Fixed Dose Combinations

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Fixed Dose Combinations

  1. 1. <ul><li>Hypertension even today is a triple paradox which is : </li></ul><ul><li>Easy to diagnose OFTEN remains undetected </li></ul><ul><li>Simple to treat OFTEN remains untreated </li></ul><ul><li>Despite availability of potent drugs, treatment all too OFTEN is ineffective </li></ul>
  2. 2. <ul><li>Large amount of attention is given to the treatment of Hypertension : </li></ul><ul><li>Hypertension is a major cardiovascular risk factor that contributes to MI, CHF, stroke and PREMATURE MORTALITY </li></ul><ul><li>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 . </li></ul><ul><li>The JNC VI & WHO-ISH (1999) guidelines reinforce these findings </li></ul>
  3. 3. Hypertension : A Multifactorial Entity <ul><li>Hypertension is a multifactorial entity, it is therefore not surprising that there is heterogeneity in responsiveness to treatment. </li></ul><ul><li>Today, there is no simple way of predicting which patients will respond to which class of antihypertensive agents. </li></ul><ul><li>- Journal of Human Hypertension 1995 ; 9 : S33-S36 </li></ul>
  4. 4. Why combination therapy <ul><li>Multiple mechanisms involved in the pathogenesis of hypertension </li></ul><ul><li>Effectiveness of monotherapy limited by stimulation of counter-regulatory mechanisms </li></ul><ul><li>Effective BP control seen in only 50% of patients on monotherapy; combination therapy results in a much higher responder rate (>80%) </li></ul><ul><li>BP goals difficult to attain with monotherapy in patients with diabetes or target organ damage </li></ul>
  5. 5. Combination therapy for hypertension – Recommended by JNC-VI guidelines and 1999 WHO-ISH guidelines <ul><li>With any single drug, not more than 25–50% of hypertensives achieve adequate blood pressure control </li></ul><ul><li>J Hum. Hypertens 1995; 9:S33–S36 </li></ul>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) Add second drug from different class (Combination therapy) If inadequate response obtained
  6. 6. American Heart Association <ul><li>“ Starting with combination therapy may be the best way to get hypertensive patients’ blood pressure down to goal levels.” </li></ul>
  7. 8. Advantages of fixed-dose combination therapy <ul><li>Better blood pressure control </li></ul><ul><li>Lesser incidence of individual drug’s side-effects </li></ul><ul><li>Neutralisation of side-effects </li></ul><ul><li>Increased patient compliance </li></ul><ul><li>Modification of risk factors </li></ul><ul><li>Lesser cost of therapy </li></ul>
  8. 9. Theoretical requirements for a rational fixed-dose antihypertensive combination <ul><li>Each component should contribute to the final effect. </li></ul><ul><li>Results should be superior to those achieved with a single agent. </li></ul><ul><li>Dosage form(s) should be adequate relative to bioavailability </li></ul><ul><ul><li>absence of unwanted interactions </li></ul></ul><ul><ul><li>selection of doses of each component </li></ul></ul><ul><li>A major proportion of the target population should respond. </li></ul><ul><li>Physicians should be easily familiarised with individual components. </li></ul>
  9. 10. Fixed-dose combinations as recommended by JNC-VI (1997) guidelines and 1999 WHO-ISH guidelines <ul><li>Calcium channel blocker and  -blocker (e.g. Amlodipine and Atenolol) </li></ul><ul><li>Calcium channel blocker and ACE-inhibitor (e.g. Amlodipine and Lisinopril) </li></ul><ul><li>ACE-inhibitor and Diuretic (e.g. Lisinopril and Hydrochlorothiazide </li></ul><ul><li> -blocker and Diuretic (e.g. Atenolol and Hydrochlorothiazide) </li></ul>
  10. 11. Amlopres L + Lisinopril 5 mg Amlodipine 5 mg
  11. 12. 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). J. Hyper. 1993; 11:839-847
