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Pranav et al. World Journal of Pharmaceutical Research

CHRONOLOGICAL EFFECTS OF ANTIHYPERTENSIVES IN A

TERTIARY CARE HOSPITAL

Mangu Pranav*, Kainat Panjwani, Sandhya Vinjamoori and Dr. Manjari Bodasu

Assistant Professor, Department of Clinical Pharmacy, Malla Reddy Pharmacy College,

Maisammaguda, Secunderabad, 500041.

ABSTRACT

Hypertension has been a major public health issue and is common

among all the ages indeed. In coming years frequency is expected to be

increase considerably. According to International Society of

Hypertension (ISH) patients with hypertension will progress to cross

1.56 billion by 2025! chronobiology has important effects on a drug's

action. Blood pressure (BP) follows a circadian rhythm, with BP levels

falling during sleep and increasing in the early morning hours in most

individuals. The current prospective study is based on the

chronological effects of morning Vs bed time administration of the

most commonly prescribed antihypertensives in a tertiary care hospital

and which is beneficial. Chronotherapeutics is the purposeful alteration

of drug level to match rhythms to optimize therapeutic outcomes and minimize size effects. A

sample size of 178 patients has been chosen from the study site limiting to the inclusion

criteria precisely. Majorly the drugs chosen for this study were ARBs, calcium channel

blockers and beta blockers which are most commonly used in any tertiary care hospital.

Among the three classes of drugs calcium channel blockers showed a significant difference

from the baseline when administered in the morning than evening, the remaining classes

which were taken into consideration did not show any significant differences from baseline

blood pressure. This experimental study gives us the potential drug administration and

knowing the effective therapeutic potency of the drugs. On the other hand, physicians and

practitioners all over the world should guide the public regarding the high or low blood

pressure may be the major signs that many other body organs are in high risk. The message

conveyed should be in such a way it should make every individual think regarding the

unhealthy lifestyle consequences.

World Journal of Pharmaceutical Research

SJIF Impact Factor 7.523

Volume 6, Issue 16, 1174-1208. Research Article ISSN 2277–7105

Article Received on

13 October 2017,

Revised on 02 Nov. 2017,

Accepted on 23 Nov. 2017

DOI: 10.20959/wjpr201716-10288

*Corresponding Author

Mangu Pranav

Student, Department of

Clinical Pharmacy, Malla

Reddy Pharmacy College,

Maisammaguda,

Secunderabad, 500041.


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KEYWORDS: Chronobiology, circadian rhythm, drug administration, chronotherapuetics,

chronological effects.

BACKGROUND

Hypertension has been a major health public issue and is common among all the ages indeed.

In coming years frequency is expected to be increase considerably. According to

International Society of Hypertension (ISH) 972 million adults were affected with blood

pressure issues i.e. either high or low in year 2000, which will progress to cross 1.56 billion

by 2025! Generalized lifestyle factors, such as physical inactivity, diet rich in salt, highly

processed foods, alcohol and tobacco use, leads to proliferation of disease burden and in

developed countries like INDIA, CHINA and African countries it is spreading vigorously at

alarming rate. On the other hand, physicians and practitioners all over the world should guide

the public regarding the high or low blood pressure may be the major signs that many other

body organs are in high risk. The message conveyed should be in such a way it should make

every individual think regarding the unhealthy lifestyle consequences.

INTODUCTION

According to WHO hypertension is a common disease that is simply defined as persistently

elevated arterial Blood Pressure (BP). It is also defined as sustained systolic pressure greater

than 140 mmHg accomplished by an elevated diastolic pressure is greater than 90 mmHg.

BP is classified on the basis of systolic and diastolic values.

Classification Systolic Pressure

mmHg

Diastolic Pressure

mmHg

Normal <120 <80

Pre hypertension 120-139 80-89

Hypertension Stage 1 140-159 90-99

Hypertension Stage 2 >160 >100

ETIOLOGY

In most patients, hypertension results from an unknown pathophysiologic aetiology (essential

or primary hypertension). This form of hypertension cannot be cured, but it can be

controlled.

A small percentage of patients have a specific cause of their hypertension (secondary

hypertension). There are many potential secondary causes that are either concurrent to


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medical conditions or are endogenously induced. If the cause can be identified, hypertension

in these patients has the potential to be cured.

Essential Hypertension

More than 90% of individuals with hypertension have essential hypertension. Numerous

mechanisms have been identified that may contribute to the pathogenesis of this form of

hypertension, so identifying the exact underlying abnormality is not possible.

Genetic factors may play an important role in the development of essential hypertension.

Many of the genetic traits feature genes that affect sodium balance, nitric oxide release,

and excretion of aldosterone, other adrenal steroids, and angiotensinogen are also

documented.

Secondary hypertension

Fewer than 10% of patients have secondary hypertension where either a co morbid disease or

drug is responsible for elevating BP. In most of these cases, renal dysfunction results from

severe chronic kidney disease or renovascular disease is the most common secondary cause.

Certain drugs, either directly or indirectly, can cause hypertension or exacerbate

hypertension.

EPIDEMIOLOGY

Approximately 31% of the population (72 million Americans) has high BP (140/90 mm

Hg).The percentage of men with high BP is higher than that of women before the age of 45

years, but between the ages of 45 and 54 years the percentage is slightly higher with women.

