Combination therapy of essential hypertension with pindolol (Visken) and hydralazine

Persson, I

doi:10.1007/bf00614002

Cited by 15 publications

(6 citation statements)

References 11 publications

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“…During recent years ~-adrenoceptor blocking drugs have replaced the ganglion blockers,. and the combined use of hydrallazine and a ~-blocker is well supported from theoretical considerations and clinical experience (Gottlieb et a!., 1972;Pape, 1974;Persson, 1975;Sannerstedt et aI., 1972;Zacest et aI., 1972).…”

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confidence: 88%

Clinical Pharmacokinetics of Hydrallazine

Talseth¹

1977

Clinical Pharmacokinetics

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Hydral/azine is widely used as a peripheral vasodilator antihypertensive drug. During recent years. knowledge has accumulated on the pharmacokinetics of hydral/azine in man. It is subjected to polymorphic N-acetylation. with phenotypically slow acetylators having higher steady state plasma concentrations and higher bioavailability of the drug in single dose studies. compared with subjects who are fast acetylators. However. the terminal elimination half-life of hydrallazine is only slightly longer among slow acetylators. thus it does not seem very likely that polymorphic N-acetylation can represent the major metabolic pathway of the drug in man. Hydrallazine is subject to significant /irst-pass metabolism and there are indications that the N-acetylation process involved may be capacity-limited.About 10 % of a single oral dose can be recovered from the urine as the parent drug. but in spite of the apparent independence of renal function for its elimination thus suggested. hydrallazine is eliminated at a considerably slower rate in uraemic patients; possibly as a consequence of impaired hepatic metabolism or underestimation of the amount excreted unchanged in subjects with norma!.renalfunction. In spite of very high steady state plasma concentrations and prolonged clearance of hydrallazine in renal failure. no harmful effects have been reported.At least 2 active metabolites have been identified. but their clinical importance and kinetic properties have not been elucidated.The duration of the hypotensive effect of hydral/azine exceeds that predicted from the rate of elimination of the parent compound from plasma. Since there is no clear-cut correlation between the plasma concentration of the drug and its effect upon blood pressure, there is at present no reason to routinely measure plasma levels of hydrallazine in treated hypertensive patients.The earliest reports on the hypotensive effect of hydrallazine (I-hydrazinophthalazine) appeared in 1950 (Gross et aI., 1950). Following a screening of phthalazine derivatives for their hypotensive effect, it was found that several compounds were able to induce sustained reductions in blood pressure. A prerequisite for the hypotensive effect was that at least one nitrogen molecule was substituted into the ring, in a position adjacent to the hydrazine side chain (Schulert, 1961). The interest in hydrallazine as an antihypertensive drug was further strengthened by the observation that the decreaSe in systemic blood pressure was accompanied by an increase in renal blood flow (Reubi, 1950;Stein and Hecht, 1955).The mode of action of hydrallazine is due to a direct relaxing effect upon the musculature of the precapillary arterioles (Kirpekar and Lewis, 1957; Stunkard et aI., 1954;Ablad, 1959), thereby inducing a lowering of the total peripheral resistance (Freis et aI., 1953;Ablad, 1963). Although hydrallazine has a

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confidence: 88%

Clinical Pharmacokinetics of Hydrallazine

Talseth¹

1977

Clinical Pharmacokinetics

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“…Studies comparing hydralazine monotherapy with placebo are limited, but oral hydralazine was noted to have significant blood pressure-lowering effects. 12 –15 Combining hydralazine with a β-blocker was found to have an even greater capacity to reduce blood pressure while limiting the rise in pulse rate observed with hydralazine alone. 14 –18 This combination has been compared to various other regimens: β-blocker or verapamil monotherapy, the combination of a thiazide diuretic with either methyldopa or a β-blocker, and the combination of a β-blocker with prazosin.…”

Section: Hydralazinementioning

confidence: 99%

“…12 –15 Combining hydralazine with a β-blocker was found to have an even greater capacity to reduce blood pressure while limiting the rise in pulse rate observed with hydralazine alone. 14 –18 This combination has been compared to various other regimens: β-blocker or verapamil monotherapy, the combination of a thiazide diuretic with either methyldopa or a β-blocker, and the combination of a β-blocker with prazosin. 18 –24 In each case, the combination of hydralazine with a β-blocker was found to be at least as effective as the comparators in lowering blood pressure.…”

