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114 Cards in this Set
- Front
- Back
After the drug is absorbed, the drug molecules are distributed throughout the body by
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systemic circulation
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This type of drug is deposited in fat where the drug can slowly be released
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lipophilic drugs
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distribution is generally...
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rapid
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cell membrane is made up of what two things
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protein and a lipid bilayer
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what two types of drug diffuse easily across the cell membrane
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lipid soluble drugs and small molecule drugs
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drugs bound to what form a larger complex making diffusion more difficult
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plasma proteins
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what are the two processes of drug transfer from capillary into tissue
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diffusion and hydrostatic pressure
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what is the main process of drug transfer from capillary into tissue
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passive diffusion
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passive diffusion is
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drug molecules moving from HIGH concentration to LOW concentration
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Three important factors in determining rate of drug diffusion
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1. membrane thickness
2. diffusion coefficient of drug 3. concentration gradient across capillary membrane |
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If a drug diffuses RAPIDLY in such a way that BLOOD FLOW is the rate limiting step then this process is called
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perfusion or flow limited
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an example of perfusion of flow limited drug diffusion
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congestive heart failure: decreased cardiac output leads to impaired blood flow-->reduced renal clearance through reduced filtration pressure
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If a drug diffuses SLOWLY across membrane in the tissue, this process is called
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diffusion or permeability limited
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Drugs that are this may have an increased distribution volume in diseases that cause inflammation and an increased capillary membrane permeability
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permeability limited
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These three things are ALSO important in determining time for drug to be fully distributed
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blood flow, tissue size and tissue storage
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The partitioning and accumulation of drug in the tissue
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drug affinity
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These factors help determine what?
blood flow to the organ, the volume of the organ, and the partitioning of the drug into the organ tissue |
determine the distribution constant of a drug into an organ
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a physical property that measures the ratio of the solubility of the drug in the oil phase and in aqueous phase
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partition coefficient
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This is defined as a ratio of the drug concentration in the oil phase (octanol) divided by the drug concentration in the aqueous phase measured at equilibrium under specified temp
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partition coefficient
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this is one of the most important factors that determine the tissue distribution of a drug
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partition coefficient
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If each tissue has the same ability to store the drug, then the distribution half life is governed by what two things
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blood flow (Q) and organ volume (V)
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A large blood flow to the organ ________ the distribution time, whereas a large organ size/volume ________ the distribution time (because a longer time is needed to fill a large organ with drug)
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decreases, increases
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This is an important consideration in determining how rapid and how much drug reaches the receptor site
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blood flow
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Some tissues have great ability to store and accumulate drug as shown by large what values
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large R values
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Digoxin has a high what ratio, leading to a long distributional phase despite abundant blood flow to the heart
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high R ratio
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If a tissue has a long distribution half life, then does it need a longer or shorter period of time for the drug to leave the tissue when blood levels decrease
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a longer period of time is needed
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What two things lead to longer distribution times in the tissue site
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protein binding and favorable solubility in the tissue site
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Chemical knowledge in _______ ________ often helps to estimate the lipid solubility of a drug
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molecular structure
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A drug with a large _________ tend to have high R values in vivo
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oil/water partition coefficient
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A reduction of this often reduces the rate of drug uptake into the brain
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partition coefficient
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The uptake of the drug into tissue is generally controlled by
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diffusional barrier of the capillary membrane
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Drugs with good ______ _______ have high kidney, liver and lung concentrations
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aqueous solubility
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The brain capillaries are surrounded by a layer of tightly joined ______ ________ that act as a lipid barrier to stop diffusion of polar or highly ionized drugs
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glial cells
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The accumulation of drugs into tissues is dependent on what two things
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blood flow and the affinity of the drug for the tissue
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Is drug uptake reversible?
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YES, generally
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Drugs with high this tend to accumulate or concentrate in the tissue
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high tissue affinity
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Is the process of lipid soluble drugs partitioning from the aqueous environment of the plasma into the fat reversible?