  12. 13. Amlopres L : Organ Protection <ul><li>Lisinopril </li></ul><ul><li>Inhibits RAAS </li></ul><ul><li>Reduces proteinuria </li></ul><ul><li>Increases renal blood flow </li></ul><ul><li>Causes natriuresis </li></ul><ul><li>Retards progression of impaired renal function </li></ul><ul><li>Amlodipine </li></ul><ul><li>Reduces proteinuria </li></ul><ul><li>Increases renal blood flow </li></ul><ul><li>Causes natriuresis </li></ul>Renoprotection Drugs 1995, Drugs 1988, Am. J. Cardiol. 1988, Diabetes 1996
  13. 14. Organ Protection (Contd.) <ul><li>Amlodipine </li></ul><ul><li>Suppresses proliferation & migration of SMCs </li></ul><ul><li>Prevents excessive secretion of connective tissue </li></ul><ul><li>Inhibits LDL oxidation </li></ul><ul><li>Normalises elevated serum insulin and triglyceride concentrations </li></ul><ul><li>Restores and preserves endothelial function </li></ul><ul><li>Lisinopril </li></ul><ul><li>Inhibits angiotensin II-induced stimulation & proliferation of SMCs </li></ul><ul><li>Restores and preserves endothelial function </li></ul>Anti-atherosclerotic Effects - 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
  14. 15. <ul><li>Amlodipine </li></ul><ul><li>Reduces myocardial oxygen demand & increases oxygen supply </li></ul><ul><li>Increases collateral blood flow </li></ul><ul><li>Reduces calcium overload following reperfusion </li></ul><ul><li>Regresses LVH </li></ul><ul><li>Lisinopril </li></ul><ul><li>Reduces afterload and preload </li></ul><ul><li>Prevents remodelling </li></ul><ul><li>Enhances bradykinin-induced vasodilation </li></ul><ul><li>Regresses LVH </li></ul>Cardioprotection Organ Protection (Contd.) - 6th Int. Symp. on “Pharmacological control of calcium and potassium homeostasis : Biological, Therapeutic and Clinical Aspects” Italy, October 1994. - Drugs 1995, Drugs 1996
  15. 16. Amlopres L: Effect on Diabetic Nephropathy <ul><li>Amlodipine </li></ul>Lisinopril  renal afferent arteriolar pressure  Intraglomerular pressure  renal efferent arteriolar 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.
  16. 17. Percentage incidence of edema with calcium antagonist alone and with calcium antagonist-ACE inhibitor combination CA= calcium antagonist CA-ACEI = calcium antagonist-ACE inhibitor combination Edema (% incidence) Am. J. Cardiol 1997; 79:431-435
  17. 18. Amlopres-L: Safety <ul><li>Use of low doses of individual agents leads to a reduction in individual side-effects </li></ul><ul><li>Amlodipine induced-edema and reflex tachycardia are attenuated by lisinopril </li></ul><ul><li>Lisinopril induced-cough and hyperkalemia are attenuated by amlodipine </li></ul><ul><li>Combination is safe and well tolerated </li></ul><ul><li>Arch. Intern. Med. 1996, J. Clin. Pharmacol. 1993, Nephrol. Dial. Transplant. 1995, </li></ul><ul><li>Am. J. Cardiol. 1997. </li></ul>
  18. 19. Efficacy and Tolerability of combined amlodipine and lisinopril (Amlopres-L) in Indian hypertensives (n=330) Blood Pressure (mm Hg) Reduces BP effectively <ul><li>Safe and well tolerated </li></ul><ul><li>Adverse events were reported in 9.7% of patients </li></ul><ul><li>Side effects commonly reported included cough and edema </li></ul><ul><li>Only 1.76% of patients withdrew from the study. </li></ul><ul><li>Indian Practitioner 1998; 51: 441-447. </li></ul>% responders 175.4 + 19.4 143.8 + 13.2 106.8 + 10.5 88.2 + 7.6 77.65
  19. 20. Amlodipine - Atenolol combination in hypertension : Mechanism of action Peripheral Resistance Cardiac Output Sodium & fluid Retention Aldosterone Angiotensin II Angiotensin I Angiotensinogen Beta stimulation Muscle contraction Ca ++ influx Renin Kidney Amlodipine Heart BLOOD PRESSURE Atenolol x
  20. 21. Interim mean supine blood pressure results of a multicenter study.  =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 *p=0.019 Atenolol plus Amlodipine (  22.3)* Atenolol plus Placebo (  11.2)* *p=0.057 Atenolol plus Amlodipine (  22.3)* Atenolol plus Placebo (  10.6)* Systolic Diastolic mmHg Weeks On Drug Weeks On Drug mmHg