After age 55 years, a much higher percentage of women have high BP than men.

BP values increase with age, and hypertension (persistently elevated BP values) is very

common in the elderly. The lifetime risk of developing hypertension among those 55 years of

age and older who are normotensive is 90%.

PATHOPHYSIOLOGY

underlying hemodynamic effect

BP can be expressed as the product of cardiac output and peripheral resistance:

BP=CO×PR


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So an elevated BP implies that one or both of these factors must also be expressively raised.

Raised cardiac output is the prime cause. Fluid retention which is known to be an occasional

cause of hypertension (secondary).

In hemodynamic terms blood volume is increased, venous return and preload are raised and

cardiac output rises initially. The systemic peripheral resistance would increase, as part of the

normal auto regulation of blood flow to limit the resulting excessive perfusion. Cardiac

output would then return to normal. Thus possible causes for an initially high cardiac output

or circulating blood volume are currently being investigated; there is a link here with the

SALT HYPOTHESIS.

Primary and Secondary Hypertension

In about 10 percent of cases there may be very obvious reasons for an elevated pulse rate or

cardiac output. In majority of the cases there is usually only a mild or moderate elevation of

BP for which no obvious causes can be ruled out. The body resists attempts to lower the

pressure. It seems the body‘s pressure control mechanism has been reset higher. Hence it is

termed ―ESSENTIAL HYPERTENSION‖.

Accelerated Hypertension

Accelerated hypertension is a disease characterized by a rapid and sudden increase in blood

pressure over the baseline level that, if untreated, poses a threat for damage to organs and

tissues.

Hypertensive Crisis

A hypertensive crisis is a severe increase in blood pressure that can lead to a stroke.

Extremely high blood pressure — a systolic blood pressure of 180 millimeters of mercury

(mm Hg) or higher & diastolic blood pressure of 120 mm Hg or higher — damages blood

vessels. They become inflamed and may leak fluid or blood.

Hypertensive crises can present as hypertensive urgency or as a hypertensive emergency.

Hypertensive Urgency

Hypertensive urgency is a situation where the blood pressure is severely elevated [180 or

higher for your systolic pressure (top number) or 110 or higher for your diastolic pressure

(bottom number)], but there is no associated organ damage. Those experiencing hypertensive

urgency may or may not experience one or more of these symptoms


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• Severe headache

• Shortness of breath

• Nosebleeds

• Severe anxiety

Hypertensive Emergency

A hypertensive emergency exists when blood pressure reaches levels that are damaging

organs. Hypertensive emergencies generally occur at blood pressure levels exceeding 180

systolic OR 120 diastolic, but can occur at even lower levels in patients whose blood pressure

had not been previously high.

SOME CAUSES OF SECONDARY HYPERTENSION

Glomerular damage

Increased rennin secretion

Vasomotor constriction

Aortic coarctation

Iatrogenic

PATHOGENESIS OF ESSENTIAL HYPERTENSION

Most theories of hypertension implicate the kidney. This creates a difficulty because renal

damage is commonly a consequence of prolonged hypertension owing to damage to renal

arterioles. Renal damage raises blood pressure which in turn causes further renal damage.

Renal damage found in a patient with hypertension of intermediate duration could be either a

cause or consequence.

CLINICAL PRESENTATION OF HYPERTENSION

Generally the patient may appear very healthy, or may have the presence of additional cardio

vascular (CV) risk factors.

Age (≥55 years for men and 65 years for women)

Diabetes mellitus

Dyslipidemia (elevated low-density lipoprotein-cholesterol, total cholesterol, and/or

triglycerides; low high-density lipoprotein-cholesterol)

Microalbuminuria

Family history of premature CV disease


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Obesity (body mass index ≥30 kg/m2)

Physical inactivity

Tobacco use

SIGNS & SYMPTOMS

Mild to moderate essential hypertension is usually asymptomatic.

Accelerated hypertension: Accelerated hypertension is associated with headache, drowsiness,

confusion, vision disorders, nausea, and vomiting.

Secondary hypertension: Some additional signs and symptoms suggest that the hypertension

is caused by disorders in hormone regulation.

Hypertension combined with obesity distributed on the trunk of the body, accumulated fat on

the back of the neck ('buffalo hump'), wide purple marks on the abdomen (abdominal striae),

or the recent onset of diabetes suggests that an individual has a hormone disorder known as

Cushing's syndrome.

In pregnancy: increased blood pressure in pregnant women may lead to a condition that

typically starts from 20th

week of pregnancy known as preeclampsia. Pre-eclampsia causing

seizure leading to Elcampsia condition which may be a fatal death. Thought its anot proven

how to prevent pre-eclampsia.

In children:Some signs and symptoms are especially important in newborns and infants such

as failure to thrive, seizures, irritability, lack of energy, and difficulty breathing.

