In two series of antiarrhythmic drugs tested, as the octanol/water partition coefficient increases so do the following: elimination from the body by biotransformation, first-pass biotransformation in the liver and gastrointestinal tract after oral administration, protein binding to some extent, and penetration into brain tissue. Patients receiving lipophilic beta-adrenoreceptor blocking drugs may experience more central nervous system side effects than those receiving hydrophilic beta blockers. Structural modification of a drug, guided by the concept of bioisosterism, may allow the disassociation of therapeutic from toxic activities. Alpha-1 acid glycoprotein is the major plasma protein that binds the basic antiarrhythmic drugs. Antiarrhythmic drug metabolites are generally more polar (less lipophilic) and less plasma protein-bound than the parent drugs.