Nursing Pharmacology Chapter 2: General Principles: Pharmacokinetics
Termination of drug effects:
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
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.
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
Most drugs: bound to some extent to plasma proteins
Major plasma proteins important for drug binding include:
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
Sulfonamides: Sulfonamide antibiotic drugs displace unconjugated bilirubin from albumin binding sites. This effect may lead to neonatal bilirubin encephalopathy.
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)
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.
Factors affecting renal clearance:
Rates of filtration depend on:
Volume filtered in the glomerulus
Unbound drug concentration in plasma (plasma protein-bound drug is not filtered)
Drug secretion rates:
Extent of drug-plasma protein binding.
Drug transfer rates across tubular membranes.
Rate of drug delivery to secretory sites.
Changes in plasma protein concentration.
Number of functional nephrons.
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)
Body fluids where pH differences from blood pH favor trapping or reabsorption:
Aqueous humor (eye)