PHARMACOTHERAPY

TREATMENT GOALS

To reduce CV and renal morbidity and mortality

Identification and treatment of all risk factors

Management of associated clinical conditions

Treatment of elevated BP

Targeted BP for patients with pre hypertension

Categories of drugs used

ACE inhibitors

http://en.wikipedia.org/wiki/Headache

http://en.wikipedia.org/wiki/Somnolence

http://en.wikipedia.org/wiki/Confusion

http://en.wikipedia.org/wiki/Vision_disorder

http://en.wikipedia.org/wiki/Nausea

http://en.wikipedia.org/wiki/Vomiting

http://en.wikipedia.org/wiki/Centripetal_obesity

http://en.wikipedia.org/wiki/Lipodystrophy

http://en.wikipedia.org/wiki/Abdominal_striae

http://en.wikipedia.org/wiki/Cushing%27s_syndrome

http://en.wikipedia.org/wiki/Neonates

http://en.wikipedia.org/wiki/Infants

http://en.wikipedia.org/wiki/Failure_to_thrive

http://en.wikipedia.org/wiki/Seizures

http://en.wikipedia.org/wiki/Irritability

http://en.wikipedia.org/wiki/Lethargy

http://en.wikipedia.org/wiki/Infant_respiratory_distress_syndrome


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Alpha blockers

Angiotensin ІІ Antagonists

Beta blockers

Calcium antagonists

DihydropyridineCa Antagonists

Benzothiazepine&PhenylalkylamineCa Antagonists

Diuretics

Centrally acting agents

Direct vasodilators.

Ace Inhibitors

ACTION-Blocks the conversion of Angiotensin І to Angiotensin ІІ by inhibiting ACE.

Benazepril Initial dose- 10mg, PO, OD

May increase to 20mg per day

Cough, fatigue and

dizziness

Captopril

Initial dose- 12.5-25mg, PO, BID/TID

May increase gradually to 50 mg, PO,

BID/TID

unexplained rash, cough,

and decrease or loss of taste

Cilazapril Initial dose 1.25mg, PO, OD for 2 days

Maintenance dose 2.5mg-5mg, PO, OD

light-headedness , dry

cough

Delapril Initial dose 15mg, PO, OD

Maximum dose-120mg/day

Dizziness, head ache,

fatigue

Enalapril Initial dose(on diuretic) 2.5mg, OD

Initial dose(no diuretic) 5mg, OD

Hypotension, dry cough

ACE inhibitors are well tolerated with low frequency of side effects. Maybe used as

monotherapy or in combination with beta blockers, calcium antagonists, or diuretics. Side

effects are uncommon and include rash, angioedema, proteinuria, or leukopenia, particularly

in pts with elevated serum creatinine. A nonproductive cough may develop in the course of

therapy in up to 10% of patients, requiring an alternative regimen. Note that renal function

may deteriorate as a result of ACE inhibitors in patients with bilateral renal artery stenosis.

Alpha Blockers

ACTION- Lowers BP by reducing peripheral resistance and also reduces prostatic and

Uretheral smooth muscle tone

Provides symptomatic relief for patients with early BPH.

Favourable effect on lipid metabolism.


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Bunazosin Initial dose- 1.5 mg/day

May increase to 3-6mg/day

Tachycardia, Orthostatic

hypotension

Prazosin

Initial dose- 0.5mg BID/TID

increased gradually every 4-7 days

Maximum dose- 20mg/day

orthostatic hypotension,

syncope, and nasal

congestion

Terazosin Initial dose- 1mg, OD at bedtime


Dizziness, drowsiness,

lightheadedness.

Doxazosin Initial dose- 1mg, OD

Maximum dose 16mg/day

Nasal congestion,

tiredness, weakness.

Angiotensin Іі Antagonist

ACTION- Blocks type ІІ angiotensin receptor

Candesartan Initial dose- 4mg, OD


Back pain, diarrhea,

dizziness

Eposartan 600mg, OD in morning

Maximum dose- 800mg/day Back pain, dizziness.

Losartan Initial dose-50mg, OD

Maintenance dose- 50-100mg

Diarrhea, dizziness,

tiredness.

Telmisartan 20-40mg, OD, Maximum dose-

80mg/day

Sore throat, upper

respiratory tract infection.

Valsartan Initial dose80mg, OD

May increase to 160mg, OD Dizziness, headache.

These are suitable for initiation and maintenance therapy.

Beneficial effect in early and advanced type 2 diabetes mellitus neuropathy.

EFFECT- Causes vasodilation and a fall in BP.

Beta Blockers

ACTION: Competitive antagonist of the effects of catecholamine at beta adnergic sites, beta

2 receptor blockade can increase bronchial resistance and inhibition of catecholamine induce

glucose metabolism.

Acebutolol Initial dose- 200mg, PO, BID


Constipation, diarrhea,

dizziness

Alprenolol 75mg-100mg/day, PO, TID Bradycardia, hypotension

Atenolol 50-100mg, PO, OD

Maximum dose- 200mg/day Tiredness and dizziness

Metoprolol Initial dose- 50-100m,PO, OD

Maximum dose- 400mg/day Tiredness, slow heart rate

Propranolol Initial dose- 10- 80mg, PO, BID

Maximum dose- 640mg/ day

Fever, sore throat, and

headache.

Bisprolol Initial dose- 5mg, PO, OD


Abdominal cramps, diarrhea


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Particularly effective in young pts with ―hyperkinetic‖ circulation. Begin with low dosage

(e.g., Atenolol 25 mg QD).

Relative contraindications: Bronchospasm, CHF, AV block, bradycardia, and ―brittle‖

insulin-dependent diabetes.

Diuretics

ACTION- Reduce the risk of fatal & non fatal stroke and have been shown to reduce CV

morbidity and mortality at all causes.

