase and trigger oxidative stress.

14
Figure 4 : Systemic and metabolic factors that promote coexistent diabetes

mellitus, hypertension, cardiovascular, and chronic kidney disease

15
Insulin resistance and hyperinsulinemia

Insulin resistance plays an important role in the development of both

DM and HTN, as demonstrated by the fact that approximately 50% of

hypertensive patients manifest systemic insulin resistance.

Binding of insulin to its receptor (IR) triggers two major pathways. A

metabolic signaling pathway mediated by phosphatidylinositol 3-kinase

(PI3K), downstream protein kinase B signaling, ultimately results in

translocation of glucose transporter 4 (GLUT-4) to plasma membrane, thus

resulting in increased insulin mediated glucose transport in insulin sensitive

tissues such as skeletal muscle. In addition, signaling through the PI3K/Akt

pathway results in phosphorylation/activation of endothelial nitric oxide

synthase (eNOS) and consequent NO production promotes endothelium

mediated vasodilation(41).

Insulin also signals through growth/ proliferative signaling pathway,

which is mediated by mitogen-activated protein kinase (MAPK). By activating

MAPK dependent signaling pathways, insulin stimulates secretion of

vasoconstrictor mediators, such as endothelin-1, as well as increased

expression of PAI-1, vascular cell adhesion molecule-1.

In conditions of normal insulin sensitivity, the balance between these

vasoconstrictor and vasodilatory actions favors vasodilation). In insulin

resistant states there is often deficient insulin metabolic signaling in concert

with unchecked signaling through the growth pathway.

Maladaptive hyperinsulinemia/insulin resistance leads to abnormalities

in vascular function, vascular stiffness, hypertrophy, fibrosis and

16
remodelling(42). Hyperinsulinemia also results in enhanced sympathetic output

in humans through ventromedial hypothalamus mechanisms.

Additionally leptin, which is an adipokine produced in adipose tissue

and is increased in obese individuals, also increases sympathetic nerve

activation likely through a central nervous system effect involving leptin

receptor activation. Indeed, there is increasing evidence that increased

afferent

traffic from and efferent activity to the kidney plays an important role in

development of hypertension associated with obesity and insulin resistance.

Importantly, insulin enhances sodium reabsorption in the diluting

segment of the distal nephron, in part through increased expression of sodium

transporters like the epithelial sodium channel (ENaC), with consequent

decreases in sodium excretion(43).

Hyperinsulinemia-mediated sodium retention could potentially

contribute to the genesis of HTN via increased activation of sodium hydrogen

exchanger activity in the proximal tubule as well as through the effects on

ENAC more distally. While this is an attractive hypothesis, in an animal model

of knockout of IR in the renal tubule epithelial cells, the absence of insulin

action resulted in impaired natriuretic responses and HTN, likely due to

reduce NO production. Because of these contradictory results, further studies

are needed to clarify the physiological role of insulin on renal sodium

handling.

Finally, sodium and uric acid are generally handled together; hence

excess uric acid can increase along with sodium retention, thereby

contributing to hyperuricemia, which is frequently seen in hypertensive

17
patients. The propensity for increased uric acid levels is increased with our

westernized diets that are high in fructose.

Hypertension is known as an important risk factor for cardiovascular

disease. It leads to a higher risk of ischaemic heart disease, angina pectoris,

acute myocardial infarction, heart failure, arteriosclerosis, cerebral

thrombosis, stroke and kidney disease.

The increased risk is present in all age groups, and for every 20-mmHg

increase in systolic or 10-mmHg increase in diastolic pressure, the risk of

ischaemic heart disease and stroke is doubled.

The Framingham Heart Study found that an elevated BP (130–139

mmHg systolic and 85–89 mmHg diastolic) doubles the risk of cardiovascular

disease compared with those with a BP below 120/80 mmHg (44).

The risks associated with hypertension can be reduced by lowering BP

by both lifestyle intervention and antihypertensive therapy. Even small

changes in BP influence the risk of cardiovascular disease. Therefore, an

effective treatment is of great importance to prevent cardiovascular conditions

in the large group of patients suffering from hypertension. Beside

antihypertensive drugs such as thiazide diuretics, badrenoceptor antagonists

(BAA) and calcium channel blockers, which have an effect on blood volume,

heart rate and vasodilation, respectively (45), an important therapeutic

approach for hypertension is the blockade of the renin angiotensin–

aldosterone system (RAAS).

Azilsartan (AZL) was recently introduced for treatment of hypertension

mainly due to unprecedented tight binding to the angiotensin receptor, AT1,

18
and the pharmacokinetic and testing in animal studies as well as a proposed

role in the human clinic have recently been reviewed (46). Here, we have

focused on the strong interaction of the drug with the AT1 receptor and

whether that is reflected in the clinical effects of the drug and compared with

other angiotensin receptor antagonists.

Treatment Modalities for Hypertension

I. Non Pharmacological :

Non-pharmacological lifestyle interventions, which include dietary

changes, low salt diet, weight loss, increased physical activity on a regular

basis, and alcohol restriction, have shown to reduce BP in several controlled

studies. Lifestyle changes including individualized counseling aimed at

reducing total intake of fat, intake of saturated fat and increasing intake of

fiber and physical activity result in significant improvements in BP and

reduction in the incidence of DM.

