Prichard B N
Postgrad Med J. 1976;52 Suppl 4:35-41.
The use of beta-adrenergic blocking drugs in angina pectoris was one of the original indications for these drugs suggested by Black. An anti-anginal effect was demonstrated with the first beta-adrenergic blocking drug, pronethalol, that was used clinically. This benefit in angina was confirmed in the early trials with propranolol in 1964-65. Although some definite anti-anginal effect can be demonstrated with low fixed dosage, evidence suggested that those trials which used a higher and a variable dose displayed a greater anti-anginal action of the drug. After a two dose trial (Gillam and Prichard, 1966,) demonstrated a dose dependent anti-anginal effect, a log-dose response study demonstrated a progressive reduction in angina attacks as dosage was increased (Prichard and Gillam, 1971). While a highly significant effect was found with an average dose of 52 mg a day a progressive reduction in angina attacks was found with logarithmic increases in dosage up to an average of 417 mg a day. Dosage in this trial was adjusted to produce a supine heart rate of 55-60 beats/minute provided this was not prevented by side effects. As the dosage of 417 mg a day was still on the straight line part of the dose response curve and therefore suboptimal, we not adjust dosage to produce a standing heart rate of 55-60. Fully meaningful comparative trials require that optimum dose of the drugs being compared are used. A variable dose comparative trial comparing propranolol and practolol, showed propranolol was the more effective agent. More recently a variable dose comparative trial of sotalol and propranolol indicated propranolol had greater anti-anginal action although sotalol, unlike practolol, was more effective than low dose propranolol. The use of beta-blocking agents in angina pectoris is relatively safe provided that the contraindications of asthma and cardiac insufficiency are observed and that treatment is commenced at a low dosage. The most dramatic change in the sympathetic environment of the heart takes place when treatment with a beta-blocking drug is commenced. The greatest danger of precipitating heart failure is therefore at the beginning of treatment even with a small starting dose. Once treatment has begun even an increase of 25% per dose represents a small pharmacological increment as there is no great change in the sympathetic drive to the heart. The larger dosage of beta-blocking drugs required for optimum treatment of angina may be gradually approached, but it has been my experience that heart failure is not likely to be precipitated at larger doses, provided they are not used initially. In other than mild angina pectoris the average optimum dosage of propranolol is 500-800 mg a day, similar, or perhaps more than the average dose in hypertension.
β-肾上腺素能阻滞剂用于心绞痛是布莱克提出的这些药物最初的适应证之一。首个临床使用的β-肾上腺素能阻滞剂普萘洛尔显示出抗心绞痛作用。1964 - 1965年用普萘洛尔进行的早期试验证实了其在心绞痛方面的益处。尽管低固定剂量能显示出一定的抗心绞痛作用，但有证据表明，那些使用较高和可变剂量的试验显示出该药物更大的抗心绞痛作用。在一项两剂量试验（吉勒姆和普里查德，1966年）显示出剂量依赖性抗心绞痛作用后，一项对数剂量反应研究表明，随着剂量增加心绞痛发作逐渐减少（普里查德和吉勒姆，1971年）。虽然每天平均剂量52毫克时发现有高度显著的效果，但随着剂量对数增加直至平均每天417毫克，心绞痛发作也逐渐减少。该试验中剂量调整为使仰卧心率达到55 - 60次/分钟，前提是无副作用阻止。由于每天417毫克的剂量仍处于剂量反应曲线的直线部分，因此并非最佳剂量，我们未将剂量调整为使站立心率达到55 - 60次/分钟。完全有意义的比较试验要求使用所比较药物的最佳剂量。一项比较普萘洛尔和心得宁的可变剂量对比试验表明，普萘洛尔是更有效的药物。最近一项索他洛尔和普萘洛尔的可变剂量对比试验表明，普萘洛尔具有更大的抗心绞痛作用，尽管索他洛尔与心得宁不同，比低剂量普萘洛尔更有效。只要注意哮喘和心功能不全的禁忌证并从小剂量开始治疗，β受体阻滞剂用于心绞痛相对安全。开始用β受体阻滞剂治疗时，心脏交感神经环境变化最为显著。因此，即使起始剂量很小，在治疗开始时诱发心力衰竭的风险也最大。一旦开始治疗，即使每次剂量增加25%，由于对心脏的交感神经驱动没有太大变化，也只是一个小的药理学增量。可以逐渐增加β受体阻滞剂的剂量以达到心绞痛最佳治疗所需的较大剂量，但根据我的经验，只要不是一开始就使用大剂量，大剂量时不太可能诱发心力衰竭。在非轻度心绞痛中，普萘洛尔的平均最佳剂量为每天500 - 800毫克，与高血压的平均剂量相似，甚至可能更高。
