Nursing Pharmacology Chapter 2: General Principles: Pharmacokinetics
Half-life: (t1/2), the time required to decrease the amount of drug in body by 1/2 during elimination (or during a constant infusion).
Single body compartment size = volume of distribution (Vd)
Blood or plasma considered in equilibrium with total volume of distribution
Factors affecting t1/2:
Disease states-- affects volume of distribution and clearance
Example 1: a patient with chronic renal failure may exhibit:
Decreased digoxin (Lanoxin, Lanoxicaps) renal clearance
Decreased Vd due to decreased renal and skeletal muscle mass (decreased digoxin tissue binding)
and therefore a resultant increase in digoxin half-life less than expected based on renal function change
Example 2: half-life of diazepam (Valium) increases with age:
Clearance does not change
Volume of distribution changes
Example 3: half-life changes secondary to changes in plasma protein binding.
In patients with acute viral hepatitis, the half-life of Tolbutamide (Orinase) decreases (opposite of expected?)
In acute viral hepatitis alters plasma and tissue drug-protein binding, the disease does not change volume of distribution but increases total clearance because more free drug (not bound to protein) is present.
Useful in estimating time to steady-state: approximately 4 half-lives are required to reach about 94% of a new steady-state
Useful in estimating time required for drug removal from the body
a way for estimation of appropriate dosing interval
With repeating drug doses, the drug will accumulate in the body until dosing ceases.
Practically: accumulation will be observed if the dosing interval is less than 4 half-lives.
Accumulation: inversely proportional to the fraction of the dose lost in each dosing interval
Accumulation factor = 1/Fraction lost in one dosing interval = 1/(1 - fraction remaining)
For example, the accumulation factor for a drug given once every half-life: 1/0.5 equals 2.
Definition: fraction of unchanged drug that reaches systemic circulation following administration (by any Route of Administration)
IV administration: bioavailability = 1
Other routes of administration = < 1
Major factors that reduce bioavailability to less than 100%:
First-pass effect (liver metabolizes drug before drug reaches systemic circulation)
Incomplete absorption following oral drug administration is common:
For example -- only 70% of a digoxin dose reaches systemic circulation. Factors:
Poor GI tract absorption
Digoxin metabolism by gastrointestinal flora
Very hydrophilic drugs: not be well absorbed; cannot cross cell membrane lipid component
Excessively lipid-soluble (hydrophobic) drugs may not be soluble enough to cross a water layer near the cell membrane.
Holford, N. H.G. and Benet, L.Z. Pharmacokinetics and Pharmacodynamics: Dose Selection and the Time Course of Drug Action, in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 34-49.
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
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 with respect to local anesthetics
Fetal pH is lower than maternal pH.
Lipid-soluble, nonionized local anesthetic crosses the placenta and is converted to poorly lipid-soluble ionized drug.
The drug gradient is maintained for continual transfer of local anesthetic from maternal circulation to fetal circulation, where the drug accumulates.
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