19
 Figure 5 : Correlation Of Lifestyle Modification With Reduction Of SBP

Five lifestyle modifications are recommended by JNC 7 for reducing blood

pressure:

(1) Reducing sodium intake

(2) Increasing exercise

(3) Moderating alcohol consumption

(4) Dietary Approaches to Stop Hypertension (DASH) eating plan (47)

(5) Losing weight.

These modifications have been proven to reduce blood pressure, although

their direct impact on morbidity and mortality is not yet known.

The DASH Eating Plan

20
 High in:
Fruits and vegetables (four or five servings each per day)

Fiber (seven or eight servings per day)

Low-fat dairy products (two or three servings per day)

Lean meat (two servings per day)

Calcium
Magnesium
Potassium
Low in:
Saturated fat
Cholesterol
Salt*
DASH = dietary approaches to stop hypertension.
*— Low sodium intake was a later addition to the plan.
Information from references 8 through 10.
Table 1 : DASH PLAN

Other Lifestyle Interventions

· SMOKING CESSATION

Nicotine released while smoking cigarettes is believed to impact blood

pressure through arousal of the sympathetic nervous system followed by the

release of norepinephrine and epinephrine.

Cigarette use causes a 4-mm Hg increase in systolic blood pressure

and a 3-mm Hg increase in diastolic blood pressure compared with

placebo(48).

Smoking cessation should be part of any comprehensive lifestyle

modification plan to reduce the risk of high blood pressure and cardiovascular

disease.

21
 · MEDITATION

Meditation includes a variety of techniques, such as repetition of a

word or phrase (the mantra) and careful attention to the process of breathing,

to achieve a state of inner calm, detachment, and focus. Meditation was

shown to reduce blood pressure in one well-designed study that addressed

baseline blood pressure measurements adequately (49).

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 II. Pharmacological Treatment :

A) ANGIOTENSIN CONVERTING ENZYME INHIBITORS (ACEIS)

RAMIPRIL

ACEIs are widely used

to treat hypertension because

they are

effective, have relatively few side effects

and reduce the complications of hypertension

such as heart attacks and strokes.

They have a special use in patients with diabetes mellitus who have

protein in the urine ("diabetic nephropathy") and in patients with chronic

kidney disease (CKD) in whom they appeared to have beneficial actions in

slowing the loss of kidney function above that achieved by other agents.

Ramipril is absorbed rapidly(peak concentrations are achieved

in 1 hour),and the rate but not extent of its oral absorption is reduced by food.

Cleavage of ester moiety by hepatic esterases transforms Ramipril into

Ramiprilat,an ACE Inhibitor that in vitro is potent.

PHARMACOKINETICS:

23
Ramipril is metabolized to Ramiprilat and to inactive metabolites

(glucouronides of ramipril and ramiprilat and the diketopiperazine ester and

acid) that are excreted predominantly by the kidneys.

peak concentrations of Ramipril is achieved in ~3hours.

Ramiprilat displays triphasic elimination kinetics with half-lives of 2-4 hours,

9-18 hours,and >50 hours.

This triphasic elimination is due to extensive distribution to all tissues

(initial t1l2), clearance of free ramiprilat from plasma (intermediate t 1l2),and

dissociation of ramiprilat from tissue ACE(long terminal t 1l2). The oral dosage

of ramipril ranges from 1.25 to 20mg daily.

Mechanism Of Action :

ACEIs block the action of the renin angiotensin system (RAS). ACE

inhibitors block the conversion of Angiotensin I (ATI) to Angiotensin II (ATII) (50).

They thereby lower arteriolar resistance and increase venous capacity;

decrease cardiac output, cardiac index, stroke work, and volume; lower

resistance in blood vessels in the kidneys; and lead to increased natriuresis

(excretion of sodium in the urine).

Renin increases in concentration in the blood as a result of negative

feedback of conversion of ATI to ATII. ATI increases for the same reason;

ATII and aldosterone decrease. Bradykinin increases because of less

inactivation by ACE. The production of ATII is decreased, which prevents

aldosterone release from the adrenal cortex. This allows the kidney to excrete

sodium ions along with obligate water, and retain potassium ions. This

decreases blood volume, leading to decreased blood pressure.

24
Figure 6 : Mechanism Of Action Of ACEIs

Individual Drugs:

The following are examples of ACEIs in clinical practice:

 captopril ,

 enalapril,

 fosinopril,

 Lisinopril,

 Ramipril.

Adverse Effects:

Common adverse drug reactions include: hypotension,

25
  cough,

 hyperkalemia,

 headache,

 dizziness,

 fatigue,

 nausea,

 renal impairment(51).

ACE inhibitors might increase inflammation-related pain, perhaps

mediated by the buildup of bradykinin that accompanies ACE inhibition.

The main adverse effects of ACE inhibition can be understood from

their pharmacological action. The other reported adverse effects are

hepatotoxicity and effect on the fetus.

Renal impairment is a significant potential adverse effect of all ACE

inhibitors that directly follows from their mechanism of action. Patients starting

on an ACE inhibitor usually have a modest reduction in glomerular filtration

rate (GFR) that stabilizes after several days.