Thiazides preferred over loop diuretics because of longer duration of action; however, the

latter are more potent when Glomerular filtration rate ≤ 25 mL/min. Major side effects

include hypokalemia, hyperglycemia and hyperuricemia, which can be minimized by using

low dosage.

Aldosterone Antagonists

Spironolactone - 50-100mg/day, Maximum dose 200mg/day

ADR- ataxia, erectile dysfunction, drowsiness

Loop Diuretics

Bumetadine - 0.5-2mg/day, PO, Max dose- 5-10mg/day.

ADR- Dizziness or lightheadedness.

Furosemide - 20-80mg, PO, OD

ADR- Dizziness or lightheadedness.

Potassium Sparing Diuretics

Amiloride - 5-10mg, PO, OD, Max dose- 20mg/day.

ADR- Diarrhea, headache, loss of appetite

Thiazide Diuretics

1) Chlorothiazide - 250-500mg/day, PO, OD

ADR- Blurred vision, dizziness, headache

2) Chlorthalidone - 25-100mg, PO, OD

ADR- Constipation, dizziness, headache

3) Cyclopenthiazide - 0.25-1.5mg, PO, OD

ADR- Electrolyte imbalance, hyperglycaemia, gout


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4) Hydrochlorothiazide - 12.5mg, PO, OD

ADR- Constipation, diarrhea, dizziness

NONPHARMACOLOGIC THERAPY

Hypertension is two to three times more likely in overweight than in lean persons. More

than 60% of patients with hypertension are overweight.

Diets rich in fruits and vegetables and low in saturated fat lower BP in patients with

hypertension.

Most people experience some degree of SBP reduction with sodium restriction.

Cigarette smoking is a major, independent, modifiable risk factor for CV disease. So quit

smoke as soon as possible.

CHRONOBIOLOGY AND HYPERTENSION

Chronobiology has important effects on a drug's action. Blood pressure (BP) follows a

circadian rhythm, with BP levels falling during sleep and increasing in the early morning

hours in most individuals. Most patients, however, receive all of their drugs in a single

morning dose.

Chronotherapeutics has been defined as the purposeful timing of medications to proportion

their serum and tissue concentrations in synchrony with known circadian rhythms in disease

processes and symptoms as a means of enhancing beneficial outcomes and/or attenuating or

averting adverse effects. Chronotherapeutics is the purposeful alteration of drug level to

match rhythms to optimize therapeutic outcomes and minimize size effects.

For the treatment of hypertension, this idea has the potential for a therapeutic paradigm shift.

Chronotherapy involves the administration of medication in coordination with the body's

circadian rhythms to maximise therapeutic effectiveness and minimise/avoid adverse effects.

Chronotherapy provides a means of individualizing treatment of hypertension according to

the circadian profile of blood pressure of each patient.

The chronotherapeutic strategy constitutes a new option to optimize blood-pressure control

and to reduce risk.

Antihypertensive medications may display a circadian time-dependency in their

pharmacokinetics and effects. BP exhibits considerable variation during the day and follows a


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circadian rhythm, with SBP and DBP falling during sleep and rising rapidly with the start of

morning activity.

In patients with essential hypertension, the day-night pattern of blood pressure change is

generally similar to that of normotensives, with a significant nocturnal blood pressure fall.

Blood pressure variability and the blunted nocturnal fall in blood pressure may be clinically

relevant. Several studies have demonstrated that subjects whose 24-h variability was higher

than the group average were more likely to have target-organ damage.

If a once-daily antihypertensive agent is given in the morning, it is important that it maintains

BP control throughout the day-time and night-time periods, particularly towards the end of

the dosing interval, to cover the critical early morning hours.

To better ensure coverage during the night-time and early morning periods, dosing of

antihypertensive agents, particularly ARBs, at bedtime has been recommended, with a

number of studies providing support. Antihypertensive treatment that reduces blood pressure

variability and preserves the nocturnal fall in blood pressure will help to protect target organs

in hypertension.

Several studies with angiotensin receptor blockers (ARBs) and angiotensin-converting

enzyme (ACE)-inhibitors, both agents that reduce the renin–angiotensin–aldosterone system

(RAAS) activity, have reported improvements in night-time BP and a reduction in the early

morning rise in BP with bedtime dosing compared with traditional dosing upon awakening.

The proposed mechanism for the benefit of night-time dosing of the ACE-inhibitor or ARB is

ascribed to more effective RAAS blockade during the sleep and early morning periods.

The pharmacologic rationale for more effective BP lowering with evening dosing of

antihypertensive therapy presupposes the inability of morning dosing to effectively lower BP

at night and during the early morning period. This cannot be supported, however, as studies

that evaluated morning versus evening administration of amlodipine, a long-acting calcium

channel blocker (circulating half-life >24 h), reported no benefit of evening versus morning

dosing.


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Several of these known abnormalities can be modified by clinical interventions, including

proper timing of antihypertensive drug therapy and use of classes of antihypertensives for

which a substrate exists to induce a pharmacologic effect.

It is particularly important to use therapies that will provide control throughout a 24-hour

dosing interval. Morning administered amlodipine had a better effect on the circadian BP

compared with evening administrated amlodipine in mild-to-moderate essential hypertension.

Differences in efficacy depending on the time of day of drug administration lead to

differences in effects on the circadian pattern of BP and, in particular, on the nocturnal

decline relative to the diurnal mean of BP.

