Drug Distribution Lecture Notes PDF

L5 Dr. Alaa AL- Sheek Mashhad Drug Distribution Drug distribution is the process by which a drug reversibly leaves the bloodstream and enters the interstitium (extra cellular fluid) and/or the cells of the tissues....

L5 Dr. Alaa AL- Sheek Mashhad Drug Distribution Drug distribution is the process by which a drug reversibly leaves the bloodstream and enters the interstitium (extra cellular fluid) and/or the cells of the tissues. 1 The delivery of a drug from the plasma to the interstitium primarily depends on: Blood flow Capillary permeability The degree of drug binding to plasma proteins The relative hydrophobicity of the drug. A-Blood flow The rate of blood flow to tissues 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, most viscera, skin, and fat. 2 This differential blood flow explains the short duration of hypnosis produced by a bolus IV injection of thiopental. The high blood flow, together with the high lipid solubility of thiopental, permit it to rapidly move into the 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. This phenomenon called “Redistribution” and it accounts for the extremely short duration of action of thiopental and compounds of similar chemical and pharmacologic properties. 3 B. Capillary permeability Capillary permeability is determined by capillary structure and by the chemical nature of drugs Capillary structure: Capillary structure varies widely in different tissues, in the brain, the capillary structure is continuous, and there are no slit junctions. In contrasts, in the liver and spleen capillaries, a large part of the basement membrane is exposed due to large fenestrations that allow drugs to exchange freely between blood and interstitium. To enter the brain, drugs must pass through the endothelial cells of the capillaries. 4 Lipid-soluble drugs readily penetrate into the CNS because they can dissolve in the membrane of the endothelial cells, while 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. Drug structure: The chemical nature of a drug strongly influences its ability to cross cell membranes. 5 Hydrophobic drugs 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, do not readily penetrate cell membranes, and therefore, must go through the slit junctions. C. 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. 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. Bound drugs are pharmacologically inactive; only the free, unbound drug can act on target sites in the tissues, Albumin has the strongest affinities for hydrophobic drugs, while hydrophilic drugs do not bind to albumin. 6 Bound drug is always in equilibrium with free drug. Bound drug slowly dissociates from the protein so, the highly protein bound drug remain inside the body for long period. Free drug confers immediate starting of action of the drug in the body. More the protein binding of the drug, more the vascular distribution of the drug. 7  Competition for binding between drugs: When two drugs are given, each with high affinity for albumin, they compete for the available binding sites, and can result in drug displacement. Example on the Clinical importance of drug displacement: (Warfarin is highly bound to albumin, and only a small fraction is free. If a sulfonamide is administered, it displaces warfarin from albumin, leading to a rapid increase in the concentration of free warfarin in plasma, the increase in warfarin concentration may lead to increased therapeutic effects, as well as increased toxic effects, such as bleeding). Plasma protein binding for some drugs: Drug PPB Drug PPB Drug PPB Drug PPB Warfarin 99 % Amitriptyline 95 % Morphine 35 % Amoxicillin 18 % Diazepam 98 % Trimethoprim 70 % Digoxin 25 % Ethosuximide 0.0 % Factors that decrease drug distribution Drug with large molecular weight Tissues in which the vessels have tight junctions Hydrophilic drugs. Drug that extremly bound to plasma protein Highly ionized drug Pathological status like uremia and liver cirrhosis 8  Volume of Distribution The volume of distribution is a hypothetical volume of fluid into which a drug is dispersed. Although the volume of distribution has no physiologic or physical basis, it is sometimes useful to compare the distribution of a drug with the volumes of the water compartments in the body. Water compartments in the body: 1-Plasma compartment: If a drug has a very large molecular weight or binds extensively to plasma proteins. It is too large to pass through slit junctions of the capillaries. It will effectively trapped within the plasma (vascular) compartment (6% of the body weight). Heparin shows this type of distribution. 9 2-Extracellular fluid: If a drug has a low molecular weight but is hydrophilic, it can move through the endothelial slit junctions of the capillaries into the interstitial fluid but cannot move across the lipid membranes of cells to enter the water phase inside the cell. Therefore, these drugs distribute into a volume that is the sum of the plasma water and the interstitial fluid, which together constitute the extracellular fluid (20% of the body weight). Aminoglycoside antibiotics show this type of distribution. 3-Total body water: If a drug has a low molecular weight and is hydrophobic, it can also move through the cell membranes into the intracellular fluid. The drug, therefore, distributes into a volume of about 60% of body weight. Ethanol show this type of distribution 4- Other sites: In pregnancy, the fetus may take the drug and thus increase the volume of distribution. Drugs that are extremely lipid soluble, such as thiopental may also have unusually high volume of distribution. Any factor that increases Vd can lead to an increase in the t1/2 and extend the duration of action of the drug. 10 Half-Life(t1/2): It is the time required to change the amount of drug in the body by one- half. The time it takes of the concentration of a drug in the plasma to drop by half from the peak concentration. 11 Steady state: It is a state at which drug intake= drug clearance. It is reached after 4-5 t1/2. The dosage regimen To initiate drug therapy, a dosage regimen must be designed to reach a steady state Such that the plasma and tissue levels remain constant in the case of IV administration and fluctuate around a mean in the case of oral fixed dosage. Generally a drug will reach the steady state in about 4 half-lives. 12 13 14 Maintenance dose: The dosage regimen that maintains a steady-state concentration. It takes four to five half-lives of a drug. Loading dose: A dose of medication, often larger than the subsequent doses, given to establish the therapeutic level of the medication. This help to avoid delay in achieving the desired plasma levels, as the loading dose achieves it rapidly, followed by the maintenance dose. The primary purpose of using a loading dose is to attain steady-state concentration of the drug as quickly as possible, usually right from the start of the dosage regimen for the treatment. Loading doses are given when half-life of the drug is long and the therapeutic benefit is required immediately (for example, lidocaine for arrhythmias). Disadvantages of loading doses include increased risk of drug toxicity. 15