Contraindications and precautions :

The ACE inhibitors are contraindicated in patients with:

· Previous angioedema associated with ACE inhibitor therapy

· Renal stenosis

· Hypersensitivity to ACE inhibitors

· Pregnancy (Teratogenic)(52)

ACE inhibitors should be used with caution in patients with:

· Impaired renal function

26
 · Aortic valve stenosis or cardiac outflow obstruction

· Hypovolemia or dehydration

· Hemodialysis with high-flux polyacrylonitrile membranes

ACE inhibitors are ADEC pregnancy category D, and should be avoided in

women who are likely to become pregnant

B) ANGIOTENSIN RECEPTOR BLOCKERS (ARBS):

AZILSARTAN

ARBs also block the renin angiotensin system (RAS), similar to ACEIs, but

have a different mechanism of action by blocking the actions of angiotensin II

in the tissues rather than the generation of angiotensin II, which is the action

of ACEIs. These drugs also have an excellent acceptability and preservation

of quality of life.

Moreover, they do not cause an irritant cough or the rare danger of

swelling of the lips, tongue and throat, that can occur with ACEIs.

In general, the indications for their use, their effectiveness and

beneficial interactions with thiazides and loop diuretics are similar to ACEIs.

Some studies have suggested they are particularly effective in preventing

stroke.

Mechanism of action :
27
 Azilsartan is a selective blocker of AT1 receptors that prevents

angiotensin II binding, resulting in vasodilation and decrease in the effects of

aldosterone, because of the presence of such receptors in the vascular

smooth muscle and in the adrenal gland. With respect to other ARBs,

Azilsartan is highly selective for the AT1 receptor and not the AT2 receptor (52).

Figure 7 : Mechanism Of Action Of ARBs (AZILSARTAN)

Pharmacokinetics :

Azilsartan medoxomil is a prodrug subject to hydrolyzation of its active

moiety, Azilsartan, at the level of the gastrointestinal tract. Azilsartan reaches

28
its peak plasma concentration between 1.5 and 3 hours following oral

administration. Coadministration with food does not affect bioavailability,

which is approximately 58%.

Metabolization of Azilsartan occurs in the liver via cytochrome P450

(CYP) 2C9, resulting in the formation of a nonactive metabolite, M-II (formed

by O-dealkylation). Metabolization to a lesser extent is then provided by

CYP2B6 and CYP2C8, resulting in the formation of another inactive

metabolite, M-I (formed by decarboxylation).

Azilsartan is primarily excreted by the kidney, as inactive metabolites,

with a clearance of 2.3 mL/min. The elimination half-life is approximately 11

hours, with steady-state plasma concentrations reached 5 days after oral

administration.18 In conclusion, the dose range of 20–320 mg does not need

any adjustment based on patient’s age, sex, race, or degree of renal/hepatic

impairment.

Drug interactions :

Drug interactions of Azilsartan with caffeine, antacid, warfarin, digoxin,

tolbutamide, glyburide, metformin, pioglitazone, chlorthalidone, amlodipine,

dextromethorphan, midazolam, and fexofenandine have been studied; any

other significant interactions have also been observed.

In another drug interaction study, Azilsartan clearance was reduced

when coadministered with fluconazole (a CYP2C9 inhibitor), but not when

coadministered with ketoconazole (a CYP3A4/5 inhibitor).It is well known that

angiotensin II increases the glomerular filtration rate by means of efferent

29
arteriole vasoconstriction, therefore reduced angiotensin II binding caused by

Azilsartan slightly decreases the glomerular filtration rate because of efferent

arteriole vasodilation. Given that, nonsteroidal anti-inflammatory agents and

COX-2 inhibitors cause prerenal acute renal failure by blocking prostaglandin

production, which also alters local glomerular arteriolar perfusion (53) the use of

these agents concurrently with Azilsartan may increase the risk of renal

function deterioration.

Individual Drugs ARBs include :

 Azilsartan,

 candesartan,

 eprosartan,

 irbesartan,

 losartan,

 olmesartan,

 telmisartan and

 valsartan.

As with ACEIs, there are only minor differences between agents in this class

of drugs. All are effective in lowering blood pressure when given once, or

perhaps twice daily.

Adverse Effects: these drugs do not cause irritant cough, but otherwise

have a similar spectrum of adverse actions to ACEIs.

C) CALCIUM CHANNEL BLOCKERS (CCBS) :

30
 These are very effective in lowering blood pressure. They act directly

on the blood vessels to cause relaxation. They are used sometimes as first

line therapy but more often with diuretics or ACEIs or ARBs as second or third

line therapy. They are especially effective in lowering blood pressure in

elderly, black, obese, and diabetic patients.

They are excellent in preventing stroke but rather less effective than

diuretics, ACEIs, and ARBs in preventing heart failure.

Adverse Effects:

Dihydropyridine CCBs do cause swelling of the ankles (edema), which

is worse in hot weather and at higher dosage.

Non-dihydropyridine CCBs cause decreased cardiac out put.

(tiredness, lethargy, and dizziness on exertion).

This group of drugs also can cause constipation, especially in the

elderly but rarely cause edema.

D) DIURETICS

There are three classes of diuretic drugs that are used to treat

hypertension. Most commonly used are thiazide diuretics such as

hydrocholrothiazide or chlorthalidone.

