Hypertension even today is a triple paradox which is :

1

• Hypertension even today is a triple paradox which
  is
• Easy to diagnose OFTEN remains undetected
• Simple to treat OFTEN remains untreated
• Despite availability of potent drugs, treatment
  all too OFTEN is ineffective

2

• Large amount of attention is given to the
  treatment of Hypertension
• Hypertension is a major cardiovascular risk
  factor that contributes to MI, CHF, stroke and
  PREMATURE MORTALITY
• The last 3 decades have shown through clinical
  trials (HOT UKPDS) that AGGRESSIVE
  pharmacological treatment of moderate and even
  mild Hypertension leads to better survival and
  less cardiovascular morbidity.
• The JNC VI WHO-ISH (1999) guidelines reinforce
  these findings

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Hypertension A Multifactorial Entity

• Hypertension is a multifactorial entity, it is
  therefore not surprising that there is
  heterogeneity in responsiveness to treatment.
• Today, there is no simple way of predicting which
  patients will respond to which class of
  antihypertensive agents.
• - Journal of Human Hypertension 1995 9 S33-S36

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Why combination therapy

• Multiple mechanisms involved in the pathogenesis
  of hypertension
• Effectiveness of monotherapy limited by
  stimulation of counter-regulatory mechanisms
• Effective BP control seen in only 50 of patients
  on monotherapy combination therapy results in a
  much higher responder rate (gt80)
• BP goals difficult to attain with monotherapy in
  patients with diabetes or target organ damage

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Combination therapy for hypertension
Recommended by JNC-VI guidelines and 1999 WHO-ISH
guidelines

• With any single drug, not more than 2550 of
  hypertensives achieve adequate blood pressure
  control
• J Hum. Hypertens 1995 9S33S36

For patients not responding adequately to low
doses of monotherapy
Substitute with another drug from a different
class
Increase the dose of drug. This, however, may
lead to increased side effects
Add a second drug from a different
class (Combination therapy)
If inadequate response obtained
Add second drug from different class (Combination
therapy)
6
American Heart Association

• Starting with combination therapy may be the
  best way to get hypertensive patients blood
  pressure down to goal levels.

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Advantages of fixed-dosecombination therapy

• Better blood pressure control
• Lesser incidence of individual drugs
  side-effects
• Neutralisation of side-effects
• Increased patient compliance
• Modification of risk factors
• Lesser cost of therapy

9
Theoretical requirements for a rationalfixed-dose
antihypertensive combination

• Each component should contribute to the final
  effect.
• Results should be superior to those achieved with
  a single agent.
• Dosage form(s) should be adequate relative to
  bioavailability
• absence of unwanted interactions
• selection of doses of each component
• A major proportion of the target population
  should respond.
• Physicians should be easily familiarised with
  individual components.

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Fixed-dose combinations as recommended byJNC-VI
(1997) guidelines and 1999 WHO-ISH guidelines

• Calcium channel blocker and b-blocker(e.g.
  Amlodipine and Atenolol)
• Calcium channel blocker and ACE-inhibitor (e.g.
  Amlodipine and Lisinopril)
• ACE-inhibitor and Diuretic (e.g. Lisinopril and
  Hydrochlorothiazide
• b-blocker and Diuretic (e.g. Atenolol and
  Hydrochlorothiazide)

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Amlopres L

Amlodipine 5 mg
Lisinopril 5 mg
12
Supine systolic and diastolic blood pressure 24h
after the last dose of treatment in 15 patients
with essential hypertension
J. Hyper. 1993 11839-847
ANOVA, analysis of variance RX, therapy. Values
are expressedas means SEM. P lt0.05, P lt
0.005, versus both (Combination).
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Amlopres L Organ Protection
Renoprotection

• Lisinopril
• Inhibits RAAS
• Reduces proteinuria
• Increases renal blood flow
• Causes natriuresis
• Retards progression of impaired renal function

