Lennart Andrén

Angio-oedema in relation to treatment with angiotensin converting enzyme inhibitors.

OBJECTIVE--To evaluate and describe the clinical course of angio-oedema reactions induced by angiotensin converting enzyme inhibitors. DESIGN AND METHODS--All reports of angio-oedema reactions associated with angiotensin converting enzyme inhibitors submitted to Swedish Adverse Reactions Advisory Committee were reviewed and the clinical courses summarised. Numbers of cases judged to be induced by angiotensin converting enzyme inhibitors were related to their annual usage, estimated from total sales of defined daily doses, as well as to the estimated number of new patients. All cases of angio-oedema associated with angiotensin converting enzyme inhibitors reported to the World Health Organisations international drug information system were also summarised. RESULTS--36 of the 38 reported cases in Sweden between 1981 and 1990 were judged to be related to angiotensin converting enzyme inhibitors. During 1981 through 1990, altogether 1309 cases of angio-oedema associated with angiotensin converting enzyme inhibitors were registered with the international drug information system. The incidence of reported cases of angio-oedema increased largely in parallel with the increased sales (usage) of angiotensin converting enzyme inhibitors. Of the 36 Swedish patients, 77% experienced the reaction within the first three weeks after starting treatment. 10 patients needed hospitalisation, two of whom had life threatening laryngeal obstruction. With one exception all 36 patients were free of symptoms within one week after discontinuing the drug. CONCLUSIONS--Angio-oedema induced by angiotensin converting enzyme inhibitors is a rare but potentially life threatening reaction, which in most instances occurs shortly after the start of treatment. Any patient in whom the reaction is suspected should have the treatment interrupted and, if necessary, be admitted for observation.

Dyspnoea, asthma, and bronchospasm in relation to treatment with angiotensin converting enzyme inhibitors.

Abstract Objective: To evaluate the occurrence of asthma and dyspnoea precipitated or worsened byangiotensin converting enzyme inhibitors. Design: Summary of reports of adverse respiratory reaction in relation to treatment with angiotensin converting enzyme inhibitors that were submitted to Swedish Adverse Drug Reactions Advisory Committee and to World Health Organisations international drug information system until 1992. Sales of angiotensin converting enzyme inhibitors in Sweden were also summarised. Subjects: Patients receiving angiotensin converting enzyme inhibitors who reported adverse respiratory reactions. Main outcome measures: Clinical characteristics of adverse reactions of asthma, bronchospasm, and dyspnoea. Results: In Sweden 424 adverse respiratory reactions were reported, of which most (374) were coughing. However, 36 patients had averse drug reactions diagnosed as asthma, bronchospasm, or dyspnoea. In 33 of these cases the indication for treatment with angiotensin converting enzyme inhibitors was hypertension, in only three heart failure. The respiratory symptoms occurred in about half of the patients within the first two weeks of treatment, and about one third needed hospitalisation or drug treatment. Dyspnoea symptoms occurred in conjunction with other symptoms from the airways or skin in 23 out of the 36 cases. In the WHO database there were 318 reports of asthma or bronchospasm, 516 reports of dysponea, and 7260 reports of cough in relation to 11 different angiotensin converting enzyme inhibitors. Conclusion: Symptoms of airway obstruction in relation to treatment with angiotensin converting enzyme inhibitors seem to be a rare but potentially serious reaction generally occurring within the first few weeks of treatment.

Haemodynamic Effects of Carvedilol, A New Beta-Adrenoceptor Blocker and Precapillary Vasodilator in Essential Hypertension

Carvedilol (BM 14190) is a new antihypertensive compound which combines beta-adrenoceptor blocking and precapillary vasodilating properties but is devoid of intrinsic sympathomimetic activity. The acute and long-term effects on blood pressure and regional haemodynamics (forearm plethysmography) were studied with carvedilol 25 mg b.i.d. or 50 mg b.i.d. Comparisons were made with propranolol 80 mg b.i.d. in a randomized double-blind placebo controlled trial comprised of 30 patients with essential hypertension. After a four-week placebo period active therapy was given for four weeks. Carvedilol administered acutely reduced blood pressure at both doses, delta 13/6 mmHg (P less than 0.001/P less than 0.01) and 17/10 mmHg (P less than 0.001/P less than 0.01). Resistance in the forearm fell significantly with the higher dose. This was in contrast to propranolol which only reduced heart rate acutely, and as expected caused a rise in forearm resistance. After four weeks both compounds had reduced blood pressure significantly and to the same extent. Blood flow was still significantly reduced with propranolol in contrast to the findings with carvedilol. We conclude that carvedilol given orally has a useful antihypertensive effect both acutely and during prolonged treatment. It is well tolerated and its haemodynamic profile is attractive.