Section: Hydralazinementioning

confidence: 99%

Direct Vasodilators and Sympatholytic Agents

McComb

Chao

2015

J Cardiovasc Pharmacol Ther

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Direct vasodilators and sympatholytic agents were some of the first antihypertensive medications discovered and utilized in the past century. However, side effect profiles and the advent of newer antihypertensive drug classes have reduced the use of these agents in recent decades. Outcome data and large randomized trials supporting the efficacy of these medications are limited; however, in general the blood pressure-lowering effect of these agents has repeatedly been shown to be comparable to other more contemporary drug classes. Nevertheless, a landmark hypertension trial found a negative outcome with a doxazosin-based regimen compared to a chlorthalidone-based regimen, leading to the removal of α-1 adrenergic receptor blockers as first-line monotherapy from the hypertension guidelines. In contemporary practice, direct vasodilators and sympatholytic agents, particularly hydralazine and clonidine, are often utilized in refractory hypertension. Hydralazine and minoxidil may also be useful alternatives for patients with renal dysfunction, and both hydralazine and methyldopa are considered first line for the treatment of hypertension in pregnancy. Hydralazine has also found widespread use for the treatment of systolic heart failure in combination with isosorbide dinitrate (ISDN). The data to support use of this combination in African Americans with heart failure are particularly robust. Hydralazine with ISDN may also serve as an alternative for patients with an intolerance to angiotensin antagonists. Given these niche indications, vasodilators and sympatholytics are still useful in clinical practice; therefore, it is prudent to understand the existing data regarding efficacy and the safe use of these medications.

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“…However, they can be used in antihypertensive treatment at much lower doses and with a marked reduction of untoward reactions if they are administered with a diuretic and drugs which inhibit reflex sympathetic activity. The adrenergic blocking agents also inhibit the vasodilator induced increase of plasma renin activity and this may be an important aspect of the combined anti-hypertensive regime (Pettinger & Keeton, 1975 (Zacest, 1975 Pestalozzi-Kerpal, Dubach, Imhof & Turri, 1972;Tuckman et al, 1972;Tuckman, Messerli & Hodler, 1973;Siitonen, Janne, Keyrilainen, Koskinen, Leskinen, Pitkajarvi & Reinikainen, 1974;Freeman & Knight, 1975), alprenolol (Sannerstedt et al, 1972), pindolol (Persson, 1975), practolol (Dahr, 1972 and atenolol (Wilcox & Mitchell, 1977).…”

Section: Re-setting the Baroreceptorsmentioning

confidence: 99%

The second Lilly Prize Lecture, University of Newcastle, July 1977. beta‐Adrenergic receptor blockade in hypertension, past, present and future.

Prichard¹

1978

Brit J Clinical Pharma

102

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All beta‐adrenoceptor blocking drugs that have been described share the common property of being competitive inhibitors. They differ in their associated properties, the presence or absence of cardioselectivity, membrane stabilizing activity, and partial agonist activity. Recently some beta‐adrenoceptor blocking drugs have been reported which also possess alpha‐adrenoceptor blocking activity. The associated properties have been used as a basis for classifying beta‐adrenoceptor blocking drugs (Fitzgerald, 1969, 1972). The presence or absence of cardioselectivity is most useful for dividing beta‐adrenoceptor blocking drugs. The non‐selective drugs (Division I) can be further divided according to the presence or absence of intrinsic sympathomimetic activity (ISA) and membrane stabilizing activity (Fitzgerald's groups I‐IV). Group I possess both membrane activity and ISA, e.g. alprenolol, oxprenolol, group II just membrane action, e.g. propanolol, group III ISA but no membrane action, e.g. pindolol. Fitzgerald placed pindolol in group I but should be placed in group III as it possesses a high degree of beta‐adrenoceptor blocking potency in relation to its membrane activity (Prichard, 1974). Finally drugs in group IV have neither ISA nor membrane action, e.g. sotalol, timolol. The cardioselective drugs (Division II) can be similarly sub‐divided into groups I‐IV according to the presence or absence of ISA or membrane action (Fitzgerald grouped all these together as group V). Lastly there are new beta‐adrenergic receptor blocking drugs which in addition have alpha‐ adrenergic receptor blocking properties (Division III).

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Combination therapy of essential hypertension with pindolol (Visken) and hydralazine

Cited by 15 publications

References 11 publications

Clinical Pharmacokinetics of Hydrallazine

Clinical Pharmacokinetics of Hydrallazine

Direct Vasodilators and Sympatholytic Agents

The second Lilly Prize Lecture, University of Newcastle, July 1977. beta‐Adrenergic receptor blockade in hypertension, past, present and future.

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