• Amlodipine
• Reduces proteinuria
• Increases renal blood flow
• Causes natriuresis

Drugs 1995, Drugs 1988, Am. J. Cardiol. 1988,
Diabetes 1996
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Organ Protection (Contd.)
Anti-atherosclerotic Effects

• Amlodipine
• Suppresses proliferation migration of SMCs
• Prevents excessive secretion of connective tissue
• Inhibits LDL oxidation
• Normalises elevated serum insulin and
  triglyceride concentrations
• Restores and preserves endothelial function

• Lisinopril
• Inhibits angiotensin II-induced stimulation
  proliferation of SMCs
• Restores and preserves endothelial function

- 6th Int. Symp. on Pharmacological control of
calcium and potassium homeostasis Biological,
Therapeutic and Clinical Aspects Italy, October
1994. - J. Hum. Hyper. 1995 9S3-S9
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Organ Protection (Contd.)
Cardioprotection

• Lisinopril
• Reduces afterload and preload
• Prevents remodelling
• Enhances bradykinin-induced vasodilation
• Regresses LVH

• Amlodipine
• Reduces myocardial oxygen demand increases
  oxygen supply
• Increases collateral blood flow
• Reduces calcium overload following reperfusion
• Regresses LVH

- 6th Int. Symp. on Pharmacological control of
calcium and potassium homeostasis Biological,
Therapeutic and Clinical Aspects Italy, October
1994. - Drugs 1995, Drugs 1996
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Amlopres L Effect on Diabetic Nephropathy

• Amlodipine

Lisinopril
renal afferent arteriolar pressure
renal efferent arteriolar pressure
Intraglomerular pressure
Proteinuria
Retards progression of diabetic nephropathy
- 6th Int. Symp. on Pharmacological control of
calcium and potassium homeostasis Biological,
Therapeutic and Clinical Aspects Italy, October
1994.
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Percentage incidence of edema with calcium
antagonist alone and with calcium antagonist-ACE
inhibitor combination
Edema ( incidence)
CA calcium antagonist CA-ACEI calcium
antagonist-ACE inhibitor combination
Am. J. Cardiol 1997 79431-435
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Amlopres-L Safety

• Use of low doses of individual agents leads to a
  reduction in individual side-effects
• Amlodipine induced-edema and reflex tachycardia
  are attenuated by lisinopril
• Lisinopril induced-cough and hyperkalemia are
  attenuated by amlodipine
• Combination is safe and well tolerated
• Arch. Intern. Med. 1996, J. Clin. Pharmacol.
  1993, Nephrol. Dial. Transplant. 1995,
• Am. J. Cardiol. 1997.

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Efficacy and Tolerability of combined amlodipine
and lisinopril (Amlopres-L) in Indian
hypertensives (n330)
Reduces BP effectively
175.419.4
77.65
143.8 13.2
106.8 10.5
88.2 7.6
Blood Pressure (mm Hg)
responders

• Safe and well tolerated
• Adverse events were reported in 9.7 of patients
• Side effects commonly reported included cough and
  edema
• Only 1.76 of patients withdrew from the study.
• Indian Practitioner 1998 51 441-447.

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Amlodipine - Atenolol combination in hypertension
Mechanism of action
BLOOD PRESSURE
x
Peripheral Resistance
Cardiac Output
Sodium fluid Retention Aldosterone Angiotensin
II Angiotensin I Angiotensinogen Beta stimulation
Renin Kidney
Muscle contraction Ca influx
Heart
Atenolol
Amlodipine
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Systolic
Diastolic
Atenolol plus Placebo (D 10.6)
mmHg
mmHg
Atenolol plus Placebo (D 11.2)
p0.019 Atenolol plus Amlodipine
p0.057 Atenolol plus Amlodipine (D 22.3)
(D 22.3)
Weeks On Drug
Weeks On Drug
Interim mean supine blood pressure results of a
multicenter study. Dchange from baseline to
final value (mm Hg). p values refer to the
amlodipine-placebo differences in changes from
baseline. J Cardiovasc Pharmacol 1988 12 (suppl
7) S32
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AECG (Median episode frequency)
ETT (Time to ischemia onset)
p
lt0.001

