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

3. 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

4. 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 (>80%)
BP goals difficult to attain with monotherapy in patients with diabetes or target organ damage

5. (Combination therapy)
Combination therapy for hypertension – Recommended by JNC-VI guidelines and 1999 WHO-ISH guidelines
With any single drug, not more than 25–50% of hypertensives achieve adequate blood pressure control
J Hum. Hypertens 1995; 9:S33–S36
For patients not responding adequately
to low doses of monotherapy
Increase the dose of drug. This, however, may lead to increased side effects
Substitute with another drug from a different class
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.”

8. Advantages of fixed-dose combination therapy
Better blood pressure control
Lesser incidence of individual drug’s side-effects
Neutralisation of side-effects
Increased patient compliance
Modification of risk factors
Lesser cost of therapy

9. Theoretical requirements for a rational fixed-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.

10. Fixed-dose combinations as recommended by JNC-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)

11. Amlopres L
Amlodipine 5 mg +
Lisinopril 5 mg

12. J. Hyper. 1993; 11:
Supine systolic and diastolic blood pressure 24h after the last dose of treatment in 15 patients with essential hypertension
ANOVA, analysis of variance; RX, therapy. Values are expressed as means + SEM. *P <0.05, **P < 0.005, versus both (Combination).

13. 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

14. Anti-atherosclerotic Effects
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; 9:S3-S9

15. Organ Protection (Contd.)
Cardioprotection
Amlodipine
Reduces myocardial oxygen demand & increases oxygen supply
Increases collateral blood flow
Reduces calcium overload following reperfusion
Regresses LVH
Lisinopril
Reduces afterload and preload
Prevents remodelling
Enhances bradykinin-induced vasodilation
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

16. 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.

17. 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; 79:

18. 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

19. Efficacy and Tolerability of combined amlodipine and lisinopril (Amlopres-L) in Indian hypertensives (n=330)
Reduces BP effectively
77.65
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:

20. Sodium & fluid Retention
Amlodipine - Atenolol combination in hypertension : Mechanism of action
BLOOD PRESSURE
Peripheral Resistance
Sodium & fluid Retention
Aldosterone
Angiotensin II
Angiotensin I
Angiotensinogen
Beta stimulation x
Cardiac Output
Renin
Kidney
Muscle contraction
Ca++ influx
Heart
Atenolol
Amlodipine

21. Systolic
Diastolic
mmHg
mmHg
Atenolol plus Placebo (D 10.6)*
Atenolol plus Placebo (D 11.2)*
*p=0.019
Atenolol plus Amlodipine
*p=0.057
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.
D=change 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

22. AECG ETT (Median episode frequency) (Time to ischemia onset)* p
<0.001
Amlodipine *
Atenolol *
Combination * *
100 80 60 40 20 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) :

23. Efficacy and Tolerability of a fixed-dose combination of amlodipine and atenolol (Amlopres-AT) in Indian Hypertensives (n=369)
Reduces BP effectively
80.5%
Blood Pressure (mm Hg)
% 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:

24. Amlopres-Z LOSARTAN AMLODIPINE Vasodilation
Blocks the vasoconstrictor and aldosterone secreting effects of angiotensin II
Reverses sodium and water retention
by decreasing aldosterone secretion
Highly effective in high-renin patients
AMLODIPINE
Blood pressure
Reduces Ca-influx in vascular smooth muscle cells
Highly effective in low-renin patients

25. Amlopres-Z LOSARTAN AMLODIPINE Neutral effect on lipid profile
Improves insulin sensitivity
AMLODIPINE
Favourable effects on glucose metabolism

26. Amlopres-Z Amlodipine Atherosclerosis Losartan
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

27. Amlopres-Z

28. 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

29. Losartan-Hydrochlorothiazide Combination: Advantages
Improved Safety
LOSARTAN +
Hydrocholorothiazide
Plasma volume and natriuresis
¯ RAAS
¯ Aldosterone
­ RAAS
­ Aldosterone
­ Serum Potassium
¯ Serum Potassium
Serum potassium levels remain within normal limits

30. Drawbacks of Fixed-Dose Combinations
Dosage flexibility is lost
Can be overcome by multiple combinations of the two ingredients

31. 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
Asthma/COPD Amlodipine + Losartan
Amlodipine + Lisinopril
Elderly hypertensives Amlodipine + Losartan
Lisinopril/Losartan + HCTZ

32. 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
Renal insufficiency (not due to renal Amlodipine + Lisinopril
artery stenosis) Amlodipine + Losartan