Journal of Clinical and Basic Cardiology An Independent International Scientific Journal Journal of Clinical and Basic Cardiology 1998; 1 (1), 5-9 Pharmacological properties of beta-adrenoceptor blocking drugs Borchard U Homepage: www.kup.at/jcbc Online Data Base Search for Authors and Keywords Indexed in Chemical Abstracts EMBASE/Excerpta Medica Krause & Pachernegg GmbH · VERLAG für MEDIZIN und WIRTSCHAFT · A-3003 Gablitz/Austria REVIEWS β-blocking drugs J Clin Bas Cardiol 1998; 1: 5 Pharmacological properties of β-adrenoceptor blocking drugs U. Borchard β-adrenoceptor blocking drugs are widely used for the treat- Pharmacodynamic properties ment of cardiovascular diseases such as arterial hypertension, β β coronary heart disease and supraventricular and ventricular In many organs there is a coexistence of 1- and 2-receptors (Table 1). For example, in the normal human heart about 80% tachyarrhythmias. They may also be beneficial in the hyper- β β β kinetic heart syndrome, hypotensive circulatory disorders, of the -receptors are of the 1-subtype. In heart failure 1- receptors are down-regulated so that a relatively higher pro- portal hypertension, hyperthyroidism, tremour, migraine, β anxiety, psychosomatic disorders or glaucoma. In recent years portion of 2-receptors can be measured [3]. The physiological and therapeutic actions of a β-blocker depend on the actual even patients with heart failure have been successfully treated β β with β-blockers initially given at very low doses. density of 1- and/or 2-receptors in the different organs, on β A great number of β-adrenoceptor blocking drugs are now the affinity of the -blocker and on the local drug concen- available for clinical use which differ widely with respect to tration. their pharmacodynamic and pharmacokinetic properties [1, 2]. They all interact with β-adrenoceptors forming drug Affinity β β receptor complexes so that endogenous norepinephrine and -blockers with high affinity for -adrenoceptors (Table 2) epinephrine are hindered from accessing the receptor. This are effective in small doses if their bioavailability is not too leads to a competitive antagonism which is characterized by a low [4, 5]. Their action still continues even if they are washed parallel shift of the concentration-response curve of the agonist out of the extracellular space. Consequently their duration of β to the right. The β-receptor blockade can be completely re- action cannot be predicted by the plasma half life of the - versed by high concentrations of the agonist. phase of elimination [3]. This holds true for many drugs with β The various β-blockers differ with respect to their β- high affinity and short plasma half life (2–4 h for the -phase). receptor affinity, β -selectivity, partial agonist activity and Penbutolol, for example, has a high affinity, dissociates slowly 1 β β physicochemical properties (lipophility, stereospecificity) from the -receptor, the t1/2 value ( -phase) is about 2 h, the which all may be of particular importance for clinical use. In terminal half life is about 27 h and the duration of action after addition, pharmacokinetic properties such as absorption, bio- a 40 mg dose amounts to about 48 h. availability, metabolism, volume of distribution and elimina- tion (hepatic and/or renal clearance) may guide therapy in Table 2: Pharmacodynamic properties of ß-blockers special patients. Affinity (pA2-values) Chrono- Inotropy Trachea ß1- Sel.- PAA PC UMA tropy Sel. Index Acebutolol 7.3 7.0 6.4 + 0.9 + 0.17 (+) Alprenolol 8.6 8.6 8.4 – + 3.3 + Atenolol 7.6 7.4 5.9 + 1.7 – 0.0033 – Betaxolol 8.6 8.6 6.2 + 2.4 – 3.91) (+) Bisoprolol 8.8 8.9 6.4 + 2.4 – 3.0 + β β Table 1: Coexistence of 1- and 2-receptors in different organs Bopindolol 9.512) 9.372) 9.652) – (+) Bupranolol 8.7 9.0 9.5 – – 0.38 + Organ Subtype Function Carazolol 9.9 9.8 9.4 – – 13.7 + Carteolol4) 9.2 9.0 9.3 – + 0.214 (+) Presynaptic Carvedilol4) 9.1 8.87 – – 2261)+ Noradrenergic Celiprolol 7.6 8.1 6.8 + 0.8 + 0.152 (+) 5 nerve ending β2 Norepinephrine release ↑ Esmolol ) 6.9 6.9 5.3 + 1.6 – – Mepindolol 9.9 9.5 9.0 – + 0.54 (+) Postsynaptic Metipranolol 9.9 9.5 9.0 – + 0.214 (+) a Heart β1, (β2) Sinus rate ↑ Metoprolol 7.5 7.7 6.4 + 1.1 – 0.18 (+) Contractility ↑ Nadolol 7.9 7.2 7.5 – – 0.008 – AV-conduction ↑ Nebivolol4) 8.24 5.77 + 2.47 – + Gastrointestinal tract β1 Muscular tone ↓ Oxprenolol 8.5 8.7 8.5 – + 0.51 (+) a 3 1 Kidney β1, (β2) Renin release ↑ Penbutolol ) 8.6 8.9 9.0 – (+) 50.0 )+ a Fat cells β1, (β2) Lipolysis ↑ Pindolol 9.2 9.4 9.0 – + 0.20 (+) Propranolol 8.4 8.5 8.5 – – 5.4 + Bronchi β2 Muscular tone ↓ Sotalol 6.1 5.9 5.9 – – 0.011 – b Blood vessels β2, (β1) Muscular tone ↓ Talinolol 7.0 7.0 5.33 + 1.7 – – 4 1 Uterus β2 Muscular tone ↓ Tertatolol ) 9.37 8.83 – – 2.5 )+ a 3 Pankreas (β-cells) β2, (β1) Insulin release ↑ Timolol ) 8.7 8.7 8.2 – – 0.28 (+) a Thyroid gland β2, (β1) T4 → T3 conversion ↑ a Incretory glands β2, (β1) Secretion of parathormone ↑ Sel.