Amlodipine

Atenolol

Combination


100
80
60
40
20
0
10
20
30
40
50
Relative efficacies of amlodipine, atenolol and
their combination on time to ischemia during
treadmill exercise time versus episode frequency
during ambulatory monitoring. AECG ambulatory
electrocardiogram ETT exercise treadmill
test JACC 1995 25(3) 619-25
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Efficacy and Tolerability of a fixed-dose
combination of amlodipine and atenolol
(Amlopres-AT) in Indian Hypertensives (n369)
Reduces BP effectively
80.5
175.419.4
143.8 13.2
106.8 10.5
Blood Pressure (mm Hg)
88.2 7.6
responders

• Safe and well tolerated
• Adverse events were reported in 7.9 of patients
• Common side effects included edema, fatigue and
  headache
• Indian Practitioner 1997 50 683-688.

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Amlopres-Z
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Amlopres-Z
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Amlopres-Z

• Amlodipine
• Atherosclerosis
• Suppresses proliferation migration of SMCs
• Prevents excessive secretion of connective tissue
• Inhibits LDL oxidation
• Normalises elevated serum insulin and
  triglyceride concentrations
• Restores and preserves endothelial function

• Losartan
• Inhibits angiotensin II-induced stimulation
  proliferation of SMCs
• Restores and preserves endothelial function by
  increasing NITRIC OXIDE which is an endogenous
  vasodilator

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Amlopres-Z
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Losartan-Hydrochlorothiazide Combination
Advantages

• Synergistic Anthihypertensive effect

LOSARTAN
HYDROCHLOROTHIAZIDE

RAAS
SNS
Plasma volume and natriuresis
Cardiac output Peripheral resistance
Inhibits effects of ANG II
()
()
RAAS
SNS
BP
Blood Pressure
ANG II
Blood Pressure
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Losartan-Hydrochlorothiazide Combination
Advantages
Improved Safety
LOSARTAN
Hydrocholorothiazide

Plasma volume and natriuresis
RAAS
Aldosterone
RAAS
Aldosterone
Serum Potassium
Serum Potassium
Serum potassium levelsremain within normal limits
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Drawbacks of Fixed-Dose Combinations

• Dosage flexibility is lost
• Can be overcome by multiple combinations of the
  two ingredients

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Suggested guidelines for the use of fixed-dose
combinations

• Coexisting condition First choice
• Ischaemic heart disease Amlodipine Atenolol
• Diabetes Amlodipine Lisinopril
• Amlodipine Losartan
• Hyperlipidemia Amlodipine Lisinopril
• Amlodipine Losartan
• Congestive heart failure Lisinopril HCTZ
• Losartan HCTZ
• Tachycardia Amlodipine Atenolol
• Bradycardia Amlodipine Lisinopril
• Amlodipine Losartan
• Asthma/COPD Amlodipine Losartan
• Amlodipine Lisinopril
• Elderly hypertensives Amlodipine Losartan
• Amlodipine Lisinopril
• Lisinopril/Losartan HCTZ

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Suggested guidelines for the use of fixed-dose
combinations (contd.)

• Coexisting condition First choice
• Peripheral vascular disease Amlodipine
  Lisinopril
• Amlodipine Losartan
• Losartan HCTZ
• Lisinopril HCTZ
• Gout Amlodipine Lisinopril
• Amlodipine Losartan
• Amlodipine Atenolol
• Anxiety Amlodipine Atenolol
• Depression Amlodipine Lisinopril
• Amlodipine Losartan
• Lisinopril HCTZ
• Losartan HCTZ
• Renal insufficiency (not due to renal
  Amlodipine Lisinopril
• artery stenosis) Amlodipine Losartan