The clinical importance of cardioselectivity and lipophilicity in beta blockers

Abstract

Cardioselective beta blockers tend, as a group, to be hydrophilic. However, hydrophylicity is not an essential factor for the expression of cardioselectivity. Likewise, non-selective beta blockers are generally lipophilic; but lipophilicity is not an essential factor for expression of non-selectivity. Though beta blockers as a group are effective and cause few troublesome side effects, an agent which is cardioselective bydrophilic, and non-metabolized has, in contrast to one which is non-selective, lipid-soluble, and metabolized, several advantages in certain clinical areas. Pharmacokinetic (hydrophilicity versus lipophilicity) 1. 1. Blood levels and length of action. Consistent between-patient peak blood levels (only three- to fourfold variatin compared to twenty-fold with liver metabolized agents like propranolol and metoprolol) render a hydrophilic beta blocker such as atenolol a very predictable durg in the clinical situation and are probably contributing to its narrow dose range. Being unmetabolized and renal-excreted hydrophilid beta blockers have a long biological action which enables a low dose to be given on a once daily basis, resulting in 24-hour cover for both hypertension and angina. 2. 2. The brain. In man very little atanolol (hydrophilic) enters the brain (about one twentieth of the concentration of a lipophilic beta blocker). It has a brain/blood ratio of aproximately 0.1:1, compared to 17:1 and 14:1 with propranolol and metoprolol (both lipophilic), respectively. This possibly accounts for (1) the low incidence of side effects relating to the CNS, and (2) the disappearance of CNS side effects on changing from lipophilic beta blockers to atenolol 3. 3. The kidney. Hydrophilic beta blockers, such as atenolol and nadolol, are excreted virtually unmetabolized by the kidney. However, in the case of atenolol at glomerular filtration rates above 35 ml./minute (or serum creatinine of 5.0 mg. % or 600 mmol./L.), half the daily dose sould be given on alternate days. With lipophilic, liver-metabolized beta blockers like propranolol and metoprolol, there is likewise a tendency for increased blood levels in severe renal failure (due to the accompanying liver dysfunction). These higher blood levels plus a marked accumulation of metabolites are an indication for dosage reduction. 4. 4. The elderly. The elderly handle and tolerate hydrophilic beta blockers in a similar fashion to youner subjects. Due to the liver dysfunction associated with aging (hepatic blood flow decreased 40 to 50% in the 70-hears-old subjects), lipophilic beta blockers like propranolol achieve blood levels in the elderly up to fourfold higher than in younger subjects; this may account for the possible higher incidence of side effects in the eldorly. Parmacodynamic (cardioselectivity versus non-selectivity) 1. 1. Asthma. At low doses, atenolol and metoprolol are highly cardioselective (cardioselectivity is dose-related) and are the beta blockers probably least likely to cause a fall in forced expiratory volume (FEV4) in patients with reversible airways obstruction. Also, unlike non-selective beta blockers, they preserve the bronchodilator action of a beta-2 sthnulant such as isoprenaline. 2. 2. Cold extremities. cold extremities can occur with all beta blockers, but the temperature change is minimal on a cardioselective agent. 3. 3. Periheral blood flow. Peripheral blood flow during exercise is less compromised with a cardioselective, in contrast to a non-selective, beta blocker (with no SIA). Some patients with intermittent claudication thus will have a greater exercise toelrance with a cardioselective beta blocker. 4. 4. Antihypertensive control. Because cardioselective beta blockers preserve beta-2 vasodilator action, They are possibly slightly more effective antihypertensive agents than are non-selective bete blockers. 5. 5. Stress hypertension. Hyertension associated with increased adrenaline secretion-e.g., insulin-induced hypoglycemia, smoking, and possibly mental stress, is exacerbated (diastolic pressor effect) by a non-selective beta blocker. This is not the case with a cardioselective beta blocker. 6. 6. Renal function. Renal function (effective renal plasma flow and creatinine clearance) is less compromised on cardioselective compared to non-selective beta blockers (? nadolol excepted). This fact might be of importance to patients with already impaired renal function. 7. 7. Migraine. Non-selective propranolol is an effective prophylactic drug for migraine. It is doubtful if cardioselective beta blockers will be effective. 8. 8. Blood sugar. The majority of diabetic patients tolerate propranolol well. The return of blood sugar to normal after insulin-induced hypoglycemia is dependent to some extent n beta-2 receptor integrity (glycogenolysis and gluconeogenesis). A non-selective beta blocker, in contrast to a cardioselective beta blocker, prolongs the hypoglycemic period. Thus, for patients at risk from hypoglycemia who require beta blocker therapy a cardioselective agent is probably preferable.