• Placental 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 -- 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

  • 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