Chapter 2: General Principles: Pharmacokinetics

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Pharmacokinetics and some IV Anesthetics Agents

 
Pharmacokinetics
 

Absorption

Some Factors Influencing Absorption and Bioavailability

 

Absorption Principles:

 

"Absorption Overview"
 

 

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 

    • 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.

Drugs that are weak acids or bases

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

Summary

Figure Developed by Dr. Steve Downing, University of Minnesota

 

 

 

 

 

 
  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