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

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

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

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

(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)

American Heart Association “Starting with combination therapy may be the best way to get hypertensive patients’ blood pressure down to goal levels.”

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

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.

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)

Amlopres L Amlodipine 5 mg + Lisinopril 5 mg

J. Hyper. 1993; 11:839-847 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).

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

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

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

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.

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; 79:431-435

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.

Efficacy and Tolerability of combined amlodipine and lisinopril (Amlopres-L) in Indian hypertensives (n=330) Reduces BP effectively 175.4+19.4 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.

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

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

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) : 619-25

Efficacy and Tolerability of a fixed-dose combination of amlodipine and atenolol (Amlopres-AT) in Indian Hypertensives (n=369) Reduces BP effectively 80.5% 175.4+19.4 143.8 + 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.

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

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

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

Amlopres-Z

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

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

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

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

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