Acute and Long-Term Hemodynamic Effects of Carvedilol, a Combined β-Adrenoceptor Blocking and Precapillary Vasodilating Agent, in Hypertensive Patients

Summary: The purpose of these studies was to investigate the hemodynamic effects of carvedilol, a compound with combined properties of nonselective &bgr;‐adrenoceptor blockade and precapillary vasodilatation. The acute effects were studied with invasive technique (dye dilution) in 10 patients taking 25 mg orally and noninvasively (forearm plethysmography) in 10 patients taking 25 mg and in 10 patients taking 50 mg orally, all with essential hypertension. Significant reductions of systolic and diastolic blood pressure (p < 0.05–0.001) were observed in all groups. Total peripheral resistance (TPR) did not change acutely whereas resistance in the forearm was reduced by 16% (p < 0.05; invasive group). When a comparison with propranolol (80 mg × 2) was made in a randomized double‐blind placebo controlled trial in 30 patients, carvedilol acutely reduced blood pressure significantly by 13/6 mg Hg (25 mg) and 17/10 mm Hg (50 mg) in contrast to propranolol. Resistance in the forearm fell significantly with 50 mg carvedilol, whereas propranolol caused a significant rise. After 4 weeks, both compounds had reduced blood pressure significantly. Blood flow was still reduced with propranolol in contrast to the findings with carvedilol. In conclusion, the summary of these studies shows that carvedilol given orally has a useful antihypertensive effect both acutely and during prolonged treatment, and it has an attractive hemodynamic profile, in agreement with the hemodynamic findings in essential hypertension.

Acute haemodynamic effects of carvedilol (BM 14190), a new combined beta-adrenoceptor blocker and precapillary vasodilating agent, in hypertensive patients

SummaryCarvedilol (BM 14190) is a new compound with combined nonselective beta-adrenoceptor blocking activity, devoid of ISA, and a precapillary vasodilating effect. Its acute haemodynamic effects were studied by invasive techniques in 10 patients given 25 mg carvedilol and noninvasively in 10 patients given 25 mg and in 10 given 50 mg orally. All had essential hypertension. In the invasive study intraarterial blood pressure was measured and cardiac output was determined by the dye-dilution method using Cardio-Green as the indicator. Peripheral haemodynamics in all 30 patients were studied in the forearm using strain gauge plethysmography. Measurements were made at rest before and repeatedly for 90 minutes after oral administration of one capsule of 25 mg or 50 mg carvedilol. Significant reductions in the systolic and diastolic blood pressures (p<0.05–0.001) were observed in all groups. Cardiac output showed a small, non-significant decrease from 5.8 l/min to 5.1 l/min. Total peripheral resistance did not change, whereas resistance in the forearm fell by 16% (p<0.05). These findings are different from what would have been expected acutely after administration of a pure beta-adrenoceptor blocking agent. They indicate that carvedilol possesses vasodilating activity in addition to its beta-adrenoceptor blocking effect.

Effects of treatment with a commercially available St John's Wort product (Movina) on cholesterol levels in patients with hypercholesterolemia treated with simvastatin.

Objective. To assess the effect of treatment with a St Johns Wort product (Movina®) on cholesterol levels (total cholesterol, LDL-cholesterol, and HDL-cholesterol) in patients with hypercholesterolemia on treatment with a stable dose of simvastatin. Design. Controlled, randomized, open, crossover pharmacodynamic study. Setting. Two primary healthcare centres. Intervention. Patients were treated with Movina® one tablet (containing 300 mg of Hypericum perforatum) twice daily and control (a commercially available multivitamin tablet, Vitamineral®). The trial started with a run-in period of 4 weeks. Then the treatment order between control and active treatment was decided (randomization using sealed envelopes). The duration of each treatment period was 4 weeks and simvastatin treatment was kept unchanged during the whole study period (12 weeks). Subjects. Twenty-four patients with hypercholesterolemia treated with a stable dose of simvastatin (10–40 mg daily) for at least three months. Main outcome measures. Assessments of total cholesterol, HDL- cholesterol, LDL-cholesterol, and triglycerides were performed in the morning with the patients in a fasting condition. Results. All patients completed the study. LDL-cholesterol was significantly increased during active treatment compared with control. Thus, the mean LDL-cholesterol after 4 weeks’ active treatment was 2.72 mmol/L compared with 2.30 mmol/L after treatment with control (p <0.0001). An increase in total-cholesterol was also observed (5.08 mmol/L compared with 4.56 mmol/L, p <0.0001). Conclusion. Products containing St Johns Wort should not be given to patients with hypercholesterolemia who are on treatment with simvastatin.

