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 Pharmacokinetics: General Principles-Lecture I, slide 2

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  Figure Developed by Dr. Steve Downing, University of Minnesota, illustrating the many membrane barriers even within a single cell.

 

  • Absorption

    • Fick's Law

  • Routes of Administration

  • First-Pass Effect

  • Pulmonary Effects

  • Pharmacokinetics

    • Volume of distribution

    • Clearance

      • Renal clearance: clearance of unchanged drug and metabolites

        • Other Factors Affecting Renal Clearance

      • Factors Affecting Hepatic Clearance

      • Capacity-Limited Elimination

      • Half-life

      • Drug Accumulation

    • Bioavailablity

      • Extent of Absorption

      • First-Pass Elimination

      • Rate of Aborption

    • Placental Transfer

    • Redistribution

    • Drug-Plasma Protein Binding

    • Renal Clearance

  • Drug Metabolism

    • Introduction

    • Phase I and Phase II Reaction Overview:

    • Phase I characteristics

    • Phase II characteristics

    • Conjugates

    • Principal organs for biotransformation

      • Sequence I

      • Sequence II

    • Bioavailability

    • Microsomal Mixed Function Oxidase System and Phase I Reactions

      • The Reaction

      • flavoprotein--NADPH cytochrome P450 reductase

      • Cytochrome P450: -- terminal oxidase

      • P450 Enzyme Induction

      • P450 Enzyme Inhibition

      • Human Cytochrome P450

    • Phase II Reactions

      • Toxicities

  • Individual Variation in Drug Responses

  • Genetic Factors in Biotransformation

  • Effects of Age on Drug Responses

  • Drug-Drug Interactions

Pharmacokinetics and some IV Anesthetics Agents

  • Barbiturates

    • Thiopental

  • Benzodiazepines

  • Ketamine and Etomidate

  • Propofol

  • Opioids

    • Membrane Bilayer Structure

 

 

  • II. Lipid diffusion 

    • Most important barrier for drug permeation due to:

      • many lipid barriers separating body compartments

    • Lipid: aqueous drug partition coefficients described the ease with which a drug moves between aqueous and lipid environments

    • Ionization state of the drug is an important factor: charged drugs diffuse-through lipid environments with difficulty.

      •  pH and the drug pKa, important in determining the ionization state, will influence significantly transport (ratios of lipid-to aqueous-soluble forms for weak acids and bases described by the Henderson-Hasselbalch equation.

        • uncharged form: lipid-soluble

        • charged form: aqueous-soluble, relatively lipid-insoluble (does not pass biological membranes easily)

Henderson-Hasselbalch equation

General Form:  log (protonated)/(unprotonated) = pKa - pH

  • For Acids: pKa = pH + log (concentration [HA] unionized)/concentration [A-])
    • note that if [A-] = [HA] then pKa = pH + log (1) or (since log(1) = 0), pKa = pH
  • For Bases: pKa = pH + log (concentration [BH+] ionized)/concentration [B])
    • note that if [B] = [BH+] then pKa = pH + log (1) or (since log(1) = 0), pKa = pH

 

  1. The lower the pH relative to the pKa the greater fraction of protonated drug is found.  Recall that the protonated form of an acid is uncharged (neutral); however, protonated form of a base will be charged.

  2. As a result, a weak acid at acid pH will be more lipid-soluble because it is uncharged and uncharged molecules move more readily through a lipid (nonpolar) environment, like the some membrane,  than charged molecules

  3. Similarly a weak base at alkaline pH will be more lipid-soluble because at alkaline pH a proton will dissociate from molecule leaving it uncharged and again free to move through lipid membrane structures

  • Lipid diffusion depends on adequate lipid solubility

    • Drug ionization reduces a drug's ability to cross a lipid bilayer.