Diuretics increase the effectiveness or all other classes of

antihypertensive agents. Therefore, almost any subject, except those with a

contraindication, should receive a diuretic if their blood pressure requires

more than one drug for its management.

Adverse Effects:

 Diuretics increase the excretion of potassium and can lead to

hypokalemia (low blood potassium concentration)

31
 irregular heart beats

 muscular weakness.

 Diuretics lead to some increase in uric acid and should not normally to

be used in patients with gout.

 treatment with diuretics can lead to low blood pressure,

 orthostatic hypotension

 (weakness, dizziness and possibly fainting on standing)

32
MANAGEMENT OF HYPERTENSION IN PATIENTS WITH DIABETES MILLETUS

Algorithm for the management of hypertension in patients with diabetes. (ACE

= angiotensin-converting enzyme; ARB = angiotensin receptor blocker; BP =

blood pressure; CCB = calcium channel blocker; GFR = glomerular filtration

rate.)
Figure 8 : Approach In HTN Patients With Coexisting DM

33
Drug utilization research is an essential part of pharmacoepidemiology as it

describes the extent, nature and determinants of drug exposure (54).

Drug utilization studies are powerful tools to ascertain the role of drugs

in the society(55). They provide a sound sociomedical and health economic

basis for health care decision making.

The world health organisation (WHO) defines drug utilization as

marketing, distribution, prescription and the use of drugs in society, with

special emphasis on the resultant medical, social and economical

consequences(56).

The boost in the marketing of new drugs, wide variations in the pattern

of drug prescribing and consumption, growing concern about the delayed

adverse effects, increasing concern regarding the cost of drugs and volume of

prescription all contribute to the increasing importance of drug utilization

studies(57).

The research in this field aims to analyse the development trends of

drug usage at various levels in the health care system (58).

Scope of drug utilization evaluation –

Studies on the process of drug utilization focus on the factors related to

prescribing, dispensing, administering and taking of medication, and its

associated events, covering the medical and non medical determinants of

drug utilization, the effects of drug utilization, as well as studies of how drug

utilization relates to the effects of drug use, beneficial or adverse (59).

34
 MATERIAL AND METHODS

STUDY POPULATION:

The study population consists Patients attending medicine

department of Owaisi Hospital and Research centre (OHRC) Hyderabad.

Type of study

It was a prospective, open labelled, randomized, and comparative

study carried out after being approved by the institutional ethics

committee(appendix-1).

INCLUSION CRITERIA :

 Age of the patient between 30 to 65 years old

 Sex includes Both Male and Female

 All known and newly diagnosed cases of HTN (SBP more than

140mmHg and less than 180mmHg, DBP more than 90mmHg and less

than 110mmHg) with coexsisting type 2 DM.

 Patients who give informed consent

EXCLUSION CRITERIA :

Patients with the following characteristics were excluded:

 Patients with HIV and HBsAg positive.

 Pregnant and lactating Women.

 Uncontrolled HTN

 Patients with type 1 DM.

 Patients with severe CHF or severe renal impairment.

35
METHODS OF COLLECTION OF DATA:

A.STUDY DESIGN - Randomized, prospective, open label and comparative study.

B.STUDY DURATION - 12 months

C. SAMPLE SIZE – 120 Patients

D. PLACE OF STUDY - Owaisi Hospital and Research Centre Hyderabad

E.GROUP ALLOCATION –The whole sample of patients i.e,120 patients were

allocated into 2 groups.

1)GROUP 1 – AZILSARTAN.

2)GROUP 2 - RAMIPRIL

F. STATISTICAL ANALYSIS :

The data collected was analysed statistically using descriptive statistics

namely mean and standard deviation of quantitative variables and presented

as counts and percentages.

Chi square test was used to compare the efficacy between Azilsartan and

Ramipril groups. Unpaired t test was used to compare means between

Azilsartan and Ramipril for continuous variables.

Adverse event data were summarised in frequency tables by treatment

groups, but no statistical analysis was performed.

For all the test p value of 0.05 or less was considered for statistical

significance. Whenever necessary the results of this study were depicted

using tables and graphs using Microsoft Word 2010 and Microsoft Excel 2010.

G.STATISTICAL SOFTWARE: Data was entered in Microsoft excel and

analyses were done using statistical package for social science (SPSS)

version 20.

36
 After the patients were diagnosed by the physicians was over a written

informed consent from the patients was taken after explaining the purpose of

this study, procedure and protocol of this study , the duration of this study,

information of the drugs to be given and side effects of the drugs. Patients

were explained that they can refuse or withdraw from the study at any time ,

and their treatment would not be affected.

After taking the consent from the patients their prescriptions were

audited prospectively using a specially designed proforma containing relevant

details such as demographic, socio economic, family history, and any past

history or personal history. All the drugs prescribed are recorded including its

dosage forms, route of administration, frequency of administration, indication,

duration, generic or brand names and cost/benefit ratio of therapy.

Economic burden of drugs on the patients were also assessed by

calculating average drug cost per prescription and average number of drugs

prescribed. The patients were interviewed as per WHO CORE Indicator

guidelines.

Following (WHO Core Indicators) drug use indicators were determined :

1. Prescribing indicators.

2. Patient care indicators.

3. Facility indicators.

4. Complementary indicators.

37
 OBSERVATION AND RESULTS

The present study comprised of 120 patients aged above 30 years of either

sex, diagnosed with hypertension withtype-2 diabetes mellitus as co morbidity

and prescribed either Azilsartan or Ramipril along wih antidiabetic medication.

