Redistribution

• Termination of drug effects may occur by biotransformation (metabolism) and/or 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 redistributes into other tissues -- often ultimately concentrating in adipose tissue.

    • Redistribution is the mechanism responsible for termination of action of thiopental (pentothal) or propofol (Diprivan), anesthetic inducing agents.

Drug-Plasma Protein Binding

• Overview

  • Most drugs are 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) is inversely proportional to protein binding

  • Drug clearance is 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, consider a drug that is 98% protein-bound.  Following a decrease to 96% protein-bound, the drug exhibits   a two-fold 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: Sulfonamide antibiotic drugs displace unconjugated bilirubin from albumin binding sites.  This effect 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.

Renal Clearance

• "Renal Excretion of Drugs"

  Saffarzadeh A Renal Excretion of Drugs | Pharmacokinetics Lect 13. https://www.youtube.com/watch?v=8c3gqI6R-Vw . Areo Saffarzadeh excellent home site:  https://www.youtube.com/user/areosaf .

• 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,charged form favored)

      • Weak bases: excreted faster in acidic pH (cation, charged 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