-index = selectivity index: pA2 chronotropy minus pA2 trachea; calcitonin, glucagon ↓ PAA = partial agonist activity; PC = partition coefficent n-octanol/ phosphate buffer (temperature 20–30 °C. pH 7.0; 1) pH 7.4); UMA a 2 3 receptor subtype coexistence (eg, in the heart 20 % β2) = unspecific membrane action; ) active metabolite; ) S-isomers; b human cerebral blood vessels 4) vasodilative; 5) only i.v.-application From the Institut für Pharmakologie, Heinrich-Heine-Universität Düsseldorf, Germany. Correspondence to: Prof. Ulrich Borchard, MD, PhD, D-40225 Düsseldorf, Moorenstraße 5, Germany. REVIEWS J Clin Bas Cardiol 1998; 1: 6 b-blocking drugs β 1-selectivity Table 4: Pharmacokinetic properties of β-blockers Most of the therapeutic actions of β-blockers are due to inhibition of β -receptors whereas a great number of specific 1 1 2 3 13 side-effects are brought about by inhibition of β -receptors. Substance Resorp- Bioavail- F.P.E. ) Act. ) PPB )Vd ) 2 tion % ability % met. % l/kg In most therapeutic situations β1-selective drugs are as β effective as non-selective drugs. However, 1-selective agents Acebutolol 40–609)+ +4) 11–25 1.35 are better tolerated than non-selective β-blockers as they have Alprenolol > 95 10–309) + + 80 3.3 fewer side effects [6]. Atenolol 50 50 – – 3 0.7 Experiments on isolated heart preparations (chronotropy: Betaxolol > 95 80 – – 50 6.0 β ) and tracheal strips (bronchodilatation: β ) as well as binding Bisoprolol > 90 88 – – 30 3.2 1 2 Bopindolol > 95 60–707)+ + 657) 2.9 experiments with radio-labeled β-blockers have shown the 5 5 β Bupranolol > 95 < 10 + )+)76 following sequence of 1-selectivity: bisoprolol ~ betaxolol Carazolol > 85 < 10 + – 81 10.98) ~ nebivolol > atenolol ~ talinolol > metoprolol > acebutolol Carteolol > 90 90 – + 15 3.6 ~ celiprolol (Table 2). One major advantage of a high β1- Carvedilol 85 25 + + 98 2 9 selectivity is the lower incidence of air-way obstruction (β2- Celiprolol 50 50 ) – – 25 6.5 Esmolol11) – 56 3.4 receptor blockade) and the bronchodilatory action of β2- β Mepindolol > 95 > 95 – – 50 5.7 agonists even in the presence of a 1-selective blocker. How- 6 β Metipranolol ) > 95 50 + + 70 3.5 ever, in patients with bronchial asthma all -blockers are Metoprolol > 95 509) + – 12 5.6 contraindicated independent of their β1-selectivity. It is a fur- Nadolol 30 20–30 – – 25 2.5 12 ther advantage of β1-selective drugs that they show only minor Nebivolol > 95 12 ) + + 98 ?10 effects on glucose and lipid metabolism. The benefits of a high Oxprenolol > 90 24–60 + – 80 1.3 β -selectivity of a β-blocker in clinical practice are summarised Penbutolol > 90 > 90 – – 95 0.3 1 Pindolol 90 90 – – 60 2.0 in Table 3. Propranolol > 90 309) + + 93 3.6 Sotalol 75–90 75–90 – – 0 2.0 Partial agonist activity Talinolol 50–70 5510) – – 60 3.3 The partial agonist activity (PPA) or intrinsic sympathomimetic Tertatolol 85 64 + 94 0.43 activity (ISA) of some β-blockers (Table 2) is due to the simi- Timolol 90 50–759) + – 10 1.4–3.5 larity of the molecules of the agonist and antagonist. Binding 1) F.P.E. = first pass effect; 2) Act. met. = active metabolite clini- of β-blockers with ISA to the receptor induces a weak signal 3 4 β cally relevant; ) PPB = plasma protein binding; ) diacetolol; transduction but at the same time antagonises the action of - 5) carboxy-bupranolol (> 90 %); 6) desacetyl-metipranolol is the agonists. Maximal ISA of β-blockers needs full receptor occu- active compound; 7) hydrolysed bopindolol as active metabolite; pation and does not reach the maximal effect of a full agonist 8) results with radio-labeled carazolol; 9) dose dependent biovail- so that ISA of β-blockers is called partial agonist activity. β- ability; 10) decrease of bioavailability by food intake; 11) only i.v.- 12 13 blockers with ISA might be useful in patients with low heart application; ) 96 % in slowly metabolizing individuals; ) Vd = volume of distribution. rate [7] or with low HDL-cholesterol and/or high triglycerides [2]. However, clinical studies have shown that β-blockers with ISA are less effective in reducing mortality in patients with acute myocardial infarction [8]. In summary, the clinical signi- Stereospecificity ficance of ISA has to be regarded as low. With the exception of penbutolol or timolol all β-blockers are racemic mixtures containing 50 % of the β-receptor blocking Physico-chemical properties S-isomer and 50 % of the R-isomer which is without β- Lipophilicity β blocking action.