Drug Distribution PDF

Drug Distribution Drug distribution is the process by which a drug reversibly leaves the blood stream and enters the interstitium (extracellular fluid) and/or the cells of the tissues. The delivery of a drug from the plasma to the interstitium primarily depends on 1)blood flow, 2)capillary permea...

Drug Distribution Drug distribution is the process by which a drug reversibly leaves the blood stream and enters the interstitium (extracellular fluid) and/or the cells of the tissues. The delivery of a drug from the plasma to the interstitium primarily depends on 1)blood flow, 2)capillary permeability, 3)the relative hydrophobicity of the drug. 4)the degree of binding of the drug to plasma and tissue proteins, 1. Blood flow: The rate of blood flow to the tissue capillaries varies widely as a result of the unequal distribution of cardiac output to the various organs. Blood flow to the brain, liver, and kidney is greater than that to the skeletal muscles; adipose tissue has a still lower rate of blood flow. This differential blood flow partly explains the short duration of hypnosis produced by a bolus IV injection of thiopental. The high blood flow, together with the superior lipid solubility of thiopental, permit it to rapidly move into the central nervous system (CNS) and produce anesthesia.  Slower distribution to skeletal muscle and adipose tissue lowers the plasma concentration sufficiently so that the higher concentrations within the CNS decrease, and consciousness is regained. Although this phenomenon occurs with all drugs to some extent, redistribution accounts for the extremely short duration of action of thiopental and compounds of similar chemical and pharmacologic properties. 2. Capillary permeability: Capillary permeability is determined by capillary structure and by the chemical nature of the drug. Capillary structure: Capillary structure varies widely in terms of the fraction of the basement membrane that is exposed by slit junctions between endothelial cells. In the brain, the capillary structure is continuous, and there are no slit junctions. This contrasts with the liver and spleen, where a large part of the basement membrane is exposed due to large, discontinuous capillaries through which large plasma proteins can pass. Cross-section of liver and brain capillaries.  Blood-brain barrier: To enter the brain, drugs must pass through the endothelial cells of the capillaries of the CNS or be actively transported. For example, a specific transporter for the large neutral amino acid transporter carries levodopa into the brain. By contrast, lipid-soluble drugs readily penetrate into the CNS because they can dissolve in the membrane of the endothelial cells. Ionized or polar drugs generally fail to enter the CNS because they are unable to pass through the endothelial cells of the CNS, which have no slit junctions. These tightly juxtaposed cells form tight junctions that constitute the so-called blood-brain barrier. Cross-section of liver and brain capillaries. 3. Drug structure: The chemical nature of a drug strongly influences its ability to cross cell membranes. Hydrophobic drugs, which have a uniform distribution of electrons and no net charge, readily move across most biologic membranes. These drugs can dissolve in the lipid membranes and, therefore, permeate the entire cell's surface. The major factor influencing the hydrophobic drug's distribution is the blood flow to the area. By contrast, hydrophilic drugs, which have either a nonuniform distribution of electrons or a positive or negative charge, do not readily penetrate cell membranes, and therefore, must go through the slit junctions. 4. Binding of drugs to plasma proteins: Reversible binding to plasma proteins sequesters drugs in a non-diffusible form and slows their transfer out of the vascular compartment. Binding is relatively nonselective as to chemical structure and takes place at sites on the protein to which endogenous compounds, such as bilirubin, normally attach. Plasma albumin is the major drug-binding protein and may act as a drug reservoir; that is, as the concentration of the free drug decreases due to elimination by metabolism or excretion, the bound drug dissociates from the protein. This maintains the free-drug concentration as a constant fraction of the total drug in the plasma. Binding of Drugs to Plasma Proteins Drug molecules may bind to plasma proteins (usually albumin). Bound drugs are pharmacologically inactive; only the free, unbound drug can act on target sites in the tissues, elicit a biologic response, and be available to the processes of elimination. [Note: Hypoalbuminemia may alter the level of free drug.] Binding of Class I and Class II drugs to albumin when drugs are administered alone (A and B) or together (C). Competition for binding between drugs When two drugs are given, each with high affinity for albumin, they compete for the available binding sites. The drugs with high affinity for albumin can be divided into two classes, depending on whether the dose of drug is greater than, or less than, the binding capacity of albumin. 1. Class I drugs: If the dose of drug is less than the binding capacity of albumin, then the dose/capacity ratio is low. The binding sites are in excess of the available drug, and the bound-drug fraction is high. This is the case for Class I drugs, which include the majority of clinically useful agents. Binding of Class I and Class II drugs to albumin when drugs are administered alone (A and B) or together (C). 