The observations made were based on the changes in SBP, DBP and other

laboratory investigations at baseline, 2weeks, 4weeks, 8weeks, 12weeks,

16weeks, 20weeks and 24weeks and also the associated adverse effects in

both drug groups.

Group-1: Azilsartan

Group 2: Ramipril

I. Demographic Data:

A. Age distribution:

The subjects were categorised depending on their age group.

Table- 2 : Age wise distribution of patients in group 1

Age Group No. of Patients 60 Percentage

Upto 40 8 13%
41-50 24 40%
51-65 28 47%

Table- 3.2 : Age wise distribution of patients in group 2

Age Group No. of Patients 60 Percentage

38
 Upto 40 7 12%
41-50 27 45%
51-65 26 43%
Figure – 9 : Bar graph showing age wise distribution of patients

Group 1 Group 2

27 28
30 26
24

23

15
8 7
8

0
Up

The majority of the patients were in the age group of 40-65 years. This

indicates that in general, elderly group were more exposed to the risk of HTN

as depicted in Table – 3.1 & 3.2, Figure – 9.

B. Gender distribution :

The subjects were categorised depending on their gender.

Table – 3: Gender wise distribution in group 1

Gender No. of patients 60 Percentage

39
 Male 28 47%
Female 32 53%
Table – 3.1: Gender wise distribution in group 2

Gender No. of patients 60 Percentage

Male 24 40%
Female 36 60%

Figure – 10 : Gender distribution of patients presented with HTN

Male Female

36
32
28
24

Group 1 Group 2

A total of 120 patients with HTN were enrolled from Medicine outpatient

department during the study period of 12 months. They were divided

randomdily to group 1 and group 2. Female predominance was seen in both

the groups as depicted in Table – 4.1 & 4.2, Figure - 10.

III. Co morbidities :

Figure 11:- Pie diagram showing patients with comorbidities in both

the groups

40
 CHD
PVD
Renal stones
NO Comorbidities
0.32
0.3

0.28

0.1

In this study , 32% of the patients had no co morbidities while the

remaining 68% reported with co morbidities which includes CHD, PVD and

Kidney stones.

II. Family history and Personal history :

Patients were evaluated based on any relevant medical history

41
 Table – 4 : Distribution of patients according to family history and

personal history in both the groups

Family History 64%

Personal history 36%
Total 100%

Figure – 12 : Bar graph showing patients distributed according to the

past relevant medical history.

70 64

53
No. of patients

36
35

18

0
Family history Personal history

While considering the past medical history (history of diet and habits &

family history), 64% and 36% of the patients had family history and personal

history respectively. As depicted in Table – 5, Figure – 12.

III. Follow Up Of SBP & DBP in both the groups at 2weeks, 4weeks,

8weeks, 12weeks, 16weeks, 20weeks and 24weeks.

Table -5 : Follow Up Of SBP & DBP in Group 1 (Azilsartan)

42
 Systolic Blood Pressure Diastolic Blood Pressure
MEAN SBP FUSBP T value P value MEAN FU DBP T value P value

DBP

151.8±5.5 136.59±6.8 20.97 < 0.0001 87.78±7.9 84.55±7.0 3.79 < 0.0001

(2weeks) (2weeks)
151.8±5.5 130.89±3.9 41.72 < 0.0001 87.78±7.9 79.93±5.0 8.42 < 0.0001

(4weeks) (4weeks)

151.8±5.5 126.59±3.5 42.19 < 0.0001 87.78±7.9 79. 55±4.5 8.65 < 0.0001

(8weeks) (8weeks)

151.8±5.5 124.32±2.9 48.31 < 0.0001 87.78±7.9 77.04±3.7 11.93 < 0.0001

(12weeks) (12weeks)

151.8±5.5 120.89±2.7 47.67 < 0.0001 87.78±7.9 77.82±1.7 11.58 < 0.0001

(16weeks) (16weeks)

151.8±5.5 117.44±2.3 56.45 < 0.0001 87.78±7.9 76.23±2.5 13.18 < 0.0001

(20weeks) (20weeks)

151.8±5.5 116.63±2.0 58.47 < 0.0001 87.78±7.9 76.14±2.7 13.13 < 0.0001

(24weeks) (24weeks)

Figure – 13 : Bar graph showing follow up SBP & DBP in Group 1.

43
 SYSTOLIC BP DIASTOLIC BP

136.59
130.89
126.59 124.32
120.89
117.44 116.63
Blood Pressure In mmHg

84.55
79.93 79.55 77.82
77.04 76.23 76.14

2weeks 4weeks 8weeks 12weeks 16weeks 20weeks 24weeks

Duration Of Follow Up in weeks

44
 Table -6. : Follow Up Of SBP & DBP in Group 2 (Ramipril)

Systolic Blood Pressure Diastolic Blood Pressure

MEAN FUSBP T value P value MEAN FU DBP T value P value

SBP DBP
152.8±6 137.26±7.7 18.76 < 0.0001 88.59±8.3 83.95±7.5 5.66 < 0.0001

(2weeks) (2weeks)
152.8±6 131.22±4.5 33.13 < 0.0001 88.59±8.3 79.9±5.2 9.2 < 0.0001

