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Approaches to Meeting the Criteria for Fixed Dose Antihypertensive Combinations

Focus on Metoprolol

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Summary

Fixed dose antihypertensive combinations are being used increasingly in the management of hypertension. There are advantages and disadvantages of this form of therapy. The key aims are to: (i) achieve increased efficacy by using drugs that complement each other’s actions; (ii) use low doses to minimise adverse effects; and (iii) provide a simple once daily regimen.

Fixed dose combinations containing metoprolol have the advantage that β-blockers are drugs for which there is most evidence that they are cardioprotective; metoprolol is the best documented β-blocker in this context. The early combination of conventional release metoprolol and hydrochlorothiazide was inadequately investigated by modern standards, but proved well tolerated and effective in clinical practice. The introduction of the long acting metoprolol CR/ZOK (controlled release/zero order kinetics) produced a very satisfactory once daily preparation with no major pharmacokinetic interactions. The fixed dose combination of felodipine and metoprolol CR/ZOK has been well investigated. The two agents complement each other’s actions and together provide very effective blood pressure control, cardioprotection and very good tolerability. A case can be made that this preparation more closely meets the requirements of an ideal antihypertensive than a single agent given alone.

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References

  1. Sica DA. Fixed dose combination antihypertensive drugs. Drugs 1994; 48: 16–24

    Article  PubMed  CAS  Google Scholar 

  2. Hartford M, Wendelhag L, Berglund G, et al. Cardiovascular and renal effects of long term antihypertensive treatment. JAMA 1988; 259: 2553–7

    Article  PubMed  CAS  Google Scholar 

  3. Wikstrand J, Warnold L, Olsson G, et al. Primary prevention with metoprolol in patients with hypertension. Mortality results from the MAPHY Study. JAMA 1988; 259: 1976–82

    Article  PubMed  CAS  Google Scholar 

  4. Lund-Johansen P. Haemodynamic changes in long term diuretic therapy of essential hypertension. Acta Med Scand 1970; 187: 509–18

    Article  PubMed  CAS  Google Scholar 

  5. Smilde JG. Comparison of the antihypertensive effect of a double dose of metoprolol versus the addition of hydrochlorothiazide to metoprolol. Eur J Clin Pharmacol 1983; 25: 581–3

    Article  PubMed  CAS  Google Scholar 

  6. Rasmussen R, Rasmussen Influence of metoprolol alone and in combination with a thiazide diuretic on blood pressure, plasma volume, extracelluar volume and glomerular filtration rate in essential hypertension. Eur J Clin Pharmacol 1979; 15: 305–10

    Article  PubMed  CAS  Google Scholar 

  7. Jordo L, Johnsson G, Lundborg P, et al. Bioavailability and disposition of metoprolol and hydrochlorothiazide combined in one tablet and separate doses of hydrochlorothiazide. Br J Clin Pharmacol 1979; 7: 563–7

    Article  PubMed  CAS  Google Scholar 

  8. Castenfors J, Danielsson M. Metoprolol hydrochlorothiazide in a fixed dose combination once daily in the treatment of hypertension. Curr Ther Res 1979; 25: 228–42

    Google Scholar 

  9. Asplund J. A fixed dose combination of metoprolol and hydrochlorothiazide (co-betaloc) in essential hypertension: a combinate between the individual drags. Curr Ther Res 1981; 29: 387–94

    Google Scholar 

  10. Sandberg A, Abrahamsson B, Regardh CG, et al. Pharmacokinetic and biopharmaceutic aspects of once daily treatment with metoprolol CR/ZOK: a review article. J Clin Pharmacol 1990; 30 Suppl.: S2–S16

    PubMed  CAS  Google Scholar 

  11. Sandberg A, Blomkvist I, Jonsson UE, et al. Pharmacokinetic and pharmacodynamic properties of a new controlled-release formulation of metoprolol: a comparison with conventional tablets. Eur J Clin Pharmacol 1988; 33 Suppl. 1: S9–S14

    Article  PubMed  CAS  Google Scholar 

  12. Kendall MJ, Maxwell SRJ, Sandberg A, et al. Controlled Release Metoprolol Clinical Pharmacokinetic and therapeutic implications. Clin Pharmacokinet 1991; 21(5): 319–30

    Article  PubMed  CAS  Google Scholar 

  13. Leikersfeldt G, Rasmussen SL, Atmer et al. Efficacy and tolerability of a fixed combination of metoprolol CR/ZOK 100 mg and hydrochlorothiazide (HCT) 1 2.5mg in comparison with the fixed combination of metoprolol and HCT, J Clin Pharmacol 1990; 30 Suppl.: S78–S81

    PubMed  CAS  Google Scholar 

  14. Lundborg P, Abrahamsson B, Wieselgren I, et al. The pharmacokinetics and pharmacodynamics of metoprolol after conventional and controlled release administration in combination with hydrochlorothiazide in healthy volunteers. Eur J Clin Pharmacol 1993; 45: 161–3

