Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2021 Publisher: Generics [UK] Ltd t/a Mylan, Station Close, Potters Bar, Hertfordshire, EN6 1TL, United Kingdom
Pharmacotherapeutic group: Beta blocking agents, selective
ATC Code: C07AB07
Bisoprolol is a potent, highly beta1-selective adrenoreceptor blocking agent lacking intrinsic sympathomimetic activity and without relevant membrane stabilising activity. It only shows low affinity to the beta2-receptor of the smooth muscles of bronchi and vessels as well as to the beta2-receptors concerned with metabolic regulation. Therefore, bisoprolol is generally not to be expected to influence the airway resistance and beta2-mediated metabolic effects. Its beta1-selectivity extends beyond the therapeutic dose range.
In total 2647 patients were included in the CIBIS II trial. 83% (n=2202) were in NYHA class III and 17% (n=445) were in NYHA class IV. They had stable symptomatic systolic heart failure (ejection fraction <35%, based on echocardiography). Total mortality was reduced from 17.3% to 11.8% (relative reduction 34%). A decrease in sudden death (3.6% vs 6.3%, relative reduction 44%) and a reduced number of heart failure episodes requiring hospital admission (12% vs 17.6%, relative reduction 36%) was observed. Finally, a significant improvement of the functional status according to NYHA classification has been shown. During the initiation and titration of bisoprolol hospital admission due to bradycardia (0.53%), hypotension (0.23%), and acute decompensation (4.97%) were observed, but they were not more frequent than in the placebo-group (0%, 0.3% and 6.74%). The numbers of fatal and disabling strokes during the total study period were 20 in the bisoprolol group and 15 in the placebo group.
The CIBIS III trial investigated 1010 patients aged ≥65 years with mild to moderate chronic heart failure (CHF; NYHA class II or III) and left ventricular ejection fraction ≤35%, who had not been treated previously with ACE inhibitors, betablocking agents, or angiotensin receptor blockers. Patients were treated with a combination of bisoprolol and enalapril for 6 to 24 months after an initial 6 months treatment with either bisoprolol or enalapril.
There was a trend toward higher frequency of chronic heart failure worsening when bisoprolol was used as the initial 6 months treatment. Non inferiority of bisoprolol-first versus enalapril-first treatment was not proven in the per-protocol analysis, although the two strategies for initiation of CHF treatment showed a similar rate of the primary combined endpoint death and hospitalization at study end (32.4% in the bisoprolol-first group vs. 33.1% in the enalapril-first group, per-protocol population). The study shows that bisoprolol can also be used in elderly chronic heart failure patients with mild to moderate disease.
Antianginal mechanism: Bisoprolol by inhibiting the cardiac beta receptors inhibits the response given to sympathetic activation. That results in the decrease of heart rate and contractility this way decreasing the oxygen demand of the cardiac muscle.
In acute administration in patients with coronary heart disease without chronic heart failure bisoprolol reduces the heart rate and stroke volume and thus the cardiac output and oxygen consumption. In chronic administration the initially elevated peripheral resistance decreases.
Bisoprolol is used for the treatment of hypertension and angina pectoris. As with other Beta-1-blocking agents, the method of acting in hypertension is unclear. However, it is known that Bisoprolol reduces plasma renin activity markedly.
Bisoprolol is absorbed almost completely from the gastrointestinal tract. Together with the very small first pass effect in the liver, this results in a high bioavailability of approximately 90%.
The plasma protein binding of bisoprolol is about 30%. The distribution volume is 3.5 l/kg. The total clearance is approximately 15 l/h.
The plasma elimination half-life (10-12 hours) provides 24 hours efficacy following a once daily dosage.
50% is metabolised by the liver to inactive metabolites which are then excreted by the kidneys.
Bisoprolol is excreted from the body by two routes. 50% is metabolised by the liver to inactive metabolites which are then excreted by the kidneys. The remaining 50% is excreted by the kidneys in an unmetabolised form. Since the elimination takes place in the kidneys and the liver to the same extent a dosage adjustment is not required for patients with impaired liver function or renal insufficiency.
In patients with chronic heart failure (NYHA stage III) the plasma levels of bisoprolol are higher and the half-life is prolonged compared to healthy volunteers. Maximum plasma concentration at steady state is 64±21 ng/ml at a daily dose of 10 mg and the half-life is 17±5 hours.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity or carcinogenic potential, toxicity to reproduction and development.
Like other beta-blockers, bisoprolol caused maternal (decreased food intake and decreased body weight) and embryo/fetal toxicity (increased incidence of resorptions, reduced birth weight of the offspring, retarded physical development) at high doses but was not teratogenic.
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