Pharmacokinetics lecture 2 Flashcards
what are the four stages of drug disposition ?
Absorption from the site of administration
Distribution within the body
Metabolism
Excretion.
What are the two ways drugs move around the body ?
bulk flow (i.e. in the bloodstream, lymphatics or cerebrospinal uid) diffusion (i.e. molecule by molecule, over short distances).
what determines where and for how long a drug will be present in the body?
It is movement between compartments, generally involving penetration of non- a ueous diffusion barriers that determines where, and for how long, a drug will be present in the body after it has been administered
how do small molecules move across of cell membranes
by diffusing directly through the lipid
by combination with a solute carrier (SLC) or other
membrane transporter
by diffusing through a ueous pores formed by
special proteins (a uaporins) that traverse the lipid
by pinocytosis.
The number of molecules crossing the membrane per unit area per unit time depends on..
the permeability coefficient and the concentration gradient across the membrane . the permeability coefficient is determined by the partition coefficient and the diffusivity, expressed as the diffusion coefficient
what are the factors that influence drug distribution
drug’s lipid solubility (which can be expressed as a partition coeficient for the substance distributed between the membrane phase and the aqueous environment)
pH differences between different compartments. This gives rise to the pH partition.
binding to plasma proteins
partition into body fat and other tissues.
high affinity for particular tissue components
what does the apparent volume of distribution indicate ?
indicates the extent of distribution
what are the tissue components drugs exhibit high affinity binding for
protein, nucleic acids, melanin, calcium and keratin
what is the rate of equilibration between foetal and maternal blood influenced by ?
rate of transfer in the placenta but more particularly by blood flow in the uterine blood vessels and in the umbilical artery.
name two proteins to which drugs bind to in the plasma
albumin and alpha-acid glycoprotein (basic drugs)
how might drug binding to proteins differ in diseased states ?
in diabetes the proteins may be glycosylated (reducing binding) and in renal failure the elevated area concentration may affect binding. the plasma concentration of alpha-acid glycoprotein is raised in a variety of diseases.
what are the consequences of protein binding ? part 1
- activity. drug bound to protein is inactive.
- absorption. as the drug is absorbed into the bloodstream its binding keeps the free concentration low, maintaining the concentration gradient for absorption.
- distribution. bound drug is restricted to the distribution of the binding protein.(The total concentration of drug in the c.s.f will accordingly lower in the c.s.f than in the plasma
what are the consequences of protein binding ? part 2
- storage. for highly bound drugs the bound fraction can act as a reserve. As the free drug is eliminated dissociation will tend to minimise the fall in concentration.
- Elimination. bound drug will not be filtered in the renal glomerulus. This tends to increase the drug’s half-life, but not always.
- Interactions. Binding of drugs exhibits low specificity. . Displacement of one drug by another will lead to an increase in the free effective concentration, with the prospect of toxic effects.
how can protein binding be measured ?
equilibrium dialysis, ultrafiltration or gel filtration. or by investigating the changes in florescence of the drug or protein which occurs on binding.