  21. 22. 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 AECG (Median episode frequency) ETT (Time to ischemia onset) Amlodipine Atenolol Combination 100 80 * * * * * p <0.001 60 40 20 0 10 20 30 40 50
  22. 23. Efficacy and Tolerability of a fixed-dose combination of amlodipine and atenolol (Amlopres-AT) in Indian Hypertensives (n=369) Blood Pressure (mm Hg) Reduces BP effectively <ul><li>Safe and well tolerated </li></ul><ul><li>Adverse events were reported in 7.9% of patients </li></ul><ul><li>Common side effects included edema, fatigue and headache </li></ul><ul><li>Indian Practitioner 1997; 50: 683-688. </li></ul>% responders 175.4 + 19.4 143.8 + 13.2 106.8 + 10.5 88.2 + 7.6 80.5%
  23. 24. Amlopres-Z <ul><li>LOSARTAN </li></ul><ul><li>Vasodilation </li></ul><ul><li>Blocks the vasoconstrictor and aldosterone secreting effects of angiotensin II </li></ul><ul><li>Reverses sodium and water retention </li></ul><ul><li>by decreasing aldosterone secretion </li></ul><ul><li>Highly effective in high-renin patients </li></ul><ul><li>AMLODIPINE </li></ul><ul><li>Blood pressure </li></ul><ul><li>Vasodilation </li></ul><ul><li>Reduces Ca-influx in vascular smooth muscle cells </li></ul><ul><li>Highly effective in low-renin patients </li></ul>
  24. 25. Amlopres-Z LOSARTAN Neutral effect on lipid profile Improves insulin sensitivity AMLODIPINE Neutral effect on lipid profile Favourable effects on glucose metabolism
  25. 26. 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 Amlopres-Z
  26. 27. Amlopres-Z
  27. 28. <ul><li>Synergistic Anthihypertensive effect </li></ul>Losartan-Hydrochlorothiazide Combination: Advantages LOSARTAN HYDROCHLOROTHIAZIDE  RAAS  SNS Inhibits effects of ANG II  Blood Pressure  Plasma volume and natriuresis  Cardiac output  Peripheral resistance  Blood Pressure  RAAS  SNS   P  ANG II + (–) (–)
  28. 29. Losartan-Hydrochlorothiazide Combination: Advantages LOSARTAN  RAAS  Aldosterone  Serum Potassium Serum potassium levels remain within normal limits Hydrocholorothiazide Plasma volume and natriuresis  RAAS  Aldosterone  Serum Potassium + Improved Safety
  29. 30. Drawbacks of Fixed-Dose Combinations <ul><li>Dosage flexibility is lost </li></ul><ul><li>Can be overcome by multiple combinations of the two ingredients </li></ul>
  30. 31. Suggested guidelines for the use of fixed-dose combinations <ul><li>Coexisting condition First choice </li></ul><ul><li>Ischaemic heart disease Amlodipine + Atenolol </li></ul><ul><li>Diabetes Amlodipine + Lisinopril </li></ul><ul><li>Amlodipine + Losartan </li></ul><ul><li>Hyperlipidemia Amlodipine + Lisinopril </li></ul><ul><li>Amlodipine + Losartan </li></ul><ul><li>Congestive heart failure Lisinopril + HCTZ </li></ul><ul><li>Losartan + HCTZ </li></ul><ul><li>Tachycardia Amlodipine + Atenolol </li></ul><ul><li>Bradycardia Amlodipine + Lisinopril </li></ul><ul><li>Amlodipine + Losartan </li></ul><ul><li>Asthma/COPD Amlodipine + Losartan </li></ul><ul><li>Amlodipine + Lisinopril </li></ul><ul><li>Elderly hypertensives Amlodipine + Losartan </li></ul><ul><li>Amlodipine + Lisinopril </li></ul><ul><li>Lisinopril/Losartan + HCTZ </li></ul>
  31. 32. Suggested guidelines for the use of fixed-dose combinations (contd.) <ul><li>Coexisting condition First choice </li></ul><ul><li>Peripheral vascular disease Amlodipine + Lisinopril </li></ul><ul><li>Amlodipine + Losartan </li></ul><ul><li>Losartan + HCTZ </li></ul><ul><li>Lisinopril + HCTZ </li></ul><ul><li>Gout Amlodipine + Lisinopril </li></ul><ul><li>Amlodipine + Losartan </li></ul><ul><li>Amlodipine + Atenolol </li></ul><ul><li>Anxiety Amlodipine + Atenolol </li></ul><ul><li>Depression Amlodipine + Lisinopril </li></ul><ul><li>Amlodipine + Losartan </li></ul><ul><li>Lisinopril + HCTZ </li></ul><ul><li>Losartan + HCTZ </li></ul><ul><li>Renal insufficiency (not due to renal Amlodipine + Lisinopril </li></ul><ul><li>artery stenosis) Amlodipine + Losartan </li></ul>

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