2. Class II drugs: These drugs are given in doses that greatly exceed the number of albumin binding sites. The dose/capacity ratio is high, and a relatively high proportion of the drug exists in the free state, not bound to albumin. 3. Clinical importance of drug displacement: This assignment of drug classification assumes importance when a patient taking a Class I drug, such as warfarin, is given a Class II drug, such as a sulfonamide antibiotic. Warfarin is highly bound to albumin, and only a small fraction is free. This means that most of the drug is sequestered on albumin and is inert in terms of exerting pharmacologic actions. If a sulfonamide is administered, it displaces warfarin from albumin, leading to a rapid increase in the concentration of free warfarin in plasma, because almost 100 percent is now free, compared with the initial small percentage. [Note: The increase in warfarin concentration may lead to increased therapeutic effects, as well as increased toxic effects, such as bleeding.]  Drug Metabolism Drugs are most often eliminated by biotransformation and/or excretion into the urine or bile. The process of metabolism transforms lipophilic drugs into more polar readily excretable products. The liver is the major site for drug metabolism, but specific drugs may undergo biotransformation in other tissues, such as the kidney and the intestines. [Note: Some agents are initially administered as inactive compounds (pro-drugs) and must be metabolized to their active forms.] The biotransformation of drugs. Some representative P450 isozymes. Inducers: The cytochrome P450 dependent enzymes are an important target for pharmacokinetic drug interactions. One such interaction is the induction of selected CYP isozymes. Certain drugs, most notably phenobarbital, rifampin, and carbamazepine, are capable of increasing the synthesis of one or more CYP isozymes. This results in increased biotransformations of drugs and can lead to significant decreases in plasma concentrations of drugs metabolized by these CYP isozymes, with concurrent loss of pharmacologic effect. For example, rifampin, an antituberculosis drug, significantly decreases the plasma concentrations of human immunodeficiency virus (HIV) protease inhibitors, diminishing their ability to suppress HIV.  Consequences of increased drug metabolism include: 1) decreased plasma drug concentrations, 2) decreased drug activity if metabolite is inactive, 3) increased drug activity if metabolite is active, and 4) decreased therapeutic drug effect. In addition to drugs, natural substances and pollutants can also induce CYP isozymes. For example, polycyclic aromatic hydrocarbons (found as air pollutants) can induce CYP1A. This has implications for certain drugs; for example, amitriptyline and warfarin are metabolized by P4501A2. Polycyclic hydrocarbons induce P4501A2, which decreases the therapeutic concentrations of these agents. Inhibitors: Inhibition of CYP isozyme activity is an important source of drug interactions that leads to serious adverse events. The most common form of inhibition is through competition for the same isozyme. Some drugs, however, are capable of inhibiting reactions for which they are not substrates (for example, ketoconazole), leading to drug interactions. Numerous drugs have been shown to inhibit one or more of the CYP-dependent biotransformation pathways of warfarin. For example, omeprazole is a potent inhibitor of three of the CYP isozymes responsible for warfarin metabolism. If the two drugs are taken together, plasma concentrations of warfarin increase, which leads to greater inhibition of coagulation and risk of hemorrhage and other serious bleeding reactions.  [Note: The more important CYP inhibitors are erythromycin, ketoconazole, and ritonavir, because they each inhibit several CYP isozymes.] Cimetidine blocks the metabolism of theophylline, clozapine, and warfarin. Drugs such as amlodipine, clarithromycin, and indinavir, which are metabolized by this system, have greater amounts in the systemic circulation leading to higher blood levels and the potential to increase therapeutic and/or toxic effects of the drugs. Inhibition of drug metabolism may lead to increased plasma levels over time with long-term medications, prolonged pharmacological drug effect, and increased drug- induced toxicities. Role of drug metabolism Most drugs are lipid soluble and without chemical modification would diffuse out of the kidney's tubular lumen when the drug concentration in the filtrate becomes greater than that in the perivascular space. To minimize this reabsorption, drugs are modified primarily in the liver into more polar substances using two types of reactions: Phase I reactions that involve either the addition of hydroxyl groups or the removal of blocking groups from hydroxyl, carboxyl, or amino groups, and Phase II reactions that use conjugation with sulfate, glycine, or glucuronic acid to increase drug polarity. The conjugates are ionized, and the charged molecules cannot back-diffuse out of the kidney lumen.  Drug Elimination Removal of a drug from the body occurs via a number of routes, the most important being through the kidney into the urine. Other routes include the bile, intestine, lung, or milk in nursing mothers. Drug elimination by the kidney: 1. Glomerular filtration 2. Proximal tubular secretion 3. Distal tubular reabsorption Renal elimination of a drug Effect of drug metabolism on reabsorption in the distal tubule.