(4weeks) (4weeks)
152.8±6 127.04±3.2 39.31 < 0.0001 88.59±8.3 79.08±5.4 10.53 < 0.0001

(8weeks) (8weeks)
152.8±6 124.34±3.0 41.6 < 0.0001 88.59±8.3 76.73±3.5 12.31 < 0.0001

(12weeks) (12weeks)

152.8±6 121.02±2.7 42.6 < 0.0001 88.59±8.3 76.89±7.3 10.55 < 0.0001

(16weeks) (16weeks)

152.8±6 117.6±2.0 53.47 < 0.0001 88.59±8.3 76.33±2.4 13.49 < 0.0001

(20weeks) (20weeks)

152.8±6 116.85±1.8 53.31 < 0.0001 88.59±8.3 76.25±2.6 13.91 < 0.0001

(24weeks) (24weeks)

Figure – 14 : Bar graph showing follow up of blood pressure in

group 2.

45
 SYSTOLIC BP DIASTOLIC BP

137.26
131.22
127.04
124.34
121.02
117.6 116.85
Blood Pressure in mmHg

83.95
79.95 79.08 76.73 76.89 76.33 76.25

2weeks 4weeks 8weeks 12weeks 16weeks 20weeks 24weeks

Duration of Follow up in weeks

Table 7:Comparative reduction of SBP & DBP between baseline & at end

of treatment in both regimens

46
 SYSTOLIC BP DIASTOLIC BP

AZ RAM AZ RAM
Baseline 151.8±5.5 152.8±6 87.78±7.9 83.95±7.5

At last follow 116.63±2.0 116.85±1.8 76.14±2.7 76.25±2.6

up

Figure 15.1 : Bar graph showing reduction in blood pressure in both

groups

150

120
BLOOD PRESSURE mmHG

90

60

30

0
SBP DBP

Table -8 : Comparative of effect on Serum Creatinine & Blood Urea

between baseline & at end of treatment in both regimens

Lab Azilsartan Ramipril

Baseline After T P Baseline After T P

Mean±SD 24weeks value value Mean±SD 24weeks value value

Mean±SD Mean±SD

47
S.CRE 1.0049±0.2 1.0022±0.2 0.30 0.77 1.0123±0.2 1.0082±0.2 0.18 0.87

B.URE 30.10±6.2 29.34±5.3 0.94 0.35 29.86±6.5 29.37±4.9 0.65 0.52

Figure 15.2 : Bar graph showing effect on renal parameters from

baseline to end of 24weeks in both groups

40

30.1 29.86 29.34 29.37

30
Values in mg/dl

20

10

1.005 1.002 1.012 1.008

0
S.CRE B.URE
Duration Of follow Up

Azilsartan Ramipril

Table – 9 : Distribution of patients with adverse effects in both the

groups

Adverse Effects Azilsartan Ramipril

Dry Cough 1 6
Diziness 1 3
Headach 3 3
GI Upset 1 3

48
 6

Azilsartan
3
Ramipril

0
Dry cough dizziness headache GI Upset

Figure no:16 distribution of patients with adverse effects in both the groups

VIII. WHO CORE INDICATOR :

All 120 prescriptions were analysed for the following indicators :

1. Prescribing indicators

Table – 10: Different prescribing indicators

Indicators Data
Average number of drugs per encounter 4.38
Percentage of drugs prescribed by generic names 00
Percentage of encounters with an antibiotic prescribed 34
Percentage of encounters with an injection prescribed 00
Percentage of drugs prescribed from essential drug list or 76

formulary

49
2. Patient care indicators

Table – 11: Different patient care indicators

Indicators Data
Average consultation time 8mins
Average dispensing time 80s
Percentage of drugs actually dispensed 100
Percentage of drugs adequately labelled 100
Patients knowledge of correct dosage 98

3. Facility indicators

Table – 12: Different facility indicators.

Indicators Data
Availability of essential drug list or formulary Yes
Availability of key drugs Yes

4. Complementary drug use indicators

Table – 13 : Different complementary drug use indicators

Indicators Data
Average drug cost per prescription 808
Percentage of drug cost spent of injection 00

50
 DISCUSSION

Hypertension and diabetes mellitus are both highly prevalent, chronic,

incurable ailments requiring continuous, regular and palliative therapy almost

throughout the life of the individual.

These clinical conditions thus require continuous monitoring to prevent

various complications as well as progression of the disease. Hence, proper

optimal therapy is a must to achieve treatment goals as suggested by the

latest guidelines.

Although a wide variety of antihypertensive agents belonging to

different pharmacological classes targeting different physiological components

are being prescribed for the management of hypertension, yet therapy with

renin angiotensin system blockers has been chosen for comparative

evaluation as these two agents namely, ACE inhibitor (Ramipril) and ARB

(Azilsartan) in doses applied cause minimum adverse effects profile and are

better tolerated as well as these two agents are quite effective in Asian

populations.

The present study comprised of 120 newly diagnosed hypertensive

patients with type 2 diabetes mellitus who have reported to the medicine

outpatient department of Owaisi medical college and hospital, Hyderabad.

