Medical Pharmacology Chapter 2: General Principles: Pharmacokinetics

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  • Placental Transfer

    • "Placental Drug Transfer"

    • Placental transfer is a concern because certain drugs may induce congenital abnormalities.

    • If administered immediately prior to delivery, drugs may directly adversely affect the infant.

    • Characteristics of drug-placental transfer:

      • Mechanism: typically simple diffusion

      • Lipid-soluble,non-ionized drugs are more likely to pass from the maternal blood into the fetal circulation.

        •  By contrast, ionized drugs with low lipid-solubility are less likely to pass through the placental "barrier".

        •  The fetus is exposed to some extent to all drugs taken by the mother.

    • 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

Benet, Leslie Z, Kroetz, Deanna L. and Sheiner, Lewis B "The Dynamics of Drug Absorption, Distribution and Elimination". In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) The McGraw-Hill Companies, Inc.,1996, pp. 3-27

  • Redistribution

    • Termination of drug effects:

      • Usually by:

        • Biotransformation (metabolism)

        • Excretion

      • Drug effects may also be terminated by redistribution -- from its site of action to other tissues or sites

      • A highly lipophilic-drug may:

        • Rapidly partition into the brain

        • Act briefly

        • and then redistribute into other tissues:  often ultimately concentrating in adipose tissue.

        • Redistribution is the mechanism responsible for termination of action of thiopental (pentothal),an anesthetic inducing agent.

Benet, Leslie Z, Kroetz, Deanna L. and Sheiner, Lewis B The Dynamics of Drug Absorption, Distribution and Elimination. In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) TheMcGraw-Hill Companies, Inc.,1996, pp. 3-27.

  • Drug-Plasma Protein Binding

    • Overview:

      • Most drugs: bound to some extent to plasma proteins

      • Major plasma proteins important for drug binding include:

        •  Albumin

        •  Lipoproteins

        •  α1 -acidic glycoprotein

      • Extent of protein binding important for drug distribution since only unbound fraction may diffuse across biological membranes

      • Volume of distribution (Vd): inversely proportional to protein binding

      • Drug clearance: influenced by protein binding since only the unbound drug fraction may reach and serve as substrate for drug metabolizing enzymes

      • Small changes in fraction of drug bound significantly influences free plasma concentration for highly plasma protein bound drugs, e.g. warfarin, propranolol, phenytoin, diazepam

        • For example: a drug that is 98% protein-bound --following a decrease to 96% protein-bound results then a twofold increase in plasma drug concentration

    • Characteristics of drug-protein binding

      • Extent of protein binding: parallels drug lipid solubility

      • Drug-plasma albumin binding is often nonselective

        • Many drugs with similar chemical/physical properties may compete for the same protein-binding sites

          • Examples:

            • Sulfonamides:  displace unconjugated bilirubin from albumin binding sites (may lead to neonatal bilirubin encephalopathy)

      • Renal failure:

        • May decrease drug bound fraction (may not require changes in plasma albumin or other plasma protein concentration; suggesting elaboration of a metabolic factor from the kidney that competes with drug-plasma protein binding sites)

        • Example:

          • Phenytoin (free fraction increased in renal failure patients)

      • α1-acidic glycoprotein concentration increases following surgery, myocardial infarction and in response to chronic pain:

        •   In rheumatoid arthritis patients, increased α1-acidic glycoprotein concentration resulting increased lidocaine (Xylocaine) and propranolol (Inderal) protein binding.

         

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

 

  • Renal Clearance

    • Renal Clearance

    • Factors affecting renal clearance:

      • Renal disease

      • Rates of filtration depend on:

        1. Volume filtered in the glomerulus

        2. Unbound drug concentration in plasma (plasma protein-bound drug is not filtered)

      • Drug secretion rates:

        1. Extent of drug-plasma protein binding

        2. Carrier saturation

        3. Drug transfer rates across tubular membranes

        4. Rate of drug delivery to secretory sites

      • Changes in plasma protein concentration

      • Blood flow

      • Number of functional nephrons

    • 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:

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

          • 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

  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