    Article  PubMed  CAS  Google Scholar 

  15. Abrahamsson Edgar Lidman et al. Design and pharmacokinetics of Logimax, a new extended release combination tablet of felodipine and metoprolol. Blood Pressure 1993; 2 Suppl. 1: 10–5

    Google Scholar 

  16. Dahlöf Jonsson L, Borgholst et al. Improved antihypertensive efficacy of the felodipine-metoprolol extended-release tablet compared with each drug alone. Blood Pressure 1993; 2 Suppl. 1: 37–45

    Google Scholar 

  17. Veterans Administration Cooperative Study Group on Antihypertensive Agents. Effects of treatment on morbidity in hypertension III. Influence of age, diastolic blood pressure, and prior cardiovascular disease. Further analysis of side effects. Circulation 1972; 45: 991–1004

    Article  Google Scholar 

  18. Larochelle P, Bass MJ, Birkett NJ, et al. Recommendations from the Consensus Conference on Hypertension in the Elderly. Can Med Assoc J 1986; 135: 741–5

    CAS  Google Scholar 

  19. Myers MG, Carruthers SG, Leenen FHH, et al. Recommendations from the Canadian consensus conference on the pharmacologic treatment of hypertenson. Can Med Assoc J 1989; 140: 1141–6

    CAS  Google Scholar 

  20. Benfield P, Clissold SP, Brogden RN. Metoprolol: an updated review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy in hypertension, ischaemic heart disease and related cardiovascular disorders. Drugs 1986; 31: 376–429

    Article  PubMed  CAS  Google Scholar 

  21. Lennard MS, Tucker GT, Woods HF. The polymarphic oxidation of beta adrenoceptor antagonists. Clinical pharmacokinetic considerations. Clin Pharmacokinet 1986; 11: 1–17

    Article  PubMed  CAS  Google Scholar 

  22. Jordo L, Attman PO, Aurell M, et al. Pharmacokinetic and pharmacodynamic properties of metoprolol in patients with impaired renal function. Clin Pharmacol 1980; 5: 169–80

    Article  CAS  Google Scholar 

  23. Lloyd P, John VA, Signy M, et al. The effect of impaired renal function on the pharmacokinetics of metoprolol after single administration of a 14-190 metoprolol OROS system. Am Heart J 1990; 120: 478–82

    Article  PubMed  CAS  Google Scholar 

  24. Hoffmann K-J, Regardh C-G, Aurell M, et al. The effect of impaired renal function on the plasma concentration and urinary excretion of metoprolol metabolites. Clin Pharmacokinet 1980; 5: 181–91

    Article  PubMed  CAS  Google Scholar 

  25. Seiler K-U, Schuster KJ, Meyer G-J, et al. The pharmacokinetics of metoprolol and its metabolites in dialysis patients. Clin Pharmacokinet 1980; 5: 192–8

    Article  PubMed  CAS  Google Scholar 

  26. Quarterman CP, Kendall MJ, Jack DB. The effect of age on the pharmacokinetics of metoprolol and its metabolites. Br J Clin Pharmacol 1981; 11: 287–94

    Article  PubMed  CAS  Google Scholar 

  27. Dimenas ES, Dahlöf CG, Heibel et al. Subjective symptoms and pharmacokinetics/dynamics of metoprolol CR in elderly subjects — a comparison with atenolol. Eur J Clin Pharmacol 1990; 38: 571–8

    Article  PubMed  CAS  Google Scholar 

  28. Wikstrand J, Westergren G, Berglund G, et al. Antihypertensive treatment with metoprolol or hydrochlorothiazide in patients aged 60–75 years. Report from a double-blind international multicentre study. JAMA 1986; 255: 1304–10

    Article  PubMed  CAS  Google Scholar 

  29. Regardh C-G, Jordo M, Ervik M, et al. Pharmacokinetics of metoprolol in patients with hepatic cirrhosis. Clin Pharmacokinet 1981; 6: 375–88

    Article  PubMed  CAS  Google Scholar 

  30. Faulds D, Sorkin EM. Felodipine: a review of the pharmacology and therapeutic use of the extended release formulation in older patients. Drugs Aging 1992; 2(5); 374–88

    Article  PubMed  CAS  Google Scholar 

  31. Larsson R, Karlberg BE, Gelin A, et al. Acute and steady-state pharmacokinetics and antihypertensive effects of felodipine in patients with normal and impaired renal function. J Clin Pharmacol 1990; 30: 1020–30

    PubMed  CAS  Google Scholar 

  32. Edgar B, Regardh CG, Attman O, et al. Pharmacokinetics of felodipine in patients with impaired renal function. Br J Clin Pharmacol 1989; 27: 67–74