The patients were randomized in two groups (Azilsartan group 1 and

Ramipril group 2) to carry out non-interventional, observational study and they

received therapy with either Azilsartan 40 mg once daily, or Ramipril 5 mg

once daily.

The two groups were well balanced with regards to initial SBP and

DBP for comparative evaluation. A total of 20 patients dropped out of the

51
study period and they were not considered while computing the results as well

as for the statistical analysis.

The dropouts are probably due to the higher cost of the drugs because

the subject has to take both antihypertensive as well as antidiabetic agents

simultaneously almost throughout life, lack of compliance, adverse effects as

well as poor awareness that despite their blood pressure being controlled,

they have to take the drugs almost throughout life. Also some enrolled

patients have to be dropped out due to augmentation in therapy with two or

more drugs for hypertension. Treatment adherence is an important issue for

the therapy of chronic diseases such as hypertension and diabetes.

An improvement in adherence is expected to result in better long-term

clinical outcomes, including reduced cardiovascular and renal

morbidity/mortality. Monotherapy with once daily administration is not only

convenient but also improves treatment adherence and compliance. In the

present study monotherapy with Azilsartan or Ramipril has been used and in

none of the cases was an upward titration of the dose required.

Considering the precarious condition of the patient and the sheer

number of drugs to be employed in the treatment, the physician has to weigh

the pros and cons of each and every drug before using it.

An observational, prospective study was done after Institutional ethics

committee approval. This study was conducted on 120 hypertensive patients

presented to medicine unit in Owaisi Medical College and Hospital Hyderabad

after explaining them about the study and taking written informed consent.

(Annexure 2) The patient’s and prescribed drug details were noted on the

52
study proforma (Annexure-3) and interviewed according to the WHO CORE

INDICATORS.

In the present study the female dominance was seen in both the

groups (table 4.1, 4.2 & fig 10 ) . The incidence of gender involvement in

hypertension is in conformity with observations reported in serial

epide miological study conducted in Jaipur by Gupta et al (60) where the

prevalence of hypertension has been reported lower 30% and 36%

respectively amongst males as compared to 34% and 38% respectively in

females

Regarding distribution of patients as per age, our study has observed a

rising trend of hypertension with type II diabetes with increasing age (table

3.1, 3.2 & fig 9). This observation is in line with Dubey et al and Bansal et

al(61).

Majority of the patients in our study are in the age group of 41-50 years

followed by upto 40 years age group. Deshmukh et al (62)reported the highest

incidence of hypertension in the age group of 41 to 60 years.

These authors have also observed that age, lifestyle and

socioeconomic status are significantly associated with hypertension.

A rising trend in hypertension with increasing age is consistent with the

other studies Deshmukh et al(63) in Wardha and Prasanath et al (64) in South

India.

Moreover, diabetes mellitus is associated with increased oxidative

stress due to hyperglycaemia, which together with dyslipidemia is associated

with an excess of cardiovascular risk. Also, there are other factors contributing

to a rising trend of hypertension like increased life expectancy, urbanization

53
and its attendant lifestyle changes including increased salt intake, increased

awareness and increased detection, and increased stressful working hours.

stressful living conditions and poverty are the prime precipitating

causes.According to Pandit et al(66)

Figure 11 shows there were 68% of patients in our study with

comorbidities, while 32% had no comorbidities.

In our study,64% of patients had family history, whereas 34%

presented with risky personal history (table 5 & fig 12).

In our study the baseline blood pressure values were almost equally

matched in both the groups. SBP was 152.08±6.04 mm Hg and 151.8±5.56

mm Hg and DBP was 88.59±8.34 mm Hg and 87.78±7.92 mm Hg in Ramipril

and Azilsartan groups respectively (table 6.1,6.2 & fig 13, 14 ).

The mean SBP and mean DBP were thus comparable between the

two groups. Other workers in the field have also reported a similar baseline

value of SBP and DBP.

The SBP and DBP reductions from baseline have shown statistically

significant, regular and consistent reduction (p<0.0001) amongst all 60

patients of Ramipril group and in 60 patients of Azilsartan group (table 7 & fig

15).

SBP & DBP was significantly reduced in both the groups (p< 0.0001 for

both groups) (table 7 & fig 15).

A comparative assessment of changes in SBP with the two regimens

showed that there was no statistically significant difference (p-value > 0.05) in

SBP reduction

54
 Similarly, a comparison of changes in DBP with the two regimens

showed no statistically significant difference (p-value > 0.05) in DBP

reduction.

The fall in DBP has been noted even at the first follow-up at two weeks.

Our observations in respect to DBP are in line with the reports of previous

studies(67)(68).

Regarding adverse effects, both the drugs were well tolerated though

there were instances of dry irritating cough in six subjects of Ramipril group as

compared to one in Azilsartan group and three subjects each complained of

dizziness and GI upset in Ramipril group as compared to one each in

Azilsartan group (table 8 & fig 16).

Comparatively, Azilsartan has caused lesser incidence of adverse

effects. There was no incidence of

hypotension,

hyperkalemia,

angioedema

or any other major adverse events requiring hospitalization.

Rationality of the prescription was determined using WHO CORE

INDICATORS with a total of 120 encountered cases and 438 drugs

prescribed.