General considerations in selecting antihypertensive agents in patients with type II diabetes mellitus and hypertension

The Working Group on Hypertension in Diabetes recommends starting pharmacologic treatment of hypertension with a small dose of a thiazide, beta-blocker, prazosin hydrochloride, angiotensin-converting enzyme inhibitor, or calcium channel blocker. Thus, these alternatives are regarded as first-line treatment in hypertensive patients with diabetes mellitus. Both thiazides and beta-blockers can cause deterioration in glycemic control and have an unfavorable influence on the lipoprotein profile. These metabolic side effects may partly counteract beneficial effects. Non-selective beta-blockers should probably be avoided in diabetic patients, since blockade of the beta-2 receptor may be associated with a compromise in peripheral blood flow and with problems associated with hypoglycemia. Cardioselective beta-blockers, which may have primary preventive effects on coronary disease, are beneficial in this patient group. In patients with non-insulin-dependent diabetes mellitus without nephropathy or overt fluid retention, diuretic therapy could be replaced by sodium restriction and/or calcium channel blocker therapy, since these agents also have a mild diuretic effect. Calcium channel blockers, angiotensin-converting enzyme inhibitors, and prazosin hydrochloride have minimal metabolic side effects, making them suitable for treatment of hypertension in this patient group.

Diltiazem in hypertensive patients with type II diabetes mellitus

Twenty-three patients with essential hypertension and diabetes mellitus type II were treated with the calcium antagonist diltiazem (120 to 180 mg twice daily). The mean dose was 307 mg/day. The study was a double-blind, placebo-controlled, crossover design. All measurements were performed 12 to 14 hours after drug intake. Blood pressure, heart rate and forearm blood flow were measured noninvasively. Platelet function was studied by measuring adenosine diphosphate-induced platelet aggregation and the platelet specific proteins, beta thromboglobulin and platelet factor 4. Thromboxane B2 formation in serum and the plasma concentration of diltiazem and its metabolites N-demethyldiltiazem, deacetyldiltiazem and N-demethyldeacetyldiltiazem were measured both during placebo and diltiazem treatment. Diabetic control was evaluated by following HbA1C, fasting blood glucose and urinary glucose. Diltiazem reduced both systolic and diastolic (supine and standing) blood pressure significantly. Forearm blood flow was significantly increased by 32%, p less than 0.05. Supine heart rate decreased significantly, while no such change was seen in the standing position. No significant changes were observed in platelet function during diltiazem treatment. There was no relation between the observed blood pressure reduction and the plasma concentration of diltiazem or its metabolites. A positive correlation between the change in heart rate and the metabolite N-demethyldeacetyldiltiazem was observed (r = 0.647, p = 0.005). Three patients were excluded during diltiazem treatment (skin exanthema, headache and atrial fibrillation) and 1 during placebo treatment (angina pectoris). No negative effect on diabetes control was observed. Thus, diltiazem could be used for treatment of hypertension in diabetic patients.

Long-term experience with the combination of pindolol and isradipine in essential hypertension

Abstract Isradipine, a new dihydropyridine calcium antagonist with marked vascular selectivity, was given to 17 patients (11 men and six women, average age 56 ± 10 years) with essential hypertension for 12.5 months (range: four to 17 months). All had supine diastolic blood pressure more than 95 mm Hg with 10 mg pindolol once daily. After a short-term, double-blind, dose-finding, crossover comparison with addition of isradipine or placebo twice daily, they continued to receive pindolol and an optimal dose of isradipine in a single-blind, long-term, follow-up study. In the short-term study on the optimal dose of isradipine (5.1 mg twice daily), blood pressure was lowered by 2418 mm Hg (p

Addition of the calcium antagonist PN 200-110 to pindolol markedly augments the antihypertensive effect in essential hypertension.

Several large-scale studies have recently drawn attention to the fact that arterial hypertension frequently is inadequately controlled and that therapeutic alternatives other than the commonly employed stepped-care treatment may be needed in order to obtain normotension. For this reason PN 200-110, a new dihydropyridine calcium antagonist--at two different dose levels (average 3.8 mg b.i.d. or 5.7 mg b.i.d.)--or placebo was added in a double-blind cross-over trial to pindolol, 10 mg per day, in 20 patients with essential hypertension, after an initial 3-week placebo period. Ionized calcium in serum was determined repeatedly during the study. From an initial level of 157/100 mm Hg, PN 200-110 at the first dose level reduced blood pressure by 14/11 mm Hg (p less than 0.01/0.001) and at the second dose level reduced blood pressure by 22/18 mm Hg (p less than 0.001/0.001). The reduction in mean arterial pressure was significantly correlated to age (=0.050, p less than 0.05). There was no significant increase in heart rate, nor were there any significant correlations between ionized calcium and the effect of PN 200-110 nor between the changes in ionized calcium and the changes in blood pressure. Adverse effects were few and mild. One patient had to be withdrawn because of side effects, probably not related to the investigated drugs. Thus, addition of PN 200-110 to hypertensive patients treated with pindolol caused highly significant and clinically relevant further reductions in arterial pressure. The results show that a combination of this kind offers the possibility of good blood pressure control.