Chronotherapy provides a means of individualizing treatment of hypertension according to

the circadian BP profile of each patient, and constitutes a new option to optimize BP control

and reduce risk.

REVIEW OF LITERATURE

S.no Author Conclusions

I. Hermida et al.

ARB‘s had a mildly better effect in lowering

blood pressure when administered in the

evening when compared to morning

administration.

II. Zappe et al. Highly significant changes were not seen in

morning vs bedtime dosing of ARB‘s.

III. Hermida et al.

Telmesartan administered at bedtime, as

opposed to morning dosing, improved the sleep

time-relative blood pressure decline without a

loss in 24-hour efficacy.

IV. Qiu et al.

In contrast to their study nocturnal BP

regulation was significantly achieved with

bedtime dosing of amlodipine.

V. Kaur G. et al.

Better 24-hour blood pressure was maintained

when Beta blockers were administered as

morning doses

VI. Nold G. et al.

Bedtime administered amlodipine decreases the

early morning rise in blood pressure which may

be advantageous in reducing the early morning

cardiovascular risk.

VII. Barry et al.

Beta blockers have time-dependent

pharmacokinetics and perform better with

morning doses.

VIII. Barry et al. Beta blockers have time-dependent

pharmacokinetics and perform better with


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morning doses.

IX. White W B et al.

24-hour normal blood pressure can be

maintained only on administering beta blockers

as morning doses

X. Neutel JM et al.

angiotensin II receptor blockers for 24-hour

blood pressure control are more effective as

morning doses though not less effective as

bedtime doses either.

XI. Ayala DE et al.

Circadian pattern of ambulatory blood pressure

in hypertensive patients with type 2 diabetes is

better maintained in patients taking morning

doses of telmesartan.

XII. Xavier D et al.

Pattern of drug use in hypertension in a tertiary

hospital shows more use of telmesartan than

valsartan and other classes of antihyperensives.

XIII. Hansson L et al.

Lowering hypertension can be better achieved

by once daily doses of amlodipine at bed time

than as morning doses.

XIV Ohta Y et al

Improvement of blood pressure control in a

hypertension clinic was seen when telmesartan

was prescribed as once daily morning doses and

amlodipine was prescribed as once daily

nighttime doses.

XV Gosse P et al. Morning doses of CCB‘s were not as effective

as bedtime doses.

AIM AND OBJECTIVE OF WORK

Aim

The aim of this study is to compare the antihypertensive effects dosing of the most commonly

prescribed monotherapeutic anti-hypertensives in a tertiary care hospital.

Objective

To evaluate whether time of administration has an effect on regulation of blood pressure in

patients receiving monotherapy with antihypertensives with a focus on Telmesartan,

Olmesartan, Losartan (Angiotensin Receptor Blockers), Amlodipine (Calcium channel

Blocker) and Atenolol, Metoprolol, Propranolol (β blocker)

STUDY METHODOLOGY

Study site

Study was conducted in Malla Reddy Health City, Narasapur Main Road, Suraram,

Hyderabad, Telangana.

http://www.vidteq.com/hyderabad/?q=locate&text=Suraram


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Study time

6 months (October 2016 – March 2017).

Inclusion criteria

Age ≥18 years

Grade 1 or 2 essential hypertension.

Cardiovascular risk factors.

Type 2 Diabetes.

Three classes of anti-hypertensive drugs: Angiotensin Receptor Blockers

β-Blockers

Calcium Channel Blockers

Exclusion Criteria

Shift workers.

Heavy drinkers

Heavy smokers (>20 cigarettes per day), and heavy exercisers were excluded, as were

individuals with either severe arterial hypertension (grade 3, eg, BP ≥180/110 mm Hg).

Type 1 diabetes and class II and class III obese patients (BMI ≥ 35).

Source Of Data

Patient case reports

Study Type

Prospective Study

METHODOLOGY PROCEDURE

Identify patients falling under inclusion criteria

Identify the antihypertensive medication administered to each patient

Collect specific background information (Demographic data, present medications,

comorbidities)

Identify other medications given to the patient for comorbidities (eg. Hypoglycemics for

Diabetes)


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Measure blood pressure before administering antihypertensive medication (preferably before

meal)

Compare the morning and bed-time fall in blood pressure after administration of the

antihypertensive medication

This way we get two study populations (or) two cohorts.

Morning administr-ation Bed-time administr-ation

Find out whether the medication administered for comorbidities affect the rise or fall in

blood pressure.

RESULTS

student t- test were used for calculating mean, ‗P‘ value in the present study.

In this study, 178 subjects who were on anti-hypertensive medication WERE

RECRUITED. Treatment outcomes and safety parameters were assessed in the enrolled

patients.

Total number of individuals : 178.

1) Gender distribution among patients

Out of 178 hypertensive patients enrolled in the study, 58% i.e. 104 were males and 42% i.e.

74 were females. Males are predominantly prone to high blood pressure than females.

Table 1: distribution of gender.

Males Females

104 (58%) 74 (42%)


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Fig 1: distribution of patients based on gender.

SOCIAL HISTORY

Hypertension was recorded mostly in alcoholics with 6.17%, followed by smokers with 10.67

% and tobacco chewers were 5.05% among the patients.

Table 2: distribution according to social history.