Average number of drugs used per prescription was 438, there was no

polypharmacy which implies a good prescribing practice. None of the drugs

were prescribed using generic names, which is inappropriate prescribing

55
behaviour. Increasing generic prescribing would rationalize the use and

reduce the cost of the drugs. Prescriptions were as per the essential drug list.

(Table-10)

We noticed that the average consultation time was 8mins and average

dispensing time was 80secs. 100% of the prescribed drugs were dispensed

and adequately labelled, 98% of patients had knowledge of correct dosage

(Table-11) An average drug cost per prescription was found to be Rs. 808

(Table-12).

LIMITATIONS OF THE STUDY:

1. This study was conducted in only one tertiary care hospital with only

120 cases, requiring further studies in different hospitals with larger

sample size, so that results can be more generalized to the general

population.

2. Cost effective analysis was not done, though complementary indicator

was evaluated by calculating the average drug cost per prescription.

3. As the present study was open labeled study, further studies can be

done as a single blind or double blind trials to eliminate

subjective,unrecognized biases.

56
 CONCLUSIONS & SUMMARY

The present observational ,prospective study was undertaken in owaisi

hospital and research centre to evaluate the efficacy of Azilsartan and

Ramipril in patients with hypertension and type 2 diabetes mellitus.

The study was conducted for a period of 1 year using specially designed

proforma for collection of data.

The patients included in this study were between 30 to 65 years of age group

of either sex with hypertension and type 2 diabetes mellitus.

The findings observed were as follows:

 Sample size included 120 cases.

 it was noted that females (56%) were more in number compared to

males (43%) patients.

 Majority of the patients (87%) were in the age group of 40-60 yrs.

 68% of the patients presented with co-morbidities,

 64% of the patients had a family history of HTN & DM

 36% of the patients had risky personal history.

 76% of the drugs were prescribed from the essential drug list.

57
To conclude

 Reduction in SBP & DBP in both the groups at the end of

study was same.

 Both the drugs have same efficacy on renal parameters

 Azilsartan seemed to cause lesser adverse effects than

Ramipril.

 It can be concluded that Azilsartan has better tolerability profile

as compare to Ramipril

58
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66
 LIST OF TABLES

S.N TABLES USED IN THIS STUDY PG.NO

O
1 Dash plan 21
2 Age wise distribution of patients in group 1 & 2 39
3 Gender wise distribution group 1 & 2 40
4 Distribution of patients according to family history 42

and personal history in both the groups

5 Follow up of SBP & DBP in group 1 & 2 43-45
6 Comparative reduction of SBP & DBP between 47

baseline and at the end of treatment in both

regimens
7 Comparative effect on serum creatinine and blood 48

urea between baseline and at end of treatment in

both regimens

8 Distribution of patients with adverse effects in both 49

the groups
9 Different prescribing indicators 50
10 Different patient care indicators

50

11 Different facility indicators 51

12 Different complementary drug use indicators 51

67
 LIST OF FIGURES

SLNO.
No of Figures used Page

no.

68
1 Hypertension with co-existing diabetes mellitus risks 6

2 Overview of normal physiology of RAAS 8

3 Diagnostic criteria for hypertension 11

4 Systematic and metabolic factors that promote 15

coexistent diabetes mellitus,

hypertension,cardiovascular and chronic kidney

disease

5 Correlation of lifestyle modification with reduction of 20

SBP

6 Mechanism of action of ACEIs 25

7 Mechanism of action of ARBs 25

8 Approach in HTN with coexisting DM 28

9 Bar graph showing age wise distribution of patients 33

10 Gender distribution of patients presented with 39

hypertension

69
11 Pie diagram showing patients with co morbidities in 40

both the groups

12 Bar graph showing patients distributed according to 41

past relevant medical history

13 Bar graph showing follow up SBP and DBP in group 1 42

Bar graph showing follow up of blood pressure in

14 44
group 2

15 Bar graph showing reduction in blood pressure in both 46

groups

16 Bar graph showing effects on renal parameters from 47

baseline to end of 24 weeks in both groups

17 Bar Graph Showing distribution of patients with adverse 49

effects in both the groups

70
 Annexure – 2 (informed consent)

Consent form:

 I have been informed about the details of study in my own

language

 I have completely understood the details of the study

 I am aware of the possible risks and benefits, while taking

part in the study.

 I understood that I can withdraw from the study at any point

of time and even then, I will continue to receive the medical

treatment as usual.

 I have had the opportunity to ask questions and have

received satisfactory responses to my questions.

 All the information collected will be kept under confidential

and the results will be used for scientific purpose only.

 I freely give my consent to participate in this study

PATIENT SIGNATURE DATE

71
 ANNEXURE : 3

PROFORMA

SL NO:

Date;

OP NO:

NAME:

AGE:

SEX:

ADDRESS:

Presenting complaints:

General medical history and examination:

Family history:

Personal history:

Past history:

Weekly assessment of hypertension:

SYSTOLIC DIASTOLIC
Week 0 baseline
Week 2
Week 4
Week 8
Week 12
Week 16
Week 20
Week 24

INVESTIGATIONS

BLOOD GLUCOSE 1) FBS

2) PPBS

SERUM CREATININE

72
BASELINE AT 24 WEEKS

BLOOD UREA

BASELINE AT 24 WEEKS

ADVERSE EVENTS

DRY COUGH YES NO

GI UPSET

DIZZINESS

HEADACHE

73