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YES
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Drug accumulation and drug removal from adipose tissue is slow because
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adipose tissue is poorly perfused with blood
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This highly lipid soluble drug remains in fat tissues for years
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chlorinated hydrocarbon DDT
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How else may drugs be accumulated in tissues
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by binding to proteins
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capillary membranes in the liver and kidneys are ______ permeable to transmembrane drug movement than capillaries in the brain
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MORE
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The added layer of glial cells on cell membranes in the brain and spinal cord do what
*blood brain barrier |
slow the rate of drug diffusion into the brain
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Can the permeability of cell membranes be altered?
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YES, under certain pathophysiological conditions
*BURNS of the skin, MENINGITIS |
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The concentration of drug in the plasma or tissues depends on what two things
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the amount of drug systemically ABSORBED and the VOLUME in which it is distributed
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This is used to estimate the extent of drug distribution in the body
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Vd, volume of distribution
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Does Vd represent a true, anatomical or physical volume?
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NO
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This represents the result of dynamic drug distribution between the plasma and the tissues and accounts for the mass balance of the drug in the body
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volume of distribution, Vd
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If the amount of drug added to the system and the drug concentration after equilibrium in the system are known, can the volume of the system be estimated?
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YES
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This is used in pharmacokinetics because the tissues compartments are not easily sampled and the true volume is not known
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Vd
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As the amount of drug in the cell compartment increases, the apparent Vd of the fluid compartment ________
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increases also
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Extensive cellular drug binding pulls drug molecule out of the fluid compartment, _______ the drug concentration in the fluid compartment and ________ Vd
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decreases, increases
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In biological systems, the quantity of cells, cell compartment volume and extent of drug binding within cells can all affect what
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Vd
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A large cell volume or extensive drug binding in the cells _______ the drug concentration in the fluid compartment and _______ the apparent Vd
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reduces, increases
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Can the Vd for a drug exceed the physical volume of the body?
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YES, if the drug is distributed widely or concentrates unevenly
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Cellular binding and partitioning of drug into lipid cellular components can affect Vd how?
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inflating it
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Drugs with very large Vd values have very ______ drug concentrations in plasma
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low
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This type of drug binding increases the apparent Vd
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extravascular drug binding
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Greater tissue drug binding and drug accumulation ______ Vd while greater plasma protein drug binding _______ Vd distribution
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increases, decreases
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THis can relate the plasma drug concentration to the amount of drug in the body
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Vd
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Only this type of drug diffuses between the plasma and tissue fluids
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free unbound drug
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For many protein bound drugs, is the ratio of drug in the body to plasma drug concentration constant?
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NO
**ratio best determined at steady state |
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Protein binding to tissue has an apparent effect of ________ the apparent Vd
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increasing
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Penicillin, cephalosporin, valproic acid and furosemide are polar compounds that stay mostly within the plasma and extracellular fluids and therefore have a relatively ____ Vd
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LOW
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Drugs with lower distribution to the extracellular water are more extensively distributed inside the tissues and tend to have a ______ Vd
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large
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For many protein bound drugs, is the ratio of drug in the body to plasma drug concentration constant?
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NO
**ratio best determined at steady state |
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Protein binding to tissue has an effect of ________ the apparent Vd
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increasing
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Penicillin, cephalosporin, valproic acid and furosemide are polar compounds that stay mostly within the plasma and extracellular fluids and therefore have a relatively ____ Vd
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LOW
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Drugs with lower distribution to the extracellular water are more extensively distributed inside the tissues and tend to have a ______ Vd
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large
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This drug has a large Vd, is highly protein bound and concentrated in the plasma
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imipramine
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The formation of a drug protein complex is often called
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drug-protein binding
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Is drug-protein binding reversible or irreversible?
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both
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This type of drug binding is usually a result of chemical activation of the drug, which then attaches strongly to the protein or macromolecule by covalent chemical bonding
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irreversible drug-protein binding
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Why do protein-bound drugs have restricted distribution
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because they are a large complex and cannot easily transverse cells or membranes
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are protein-bound drugs pharmacologically active?
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NO, they are usually inactive
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Are free or unbound drug therapeutically active compared to protein bound drug?
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YES
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This is a protein that is a major component of plasma proteins (60% in plasma) responsible for reversible drug binding
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albumin
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This protein binds highly with weakly acidic drugs (salicylates, phenylbutazone, penicillins)
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albumin
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These (RBCs) may bind both endogenous and exogenous compounds
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erythrocytes
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Penetration into RBCs is dependent on what
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free concentration of the drug
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Drugs highly bound to plasma proteins have a low fraction of this in the plasma water
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free drug (fu=unbound / free drug)
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Plasma bound drugs do not diffuse easily so how are they distributed?