Social habits No. of patients (%)

Smokers 19 (10.67%)

Alcoholics 9 (5.05%)

Tobacco chewers 11 6.17%)

Fig 2: graphical data of social history.

2) MEDICAL HISTORY

No. of patients with Diabetes(Type 1) : 0

No. of patients with Diabetes(Type 2) : 53 (29.77%)

No. of patients with CVA : 72 (40.4


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Table 3: distribution of patienst according to time of admin and drugs.

ANTI-

HYPERTENSIVE

No. of patients administered in

MORNING (8:00am-10:00am)

No. of patients administered at

BED-TIME (8:00pm-10:00pm)

ARB‘s 73 11

Beta-blockers 57 4

CCB‘s 14

3) Distribution of patients based on time of administration.

Out of 178 patients enrolled in the study, 73 patients were given ARB‘s in morning, 11

patients were given ARB‘s in evening, 57 patients were on β-blockers as morning treatment,

4 patients were given β-blockers as evening treatment, 14 patients were given CCB‘s as

morning treatment and 19 patients were given CCB‘s as evening treatment

4) Distribution of patients based on Anti-Hypertensive drugs given.

Table 4: distribution of patients based on anti hypertensive drugs.

Anti-hypertensive therapy No. of patients (%)

ANGIOTENSIN RECEPTOR

BLOCKERS (TELMESARTAN,

LOSARTAN, OLMESARTAN)

84 ( 47.19%)

BETA-BLOCKERS ( ATENOLOL,

METOPROLOL, PROPRANOLOL) 61 (34.26%)

CALCIUM CHANNEL

BLOCKERS (AMLODIPINE,

CLINIDIPINE)

33 (18.53%)

Fig 3: graphical representation of anti hypertensive drugs distribution.


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This study depicted that the antihypertensive drug classes which are highly used in the study

site show a significant fall in blood pressure. These classes may vary in the onset of action

and half life respectively.In this study we covered three classes of anti-hypertensive drugs

which are highly used in the hospital in which we were carrying out our study.

The anti-hypertensive classes which we covered in this study are Angiotensin Receptor

Blockers, Calcium Channel Blockers, β-blockers.

The comparisons was made individually as follows.

Comparisons of the systolic blood pressure when drug administered in the morning;

comparison was made before administration and after administration of the drug and the

same is done for the evening dose and then there is a cumulative comparison done so that

there wuld be an accurate understanding of the drug effectiveness and chronological

effect.

On the other hand the comparison of the diastolic is done similar to that of systolic blood

pressure. Comparing the diastolic BP separately when given or administered in the

evening or in the morning.

After the individual comparison the results are clubbed for the collective comparison

MORNING VERSUS BEDTIME ADMINISTRATION

In this study 178 patients were enrolled are given with the medication as the morning daily

doses and few are given the evening daily dose. Out of which among the three classes 73

patients were given ARB‘s in the morning and patients were given as bed time doses, β-

blockers were given to 57 patients as the morning doses whereas 4 patients were given as bed

time dose.

On the other hand CCB‘s were given to 14 patients as the morning doses and the.

Table 5: distribution of patients based on morning and evening dose.

ANTI-

HYPERTENSIVE

No. of patients administered

in MORNING

(8:00am-10:00am)

No. of patients administered

at BED-TIME

(8:00pm-10:00pm)

ARB‘s 73 11

Beta-blockers 57 4

CCB‘s 14 19


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remaining 19 patients were given as bed time doses.

The table above manifests the distribution of patients according to the time of administration

of medication.

The illustration of the results are as follows.

β-BLOCKERS

The most used β-blockers in our study site are atenolol, metoprolol, proponolol.

Our study showed that Beta blockers showed little or no difference in the baseline blood

pressure (systolic and diastolic) when administered in the morning or in the evening.

Better 24-hour blood pressure was maintained when Beta blockers were administered as

morning doses.

The individual comparison of the drug administered are as follows.

The administration of the β-blockers as the morning doses showed no significant

difference inthe systolic blood pressure.

The mean of the systolic blood pressure was compared before the administration of the

drug and after the administration of the drug.

The graphical data below gives an ease in understanding that the systolic blood pressure in

the morning before the administration was to be 128.2 whereas after the morning dosing of

the medication the systolic blood pressure was found to be 122.3.

Fig 4: Comparision of systolic blood pressure in the morning.


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This exemplifiesthat there is no significant difference in the systolic blood pressure with

morning dosing.

Advancing to β-blocker administered as the evening dose demonstrated that there is no

convincing difference shown.

Much the same way of mean comparing is done for the evening doses.

Coming to the explanation of the graph the mean of the systolic blood pressure was found

to be 128.2mmHg before administration while it was 122.3 mmHg after the

administration.

This concludes that there is no suggestive significance in the systolic blood pressure when

the β-blockers are administered in the evening.

Fig 5: Comparison of systolic bp in the evening.

The collective comparison of the systolic blood pressure when β-blockers are given as a

morning dose and evening dose illustrates that there is no significant difference in fall of

blood pressure when coming to morning blood pressure it was 128.2mmHg before

administration and 122.2mmHg after administration on the other hand when medication

was given as a evening dose the systolic blood pressure before administration was

122.3mmHg and was 122.35mmHg after administration.

The below graph gives a clear illustration if the cumulative comparison of systolic blood

pressure which resulted in no significant difference in fall of blood pressure.


