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CH20(CH2)2NH2 Increases GFR

Slow onset and long duration of action extended the patent life of older drugs. The safety of DHPs was of some concern, since Furberg et «/.published a retrospective analysis of clinical studies with the rapid-release formulation of nifedipine and claimed that nifedipine may increase mortality of patients with heart disease.34 The increased mortality, if true, may have been due to a rapid fall in arterial pressure, rather than a specific effect of nifedipine. Rapid fall in pressure should be avoided, particularly in patients with heart disease. In subsequent studies long-acting DHPs or extended-release formulations of firstgeneration compounds did not increase mortality in patients with diabetes or cardiovascular disease.35 The World Health Association and International Society of Hypertension formed a subcommittee to evaluate the safety of CCAs. This subcommittee concluded that the available evidence does not prove any increased risk of cardiovascular events, cancer, or bleeding caused by CCAs.36

Many pharmacological properties of various CCAs are similar. There are, however, also substantial differences not only in their relative potency, but also in their pharmacokinetics, onset and duration of action, specificity for certain subunits of calcium channels, and effects unrelated to their action at Ca2 + channels. The clinical importance of differences in the properties of DHPs was recently emphasized in a review article by Meridith and Elliott.37 Verapamil and diltiazem belong to different chemical classes and have direct effects on cardiac contractility and conduction. The extended-release formulations of DHPs differ from each other in their pharmacokinetic properties, but the elimination half-life of either of these formulations is shorter than that of amlodipine (Table 3). Not all pharmacological differences are, however, clinically relevant. By acute oral administration all DHPs have a high therapeutic index (ratio of LD50:ED50), so that differences in their relative potencies are not clinically important. Comparative clinical studies claim differences in efficacy or maximal obtainable therapeutic effect of a drug. These claims are misleading if the drugs are compared at only one commonly used dose, since this dose may represent an ED70 of one drug and ED40 of another. Higher efficacy can only be claimed if complete dose-response curves for both drugs are obtained and the maximal obtainable effect of one drug is significantly higher than that of the other. A claim for a lower incidence of side effects may also be misleading if the drugs are compared at nonequivalent doses.

Some of the third-generation CCAs developed in the 1990s were designed to incorporate additional pharmacological properties likely to provide beneficial effects, e.g., a-adrenoceptor blockade, NO release, diuresis, cardioprotection, lipid lowering, or antithrombotic activity. Some of these effects involve incorporation of an additional mechanism of action that is not related to the blockade of L-type Ca2 + channels. Table 4 summarizes some structure-activity aspects of second- and third-generation DHPs. Vasoselectivity can apparently be achieved by replacing hydrogen in R3 position with either Cl or NO2 or by extending the side chain in R4 position. The drugs are considered vasoselective if they inhibit Ca2 + entry into VSM cells at substantially lower concentrations than required for inhibition of Ca2 + entry into myocardial cells. Bulky substitution in the R1 position may provide additional inhibitory effect at T-type channels, while inhibition of N-channels may be facilitated by the introduction of a longer side chain in R2 position. Some of the additional pharmacological effects listed in Table 4, e.g., antiatherosclerotic effects, may represent a class effect, but have been described for only a few DHPs. Incorporation of additional activities is likely to change the therapeutic indications for individual drugs. Nimodipine is used in the therapy of subarachnoidal hemorrhage and benidipine can conceivably be used in the treatment of renal insufficiency.

Side effects of CCAs are predictable on the basis of their pharmacological properties. Headache, flushing, and peripheral edema are consequences of excessive vasodilatation. These effects are dose-dependent, usually transient, and seldom require discontinuation of the therapy. Ankle edema induced by CCAs is not due to sodium retention, but rather due to arteriolar vasodilatation without corresponding venous dilation. ACEIs alleviate this type of edema.

Blood Pressure Health

Blood Pressure Health

Your heart pumps blood throughout your body using a network of tubing called arteries and capillaries which return the blood back to your heart via your veins. Blood pressure is the force of the blood pushing against the walls of your arteries as your heart beats.Learn more...

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