Medical Pharmacology Chapter 2: General Principles: Pharmacokinetics

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Pharmacokinetics and some IV Anesthetics Agents

 

 

Fick's Law

  •  Fick's Law describes passive movement molecules down its concentration gradient.

Flux  (J) (molecules per unit time) = (C1 - C2) · (Area ·Permeability coefficient) / Thickness

  1. Where C1 is the higher concentration and C2 is the lower concentration

  2. Area = area across which diffusion occurs

  3. Permeability coefficient: drug mobility in the diffusion path

    • For lipid diffusion, lipid: aqueous partition coefficient -- major determinant of drug mobility

      • Partition coefficient reflects how easily the drug enters the lipid phase from the aqueous medium.

  4. Thickness: length of the diffusion path

Katzung, B. G. Basic Principles-Introduction , in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, p 5.

  • Plasma protein-bound drugs cannot permeate through aqueous pores

  • Charged drugs will be influenced by electric field potentials {membrane potentials, important in renal, trans-tubular transport}

  • II. Lipid diffusion 

    • Lipophilic and Hydrophilic Drugs
    • 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.

        • The pH and drug pKa determine the ratio of lipid-to aqueous-soluble forms for weak acids and bases as 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. 

    1. 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 cell membrane,  compared to 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 thus free to move through lipid membrane structures

 

  • Lipid diffusion depends on adequate lipid solubility

    • Drug ionization (charged form) reduces a drug's ability to cross a lipid bilayer.

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

 
  1. Stoelting, R.K., "Pharmacokinetics and Pharmacodynamics of Injected and Inhaled Drugs", in Pharmacology and Physiology in Anesthetic Practice, Lippincott-Raven Publishers, 1999, 1-17.

  2. Dolin, S. J. "Drugs and pharmacology" in Total Intravenous Anesthesia, pp. 13-35 (Nicholas L. Padfield, ed), Butterworth Heinemann, Oxford, 2000