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Fig 6: cumulative comparison of systolic bp.

This study showed that β-blockers showed little or no difference in the baseline blood


The graph below illustrates comparison of the diastolic blood pressure. Diastolic blood

pressure recorded before administration was 79.03mmHg and after administration was

78.03mmHg.

This proves to be no minimal change when the beta blockers are administrated in the

morning.

Fig 7: Comparison of diastolic bp of morning dose.

On the other hand when β-blockers when administered as the evening doses there was little or

no significant change in diastolic blood pressure.


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The graphical representation below of the data that is been collected in the study site proves

that similar to that of the morning dose there is no major difference when beta blockers are

given as the evening dose.

The diastolic blood pressure was recorded to be 85mmHg that was before administration and

which fell down to 81mmHg after administration. Thus, this proves to be that there no

effective blood pressure fall of diastole.

Fig 8: comparison of diastolic bp in the evening.

The graph below shows the magnifying comparison between the diastolic blood pressures

when β-blockers are given as the morning dose and as the evening doses and the data showed

that there is no difference or mild difference from the baseline blood pressure.

Fig 9: cumulative comparison of diastolic bp.

The medication as the morning dose the diastolic blood pressure before administration was

found to be 79.3mmHg whereas it was found to be 78.04mmHg after administration.


1196


It was found similar to that of morning dose that there is no difference in fall of blood

pressure which was 85mmHg before administration and 81mmHg before administration.

Thus, there was no difference in fall of blood pressure significantly.

ANGIOTENSIN RECEPTOR BLOCKERS

In this study better 24-hour blood pressure was maintained when Angiotensin receptor

blockers were given as morning or evening once daily doses. Also, Angiotensin receptor

blockers had a little better effect in lowering blood pressure when administered in the evening

versus when administered in the morning, though this was not significant.

On comparing the systolic blood pressure the ARB‘s have shown mildly better effect in

lowering blood pressure when administered in the morning.

The graph below shows that blood pressure was recorded as135.5mmHg before

administration which fell down to 129.2mmHg after administration though wasn‘t any

considerable difference was not made.

Fig 10: comparison of systolic bp in the morning.

On comparing the morning dose with that of the ARB‘s given as the evening dose there was

minute difference in fall of the systolic blood pressure.

As we can see in the graph below the systolic blood pressure was recorded to be

128.070mmHg which dipped to 1255.21mmHg after administration.

Thus, there was no significant difference illustration.


1197


Fig 11: comparison of systolic bp in the evening.

When coming to the cumulative comparistion of the the systolic blood pressure when ARB‘s

are given as morning dose to that of the evening dose. The data illustrated as the graphical

representation in the graph below proves that the ARB‘s show a better effect in the systolic

blood pressure when administered as morning dose to that evening dose.

Fig 12: cumulative comparison of systolic bp of ARB’s.

The ARB‘s when given as the morning dose the diastolic blood pressure there was no great

judging difference found as we can notice in the graph below the diastolic blood pressure

before administration was found to be 84.5mmHg and then there was a minimal dip to

81.5mmHg of diastolic blood pressure. Thus, no differentiating dip of diastolic blood

pressure.


1198


Fig 13: comparison of diastolic bp.

When coming to the administration of ARB‘s given as an evening dose the diastolic blood

pressure alike to that of the morning dose even the evening dose of administration did not

show any kind of considerable difference.

Advancing to the graph below the diastolic blood pressure before administration was

81.45mmHg and was 79.5mmHg after administration these leads to a conclusion that there is

no considerable difference in diastolic blood pressure ARB‘s as an evening dose.


On comparing the time of administration of ARB‘s as the morning dose versus evening dose

both the doses did not show any considerable desired difference in fall of the diastolic blood

pressure.

The graph below gives the aggregate comparison of the diastolic blood pressure of both the

morning dose and evening dose of ARB‘s.


1199



Thus, both the doses did not show any kind of the eye catching fall of the diastolic blood

pressure.

Thus, we can come into a conclusion that ARB‘s can be given either in as a morning dose or

as an evening dose as they show the same minmal effect in dipping the diastolic blood

pressure. Thus, when compared with the β-blockers ARB‘s show a better circadian effect in

lowering the blood pressure and this can be used over the β-blockers over a few conditions.

CALCIUM CHANNEL BLOCKERS

Calcium channel blockers significantly lowered the systolic blood pressure when

administered in the evening than when administered in the morning. There were no

significant changes seen in the diastolic blood pressure.

According to this study, Calcium channel blockers demonstrated better efficacy when

administered at bed-time than when given as daily morning dose.

Better 24-hour blood pressure was maintained when Calcium channel blockers were

administered as evening once daily doses than as morning once daily doses.

The graph below give u an ease explanation regarding the systolic blood pressure fall when

calcium channel blockers(CCB) are administered as a morning dose.

Advancing to the graphical representation of mean of source data the systolic blood pressure

recorded before administration of the calcium channel blocker it was 137.57mmHg after

administration it was recorded as 131.01mmHg.


1200


Thus, this makes us conclude that there is no major difference alike the other two class when

administered as the morning dose.

Fig 16: comparison of systolic bp.

Progressing to the graphical representation of the systolic blood pressure when calcium

channel blockers are given as evening dose there was an extensive difference seen in the

systolic blood pressure.