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less extensively distributed in the tissues
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Drugs with low plasma protein binding have a larger fu (free/unbound drug) and diffuse more easily into tissues so how are they distributed?
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greater volume of distribution
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Basic drugs (like imipramine, nortriptyline and propranolol) are extensively bound to both plasma proteins and tissues, so what is their Vd?
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very large Vd
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Displacement of drugs from plasma proteins directly increases this
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the free/unbound drug concentration
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Displacement of drugs from plasma proteins directly _______ the free drug concentration as a result of reduced binding in the blood
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increases
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Displacement of drugs from plasma proteins ________ the free drug concentration that reaches the receptor sites directly causing a more intense (toxic) response
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increases
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Displacement of drugs from plasma proteins _______ the free drug concentration causing a _______ in Vd and decreasing the increase of free plasma drug concentration
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increases
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Displacement of drugs from plasma proteins _______ the free drug concentration resulting in more drug diffusion into tissues, increasing drug elimination
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increases
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When are unbound drug in plasma and tissue in equilibrium?
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Steady state
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When is Vd constant?
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When drug concentrations are in equilibrium between the plasma and tissue
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Compartment models are based on
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mass balance and the amount of drug in each compartment
*NOT on tissue volume or tissue drug concentration |
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As the fraction of unbound drug (fu) in the plasma increases, the apparent volume _________
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increases
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Reduced drug binding in the plasma results in _______ free drug concentration which diffuses into the extracellular water
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increased
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Drug showing exceptionally large volumes of distribution may have unusual what
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tissue binding
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Drugs that do not obey the general binding rule may have what two features
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very large volumes of distribution and undiscovered tissue binding
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Drugs that are highly bound to plasma protein have reduced overall what
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drug clearance
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The elimination half-lives of some drugs are ________ when the percent of drug bound to plasma proteins increases
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increases
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Some drugs (tetracycline analogs) have serum protein binding... the more bound to serum they are, the ______ their elimination half life is
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larger
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Drug that is extensively bound and actively secreted by the kidneys (penicillin) has a ______ elimination half life because active secretion takes preference in removing the drug from the proteins
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short
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This is governed by renal and other metabolic processes in the body
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drug elimination
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Extensive drug distribution has the effect of diluting the drug in a large volume... this would affect elimination how?
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making it harder for the kidney to filter the drug
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____ plasma drug concentration may be due to extensive distribution into tissues due to favorable lipophilicity/protein binding in peripheral tissues or lack of drug plasma protein binding
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Low plasma drug concentration
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When Vd is large, clearance is
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also large because it will take a long time for the drug to be removed when it is distributed extensively over a large volume
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When a drug is tightly bound to a protein, only the _______ drug is assumed to be metabolized. This is called restrictive elimination
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unbound drug is metabolized
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Drugs with this type of elimination are recognized by very small plasma clearances and extensive plasma protein binding
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restrictive elimination
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Drugs that may be eliminated even when they are protein bound are called this
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non-restrictively eliminated
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Drug protein binding is influenced by what five factors:
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1. the drug (physicochemical props, total concentration)
2. the protein (quantity,quality) 3. the affinity between drug and protein 4. drug interactions (competition, alteration of protein) 5. pathophysiologic condition of patient (uremic/hepatic disease) |
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Do plasma drug concentrations (total drug concentrations) include both protein-bound drug and unbound drug concentrations?
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YES
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Because of the high plasma protein binding of phenytoin and the narrow therapeutic index of the drug, more hospital labs are measuring both free and total phenytoin plasma levels using what
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ultra filtration
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The ______ of drug bound is often used to describe the extent of drug-protein binding in the plasma
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percent
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At low drug concentrations how much of the drug may be bound to the protein
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most of the drug
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At high drug concentrations the protein binding sites become saturated with a rapid ________ in the free drug concentration
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increase
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Is protein binding linear?
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NO, its nonlinear usually
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As the protein concentration increases, the percent of drug bound ______ to a maximum
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increases
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