Many drugs are weak acids or weak bases
  • A weak acid is a neutral molecule that dissociates into an anion (negatively charged) and a proton (a hydrogen ion) Example:

    • C8H7O2COOH  < > C8H7O2COO- + H+

    • Neutral aspirin (C8H7O2COOH) in equilibrium with aspirin anion (C8H7O2COO- ) and a proton (H+)  

    • weak acid: protonated form -- neutral, more lipid-soluble

  • weak base: a neutral molecule that can form a cation (positively charged) by combining with a proton. Example:

    • C12H11CIN3NH3+ < > C12H11CIN3NH2 + H+

    • pyrimethamine cation (C12H11CIN3NH3+) in equilibrium with neutral pyrimethamine (C12H11CIN3NH2) and a proton (H+ )

    • weak base: protonated form -- charged, less lipid-soluble

 

 
Weak acids pKa

weak bases

pKa
  • phenobarbital (Luminal)
7.1
  • cocaine
8.5
  • pentobarbital (Nembutal)
8.1
  • ephedrine
9.6
  • acetaminophen
9.5
  • chlordiazepoxide (Librium)
4.6
  • aspirin
3.5
  • morphine
7.9

 

  • III. Special Carriers

    • Peptides, amino acids, glucose are examples of molecules then enter cells through special carrier mechanisms.

    •  Carriers:

      • Active transport describes an energy requiring process which is saturable, meaning that transport is probably against the concentration gradient and involves a finite number of carriers, hence the process must be saturable when all carrier sites are filled.

      • Facilitated diffusion, while not requiring "energy" is also saturable (limited number of carrier sites)

      • Saturable (unlike passive diffusion) because of limited number of carrier sites--once those sites are filled, transport rates cannot be increased.

        • A property of carrier systems is that process is subject to inhibition by other small molecules.  

  Figure Developed by Dr. Steve Downing, University of Minnesota

 

  • IV. Endocytosis and exocytosis:

    •  Entry into cells by very large substances (e.g., iron vitamin B12 -- each complexed with its binding protein -- movement across intestinal wall into the blood)

    •  Neurotransmitter system examples for exocytosis:

      • Following neuronal electrical activation of nerve endings, two steps may be initiated: 

        1.  Storage vesicles containing neurotransmitter fuse with cell membranes followed by

        2.  release or diffusion of contents into the extracellular region.

 

Summary

Figure Developed by Dr. Steve Downing, University of Minnesota

Extent of Absorption

  • Incomplete absorption following oral drug administration is common:

    • For example -- only 70% of a digoxin dose reaches systemic circulation. Factors:

      • poor GI tract absorption

      • digoxin (Lanoxin, Lanoxicaps) --- metabolism by gastrointestinal flora

  • Very hydrophilic drugs - not be well absorbed --cannot cross cell membrane lipid component

  • Excessively lipid-soluble (hydrophobic) drugs may not be soluble enough to cross a water layer near the cell membrane.

 

Ion Trapping

  • Kidney:

    • Nearly all drugs filtered at the glomerulus:

      • Most drugs in a lipid-soluble form will be reabsorbed by passive diffusion.

      • To increase excretion: change the urinary pH to favor the charged form of the drug since charged form cannot be readily reabsorbed (they cannot readily pass through biological membranes)

        • Weak acids: excreted faster in alkaline pH (anion form favored)

          • example: urinary alkalinization to facilitate excretion of barbiturates in management of overdosage/poisonings

        • Weak bases: excreted faster in acidic pH (cation form favored)

  • Other sites:

    • Body fluids where pH differences from blood pH favor trapping or reabsorption:

      • stomach contents

      • small intestine

      • breast milk

      • aqueous humor (eye)

      • vaginal secretions

      • prostatic secretions

Ion Trapping: Anesthesia correlation:Placental transfer of basic drugs

  • Placental transfer of basic drugs from mother to fetus: local anesthetics

  • Fetal pH is lower than maternal pH

  • Lipid-soluble, nonionized local anesthetic crosses the placenta converted to poorly lipid-soluble ionized drug

    •  Gradient is maintained for continual transfer of local anesthetic from maternal circulation to fetal circulation

    •  In fetal distress, acidosis contributes to local anesthetic accumulation

  • Weak bases-- amines

    •  N + 1 carbon (R) and 2 hydrogens: primary amine (reversible protonation)

    •  N + 2 carbons (R) and 1 hydrogen: secondary amine (reversible protonation)

    •  N + 3 carbons (R): tertiary amine (reversible protonation)

    •  N + 4 carbons (R): quaternary amine (permanently charged)

Katzung, B. G. Basic Principles-Introduction , in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 1-33
Stoelting, R.K., "Pharmacokinetics and Pharmacodynamics of Injected and Inhaled Drugs", in Pharmacology and Physiology in Anesthetic Practice, Lippincott-Raven Publishers, 1999, 1-17.

 

 
 
 
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