B.DRUG SIZE The molecular size of drugs varies from very small (lithium ion,MW 7)to very large (eg, alteplase [t-PA],a protein of MW 59,050).However,most drugs have molecular weights between 100 and 1000.The lower limit of this narrow range is probably set by the requirements for specificity of action.To have a good "fit"to only one type of receptor,a drug molecule must be sufficiently unique in shape,charge,and other properties,to prevent its binding to other receptors. To achieve such selective binding,it appears that a molecule should in most cases be at least 100 MW units in size.The upper limit in molecular weight is determined primarily by the requirement that drugs be able to move within the body (eg,from site of administration to site of action).Drugs much larger than MW 1000 do not diffuse readily between compartments of the body (see Permeation,below).Therefore,very large drugs (usually proteins)must often be administered directly into the compartment where they have their effect.In the case of alteplase,a clot-dissolving enzyme,the drug is administered directly into the vascular compartment by intravenous or intra-arterial infusion. C.DRUG REACTIVITY AND DRUG-RECEPTOR BONDS Drugs interact with receptors by means of chemical forces or bonds.These are of three major types:covalent,electrostatic,and hydrophobic.Covalent bonds are very strong and in many cases not reversible under biologic conditions.Thus,the covalent bond formed between the acetyl group of aspirin and its enzyme target in platelets,cyclooxygenase,is not readily broken.The platelet aggregation-blocking effect of aspirin lasts long after free acetylsalicylic acid has disappeared from the bloodstream (about 15 minutes)and is reversed only by the synthesis of new enzyme in new platelets,a process that takes about 7 days.Other examples of highly reactive, covalent bond-forming drugs are the DNA-alkylating agents used in cancer chemotherapy to disrupt cell division in the tumor. Electrostatic bonding is much more common than covalent bonding in drug-receptor interactions. Electrostatic bonds vary from relatively strong linkages between permanently charged ionic molecules to weaker hydrogen bonds and very weak induced dipole interactions such as van der Waals forces and similar phenomena.Electrostatic bonds are weaker than covalent bonds. Hydrophobic bonds are usually quite weak and are probably important in the interactions of highly lipid-soluble drugs with the lipids of cell membranes and perhaps in the interaction of drugs with the internal walls of receptor "pockets." The specific nature of a particular drug-receptor bond is of less practical importance than the fact that drugs that bind through weak bonds to their receptors are generally more selective than drugs that bind by means of very strong bonds.This is because weak bonds require a very precise fit of the drug to its receptor if an interaction is to occur.Only a few receptor types are likely to provide such a precise fit for a particular drug structure.Thus,if we wished to design a highly selective short-acting drug for a particular receptor,we would avoid highly reactive molecules that form covalent bonds and instead choose molecules that form weaker bonds. A few substances that are almost completely inert in the chemical sense nevertheless haveB. DRUG SIZE The molecular size of drugs varies from very small (lithium ion, MW 7) to very large (eg, alteplase [t-PA], a protein of MW 59,050). However, most drugs have molecular weights between 100 and 1000. The lower limit of this narrow range is probably set by the requirements for specificity of action. To have a good "fit" to only one type of receptor, a drug molecule must be sufficiently unique in shape, charge, and other properties, to prevent its binding to other receptors. To achieve such selective binding, it appears that a molecule should in most cases be at least 100 MW units in size. The upper limit in molecular weight is determined primarily by the requirement that drugs be able to move within the body (eg, from site of administration to site of action). Drugs much larger than MW 1000 do not diffuse readily between compartments of the body (see Permeation, below). Therefore, very large drugs (usually proteins) must often be administered directly into the compartment where they have their effect. In the case of alteplase, a clot-dissolving enzyme, the drug is administered directly into the vascular compartment by intravenous or intra-arterial infusion. C. DRUG REACTIVITY AND DRUG-RECEPTOR BONDS Drugs interact with receptors by means of chemical forces or bonds. These are of three major types: covalent, electrostatic, and hydrophobic. Covalent bonds are very strong and in many cases not reversible under biologic conditions. Thus, the covalent bond formed between the acetyl group of aspirin and its enzyme target in platelets, cyclooxygenase, is not readily broken. The platelet aggregation-blocking effect of aspirin lasts long after free acetylsalicylic acid has disappeared from the bloodstream (about 15 minutes) and is reversed only by the synthesis of new enzyme in new platelets, a process that takes about 7 days. Other examples of highly reactive, covalent bond-forming drugs are the DNA-alkylating agents used in cancer chemotherapy to disrupt cell division in the tumor. Electrostatic bonding is much more common than covalent bonding in drug-receptor interactions. Electrostatic bonds vary from relatively strong linkages between permanently charged ionic molecules to weaker hydrogen bonds and very weak induced dipole interactions such as van der Waals forces and similar phenomena. Electrostatic bonds are weaker than covalent bonds. Hydrophobic bonds are usually quite weak and are probably important in the interactions of highly lipid-soluble drugs with the lipids of cell membranes and perhaps in the interaction of drugs with the internal walls of receptor "pockets." The specific nature of a particular drug-receptor bond is of less practical importance than the fact that drugs that bind through weak bonds to their receptors are generally more selective than drugs that bind by means of very strong bonds. This is because weak bonds require a very precise fit of the drug to its receptor if an interaction is to occur. Only a few receptor types are likely to provide such a precise fit for a particular drug structure. Thus, if we wished to design a highly selective short-acting drug for a particular receptor, we would avoid highly reactive molecules that form covalent bonds and instead choose molecules that form weaker bonds. A few substances that are almost completely inert in the chemical sense nevertheless have