    Article  PubMed  CAS  Google Scholar 

  33. Wing LM, Russell AE, Tonkin AL, et al. Mono- and combination therapy with felodipine or enalapril in elderly patients with systolic hypertension. Blood Pressure 1994; 3: 90–6

    Article  PubMed  CAS  Google Scholar 

  34. Wing LM, Russell AE, Tonkin AL, et al. Felodipine, metoprolol and their combination compared with placebo in isolated systolic hypertension in the elderly. Blood Pressure 1994; 3: 82–9

    Article  PubMed  CAS  Google Scholar 

  35. Elmfeldt D, Nordlander M, Edgar Renal effects of felodipine — a review. Kidney Int 1994; 46 Suppl. 36: S54–S60

    Google Scholar 

  36. Regardh CG, Edgar B, Olsson R, et al. Pharmacokinetics of felodipine in patients with liver disease. Eur J Clin Pharmacol 1989; 36: 473–9

    Article  PubMed  CAS  Google Scholar 

  37. Welling P. Pharmacokinetics of the thiazide diuretics. Biopharm Drug Dispos 1986; 7: 501–35

    Article  PubMed  CAS  Google Scholar 

  38. Carruthers G, Shearer R, Taylor W, et al. A comparison of a controlled release (CR/ZOK) formulation of metoprolol once daily with conventional metoprolol twice daily in mild to moderate hypertension. J Clin Pharmacol 1990; 30: 560–5

    Google Scholar 

  39. Dahlöf Hosie J on behalf of the Swedish/UK Study Group. Antihypertensive efficacy and tolerability of anew once-daily felodipine-metoprolol combination compared with each component alone. Blood Pressure 1993; 2 Suppl. 1: 22–9

    Google Scholar 

  40. Hoffman J on behalf of the German Multicentre Study Group. Comparison of a felodipine-metoprolol tablet vs each component alone as an antihypertensive therapy. Blood Pressure 1993; 2 Suppl. 1: L30–6

    Google Scholar 

  41. Venables T, Akhtar W, Campbell LM, et al. Low dose felodipine with low dose metoprolol as once daily antihypertensive therapy. Br J Clin Pharmacol 1990; 29: 628P–629P

    Google Scholar 

  42. Todd PA, Faulds D. Felodipine: a review of the pharmacology and therapeutic use of the extended release formulation in cardiovascular disorders. Drugs 1992; 44: 251–77

    Article  PubMed  CAS  Google Scholar 

  43. Hansson L, for the HOT Study Group. The Hypertension Optimal Treatment Study (the HOT Study). Blood Pressure 1993; 2: 62–8

    Article  Google Scholar 

  44. Kendall MJ, Akhlagi S, Bughes B, et al. Is metoprolol CR/ZOK more selective than conventional metoprolol and atenolol? J Clin Pharmacol 1990; 30 Suppl.: S98–S102

    PubMed  CAS  Google Scholar 

  45. Lofdahl C-G, Dahlof C, Westergren G, et al. Controlled release metoprolol compared with atenolol in asthmatic patients: interaction with terbutaline. Eur J Clin Pharmacol 1988; 33: S25–S32

    Article  PubMed  Google Scholar 

  46. Collins R, Peto R, MacMahon S, et al. Blood pressure, stroke, and coronary heart disease. Part 2, short-term reductions in blood pressure: overview of randomised drug trials in their epidemiological context. Lancet 1990; 335: 827–38

    Article  PubMed  CAS  Google Scholar 

  47. Held PH, Yusuf S, Furberg CD. Calcium channel blockers in acute myocardial infarction and unstable angina: an overview. BMJ 1989; 299: 1187–92

    Article  PubMed  CAS  Google Scholar 

  48. Wikstrand J and Kendall MJ. The role of beta blockers in preventing sudden death. Eur Heart J 1992; 13 Suppl. D: 111–20

    PubMed  Google Scholar 

  49. The MIAMI Trial Research Group. Metoprolol in Acute Myocardial Infarction (MIAMI), A randomised placebo-controlled international trial. Eur Heart J 1985; 6: 199–226

    Google Scholar 

  50. Hjalmarson A, Elmfeldt D, Herlitz J, et al. Effect on mortality of metoprolol in acute myocardial infarction. Lancet 1981; 2: 823–7

    Article  PubMed  CAS  Google Scholar 

  51. Olsson G, Wikstrand J, Warnold I, et al. Metoprolol induced reduction in postinfarction mortality: pooled results from five double-blind randomized trials. Eur Heart J 1992; 13: 28–32

    PubMed  CAS  Google Scholar 

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  1. Department of Medicine, Queen Elizabeth Hospital, Edgbaston, Birmingham, B15 2TH, England

    Martin J. Kendall

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Kendall, M.J. Approaches to Meeting the Criteria for Fixed Dose Antihypertensive Combinations. Drugs 50, 454–464 (1995). https://doi.org/10.2165/00003495-199550030-00004

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