The systolic blood pressure which was recorded before the administration was 136.23mmHg

which miniaturised to 127.88mmHg.

Thus, on this we can relay that calcium channel blockers showed a lowering of systolic blood

pressure when administered as an evenging dose.

Fig 17: Comparison of Systolic bp.


1201


Preceding to the diastolic blood pressure as such of systolic blood pressure there was no

notable difference in fall of blood pressure as before administration it was noted as

88.11mmHg when after administration it was 82.14mmHg. Thus, there was no considerable

change in fall of the diastolic blood pressure.


On the contrary there was a similar nature in diastolic blood pressure when calcium channel

blockers are administered as an evening dose there was eye cathing difference seen.

When the CCB‘s are administered as an evening dose the diastolic blood pressure was noted

as 87.02mmHg and after administration if was found to be 81.56mmHg.

Thus, in the same manner of the morning dose there was no considerable difference.



1202


Amass comparison of the systolic blood pressure when CCB‘s administered as a morning

dose versus evening dose which lead to clear conclusion that CCB‘s give an effective fall in

systolic blood pressure when administered as an evening dose rather than the morning dose.

The graph below gives a pictorial representation of the data which gives the conclusion that it

lead us.

Fig 20: cumulative comparison of systolic bp.

When on the other hand there was no significant or considerable difference when aggregate

comparison of the diastolic blood pressure was done. It was same as such when CCB‘s given

as a morning dose or as an evening dose the graph below gives u and ease in understanding

the fall in diastolic blood pressure.



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CONCLUSION

Most patients were prescribed with Angiotensin receptor blockers (84 patients), followed by

Beta blockers (61 patients) and Calcium channel blockers (33 patients).

In this study which was done in the study site that was Malla Reddy Health City lead us to

conviction that β blockers showed little or no difference in the baseline blood pressure

(systolic and diastolic) when administered in the morning or in the evening.

Also, Angiotensin receptor blockers had a little better effect in lowering blood pressure when

administered in the evening versus when administered in the morning, though this was not

significant.


administered in the evening than when administered in the morning. There were no

significant changes seen in the diastolic blood pressure. According to this study, Calcium

channel blockers demonstrated better efficacy when administered at bed-time than when

given as daily morning dose. When compared to Calcium channel blockers, β-blockers and

Angiotensin receptor blockers showed better efficacy when administered as morning doses.

Diastolic BP is more important in assessing Cardiovascular risk in people aged younger than

40 years. Systolic blood pressure is recognised as an important measure for the risk of

developing stroke and heart failure in patients aged above 40 years. Controlling systolic BP

decreases the risk of developing Cardiovascular diseases in elderly patients. However, current

evidence suggests that over the age of 40 years, Systolic BP holds more importance and

under the age of 40 years, Diastolic BP is of high importance.

DISCUSSIONS

According to Hermida et al. the once daily evening, in comparison to morning, ingestion

schedule of the ARB significantly improved the sleep time- relative BP decline in

hypertensive patients also observed in this studywhere ARB‘s had a mildly better effect

in lowering blood pressure when administered in the evening when compared to morning

administration, though this was not significant.

According to Zappe et al. once-daily dosing of ARB results in equally effective 24-h BP

efficacy, regardless of dosing time which is in harmony to this study that shows no

significant changes in morning vs bedtime dosing of ARB‘s


1204


According to Hermida et al. Telmesartan administered at bedtime, as opposed to morning

dosing, improved the sleep time-relative blood pressure decline toward a more dipper

pattern without loss in 24-hour efficacy which corresponds to our study

According to Qiu et al. morning administered amlodipine had a better effect on the

circadian BP compared with evening administrated amlodipine in mild-to-moderate

essential hypertension, in contrast to this study where nocturnal BP regulation was

significantly achieved with bedtime dosing of amlodipine.

This study showed that Beta blockers showed little or no difference in the baseline blood



administered in the evening than when administered in the morning.Therewere no

significant changes seen in the diastolic blood pressure.

According to this study, Calcium channel blockers demonstrated better efficacy when

administered at bed-time than when given as daily morning dose.

When compared to Calcium channel blockers, beta blockers and angiotensin receptor

blockers showed better efficacy when administered as morning doses.

According to Kaur G. et al, better 24-hour blood pressure was maintained when Beta

blockers were administered as morning doses correlating to the present study.

Better 24-hour blood pressure was maintained when Angiotensin receptor blockers were

given as morning or evening once daily doses.

Better 24-hour blood pressure was maintained when Calcium channel blockers were

administered as evening once daily doses than as morning once daily doses which

correlated to the results of White et al.

In order to imprecise daytime and night-time dosing periods, we used narrower windows

for the morning (8 a.m. to 10 a.m.) and night-time (8 p.m. to 10 p.m.) periods.

If the anti-hypertensive medication is given once daily there should be at most care to be

taken in maintaining the controlled blood pressure for the whole circadian blood pressure

until the next dosing interval.

FUTURE DIRECTIONS

More studies on the relationship between chronology and circadian rhythm on blood

pressure and blood pressure medications need to be done.


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For a better assessment regarding the chronological effect of anti hypertensive drugs on

the body a much of huge sample is to be considered. This enormous sample consideration

may help in proper usage of the drug.

Along with the gigantic sample consideration there blood pressure monitoring taken

under consideration along with measuring the drug levels in the blood during day time

and night time.

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