Basic Pharmacology Lecture 3 - Dr. Mona Gaafar PDF

Distribution of drugs Drug in blood stream is distributed into tissues Extracellular fluid Distribution of drugs  DRUG DISTRIBUTION: Drug distribution is the process by which a...

Distribution of drugs Drug in blood stream is distributed into tissues Extracellular fluid Distribution of drugs  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. Unionized lipid soluble drugs are widely distributed throughout the body.  Factors affect drug distribution 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.  2- Capillary permeability Capillary structure varies depending on the type of junctions between endothelial cells  Blood-brain barrier (BBB) The endothelial cells of the brain capillaries lack intercellular pores. In addition, glial cells envelope the capillaries and together these form the BBB. Only lipid soluble, unionized drugs can cross BBB. Placental barrier: Lipid soluble, unionized drugs readily cross the placenta while lipid insoluble drugs cross to a much lesser extent. Thus drugs taken by the mother can cause several unwanted effects in the fetus.  3- BINDING OF DRUGS TO PLASMA PROTEINS AND TISSUES A- PLASMA PROTEIN BINDING: ▪ On reaching the circulation, most drugs bind to plasma proteins; acidic drugs bind mainly to albumin and basic drugs to alpha-acid glycoprotein. ▪ The free or unbound fraction of the drug is the only form available for action, metabolism and excretion, while the protein bound form serves as a reservoir. ▪ The extent of protein binding varies with each drug, e.G. Warfarin is 99%, morphine is 35% protein bound while binding of lithium is 0% i.E (It is totally free). NB: 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.]  Remember Plasma proteins bound to many drugs. This bounded drugs have no action at receptor site and only unbounded fraction has a pharmacological action Displacement of highly bounded drug from plasma protein by other drugs can affect the pharmacological action greatly ex: warfarin Drug distribution determine the model of drug kinetics (one compartment or two compartment) ▪ Plasma albumin is the major drug-binding protein and may act as a drug reservoir of the drug and the drug is released when free drug levels fall.(that is, as the concentration of the free drug decreases due to elimination by metabolism or excretion, the bound drug dissociates from the protein. ▪ Plasma protein binding maintains the free-drug concentration as a constant fraction of the total drug in the plasma Protein binding prolongs the duration of action of the drug Chronic renal failure and chronic liver disease result in hypoalbuminemia with reduced protein binding of drugs. Highly bound protein drugs should be carefully used in such patients  B- Tissue Binding Numerous drugs accumulate in tissues, leading to higher concentrations of the drug in tissues than in the extracellular fluids and blood. Drugs may accumulate as a result of binding to lipids, proteins or nucleic acids. Drugs may also be actively transported into tissues. These tissue reservoirs may serve as a major source of the drug and prolong its actions or, on the other hand, can cause local drug toxicity. [For example, acrolein, the metabolite of Cyclophosphamide is toxic to the kidney because of its accumulation in renal cells.] NB: Tissue binding Delays elimination. Prolongs duration of action. Serves as a reservoir of the drug.  4- Drug structure: - The chemical nature of a drug strongly influences its ability to cross cell membranes. Hydrophobic drugs, readily move across most biologic membranes. These drugs can dissolve in the lipid membranes and, therefore, permeate the entire cell's surface. 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.  Volume of distribution A drug rarely associates exclusively with only one of the water compartments of the body. The vast majority of drugs distribute into several compartments. Therefore, the volume into which drugs distribute is called the apparent volume of distribution or Vd.  Volume of distribution (Apparent Volume of distribution) is a hypothetical volume that relates drug serum concentrations to the amount of drug in the body. Thus, the dimension of volume of distribution is in volume units, such as L or mL. At any given time after drug has been absorbed from extravascular sites and the serum and tissue drug concentrations are in equilibrium, serum concentration for a drug (C) is equal to the quotient of the amount of drug in the body (A) and the volume of distribution: C = A/Vd  VOLUME OF DISTRIBUTION: It relates the amount of the drug in the body to the concentration of the drug in plasma. It is calculated as: VD = AMOUNT OF DRUG IN THE BODY PLASMA CONCENTRATION E.g. : If the dose of the drug given is 500 mg and its concentration is 10 mg/liter of plasma in the body, its vd = 50 liters. 2-apparent vd (L/kg) = total volume of distribution / weight of patient in kg  WATER COMPARTMENTS 1) PLASMA COMPARTMENT: If a drug has a very large molecular weight or binds extensively to plasma proteins, it is too large to move out through the endothelial slit junctions of the capillaries and thus is effectively trapped within the plasma (vascular) compartment. As a consequence, the drug distributes in a volume (the plasma) that is about 6% of the body weight or, in a 70-kg individual, about 4L of body fluid. Aminoglycoside antibiotics show this type of distribution. 2) EXTRACELLULAR FLUID: If the drug has a low molecular weight but is hydrophilic, it can move through the endothelial slit junctions of the capillaries into the interstitial fluid. However, hydrophilic drugs cannot move across the 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. This is about 20% of the body weight, or about 14 L in a 70-kg individual. 3)TOTAL BODY WATER: If the drug has a low molecular weight and is hydrophobic, it can not only move into the interstitium, but can also move through the cell membranes into the intracellular fluid. The drug therefore distributes into a volume of about 60% of body weight, or about 42 L in a 70-kg individual. 4) other sites: In pregnancy, the fetus may take up drugs and thus increase the vd. Drugs such as thiopental, which are stored in fat, may also have unusually high volumes of distribution. Effect of a large Vd on the half-life of a drug A large Vd has an important influence on the half- life of a drug, because drug elimination depends on the amount of drug delivered to the liver or kidney through blood (or other organs where metabolism occurs) per unit of time. Delivery of drug to the organs of elimination depends not only on blood flow, but also on the fraction of the drug in the plasma.  If the Vd for a drug is large, most of the drug is in the extraplasmic space and is unavailable to the excretory organs. Therefore, Any factor that increases the volume of distribution can lead to an increase in the half- life (t1/2) and extend the duration of action of the drug. t1/2: Describes how quickly drug serum concentrations decrease in a patient after a medication is administered  Important facts about Vd are: If drug is retained mostly in the plasma, its vd is small (aspirin, aminoglycosides), while if it is distributed widely in other tissues then its vd is large (pithidine). Vd is useful because it can be used to calculate the amount of drug needed to achieve a desired plasma concentration The knowledge of vd of drugs is clinically important in the treatment of poisoning. Drugs with large vd like pithidine are not easily removed by hemodialysis because they are widely distributed in the body. Competition for binding between drugs : ▪ PLASMA PROTEIN BINDING serves as a store (reservoir) Many drugs may compete for the same binding site. Thus one drug may displace another from the binding sites and result in displacement interactions. ▪ When two drugs are given, each with high affinity for albumin, they compete for the available binding sites of albumin. 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  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. 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.  CLINICAL IMPORTANCE OF DRUG DISPLACEMENT: If patient taking a class I drug, such as warfarin, and 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 % is now free, compared with the initial small percentage. The increase in warfarin concentration may lead to increased therapeutic effects, as well as increased toxic effect, such as bleeding.] BINDING OF CLASS I AND CLASS II DRUGS TO ALBUMIN WHEN DRUGS ARE ADMINISTERED ALONE (A AND B) OR TOGETHER (C).  Important facts about Vd are: If drug is retained mostly in the plasma, its vd is small (aspirin, aminoglycosides), while if it is distributed widely in other tissues then its vd is large (pithidine). The knowledge of vd of drugs is clinically important in the treatment of poisoning. Drugs with large vd like pithidine are not easily removed by hemodialysis because they are widely distributed in the body.