Pharmacokinetics II: Drug Distribution, Metabolism and Elimination Flashcards
What is drug distribution?
- Process by which a drug reversibly leaves blood
stream and enters the extracellular fluid and/or
cells of the tissue (intracellular fluid)
Describe the pharmacokinetic process of drug
distribution.
- Determines relationship between plasma concentration and total amount of drug in the body.
- Amount of a drug that must be administered to produce a particular plasma concentration.
*Why we use loading doses.
Define the term ‘apparent volume of distribution (Vd).
- Theoretical volume of fluid a drug would occupy if
the total amount of drug in the body was in solution at the same concentration as in the plasma. - Vd is not a real, physical volume but reflects the ratio of drug in extravascular space relative to plasma space.
Why do we calculate Vd?
It gives us a measure of the tendency of a drug to
move out of the plasma to some other site.
How do we calculate Vd?
Total amount of drug in the body divided by plasma concentration.
Discuss the clinical usefulness of volume distribution.
- Reflects size of distribution space
- Large Vd = need higher dose to fill (load)
- Small Vd = need lower dose to load
- Vd used to calculate loading dose(LD)
Discuss the range of Volumes of Distribution.
High range = located mainly in tissue, very little in plasma
Middle range = Similar concentration in both plasma and tissues
Low range = Localised mainly in plasma, little in tissues
Why do we give loading doses?
- Given so therapeutic concentrations are achieved quickly.
- LD= Vd x desired plasma concentration.
Describe the main routes of drug elimination from the
body.
Irreversible loss of drug from the body; occurs by two processes:
1. Metabolism:
- usually converts lipid soluble chemical to water soluble species.
- Phase 1 (oxidation, reduction, hydrolysis)
- Phase 2 (conjugation)
2. Excretion:
- Fluids (urine, bile, sweat, tears, milk)
- Solids (faeces, hair)
- Gases (expired air)
What are the routes of drug excretion?
Major routes:
- Renal
- Biliary/ GI
-Pulmonary
Significant for other reasons
- Mammalian
- Salivary, Skin & Hair
Discuss renal excretion.
3 renal processes:
- Glomerular filtration
- Active tubular secretion
- Reabsorption
What happens on glomerular filration?
- Molecules less than 20kDa filtered (enter filtrate)
- Protein bound drugs not filtered (plasma albumin 68kDa)
What happens in tubular secretion?
- Active carrier mediated elimination
- Secretory mechanisms for both acidic and basic compounds
- Can transport against electrochemical gradient and when drug protein bound
What happens in re-absorption in renal excretion?
- Passive diffusion back across tubular epithelium
- Lipid soluble drugs (high tubular permeability), excreted slowly:
- Polar water soluble drugs remain in urine
- pH partitioning relevant
Discuss biliary excretion.
- Hepatocyte uptake of lipid soluble drugs, metabolise and excrete into bile.
- But get re-absorbed along with the bulk of the water in small intestine
- Not excreted efficiently
*Only works effectively if Mol. Wt. high enough (>500Da). Most drugs’ Mol. Wt. too low.
When is bile excretion most favourable?
Significant route of excretion for:
1. Glucuronide conjugates (e.g. morphine)
2. Limited number of ionised drugs with very high Mol. Wt
Discuss the entero-hepatic circulation.
- Drug conjugates hydrolysed mainly by bacteria in lower intestine
- Active drug released once more; free drug reabsorbed and cycle repeated
- Creates a reservoir of recirculating drug, prolongs drug action
Discuss pulmonary excretion.
- Excretion via the lungs and breath
- Significant route of excretion for some volatile molecules:
– E.g. anaesthetics, ethanol
Discuss mammary excretion.
- Concentration in milk generally reflects free concentration in maternal blood.
- Clinical relevance for the effect of a drug on a breastfeeding baby e.g.
1. Tetracyclines: Incorporated into teeth which become weakened and ‘mottled’
2. Chloramphenicol: Bone marrow toxicity and ‘grey baby’ syndrome, (baby’s liver cannot metabolise the drug effectively)
Explain first order drug elimination kinetics.
- “Elimination of a constant fraction per time unit of the drug quantity present in the organism. The elimination is proportional to the drug concentration
- The fraction of the drug eliminated (not the amount of drug eliminated) is constant.
- Most drugs are eliminated by this process.
Explain zero order drug elimination kinetics.
- Elimination of a constant quantity per time unit of the drug quantity present in the organism
- Independent of drug concentration
- e.g. Protein mediated reactions (metabolism of ethanol*).
Define the term half-life (t1/2) and its clinical relevance.
- Rates of Drug Elimination usually obey 1st Order Kinetics, and may be summarised by the Plasma Half-Life (t1/2).
- Plasma t1/2 = time for plasma concentration to
fall by 50%. - Is independent of dose.
What determines plasma half life?
- Activity of metabolising enzymes or excretion mechanisms – clearance.
- Distribution of drug between blood into tissues - high Vd (drug mainly located in tissue) results in prolonged t1/2.
What are the general rules of plasma half life t1/2?
- 4 half-lives after stopping drug plasma concentration will have fallen by ~94%
- 4 half-lives after starting drug plasma concentration at steady-state.
