Drug distribution and excretion Flashcards
Discuss factors that determine bioavailability.
- Physicochemical properties of the drug and its excipients that determine its dissolution in the intestinal lumen and its absorption across the intestinal wall.
- Decomposition of the drug in the lumen.
- pH and perfusion of the small intestine.
- Surface and time available for absorption.
- Competing reactions in the lumen (for example of the drug with food).
- Hepatic first-pass effect.
Discuss factors that determine drug distribution.
o Plasma Protein Binding
o Tissue Perfusion
o Membrane Characteristics
- Blood-brain barrier
- Blood-testes/ovary barrier
o Transport Mechanisms
o Diseases/Other Drugs
o EliminationDescribe the mechanism of renal drug excretion and the relevance to renal disease states.
Excretion by the kidneys depends on three important mechanisms:
o Glomerular Filtration - All unbound drugs are filtered at the glomerulus provided their size or charge doesn’t prevent this. Anything that affects the filtration rate will affect the clearance rate of a drug.
o Passive Tubular Reabsorption - As the filtrate moves down the tubules of the kidneys, it becomes more concentrated, as do any drugs it carries. Passive diffusion means that the body can reabsorb some of this drug. Only un-ionised drug can be absorbed. Can also be affected by renal failure.
o Active Tubular Secretion - Some drugs are actively secreted into the proximal tubules of the kidneys. This is the main method of excretion for protein bound cationic and anionic drugs.
What factors affect the amount of drugs bound to plasma proteins?
- Renal failure
- Hypoalbuminaemia
- Pregnancy
- Other drugs
- Saturability of binding
Define drug distribution
Drug Distribution refers to the reversible transfer of a drug between the blood and the extra vascular fluids and tissues of the body (for example, fat, muscle, and brain tissue).
What is important to characterise when calculating the therapeutic range of a drug?
Volume of distribution (Vd)
Clearance (Cl)
Half-life (t1/2)
Define the apparent volume of distribution
It is defined as the volume in which the amount of drug would be uniformly distributed to produce the observed blood concentration.
Define clearance
Clearance is defined as the theoretical volume of fluid from which a drug is completely removed over a period of time.
Define the half life of a drug and what it depends on.
The half-life is defined as the time taken for the drug concentration in the blood to decline to half of the current value. Depends on the volume of distribution and clearance
Define the steady state concentration of a drug
In pharmacokinetics, steady state refers to the situation where the overall intake of a drug is fairly in dynamic equilibrium with its elimination. In practice, it is generally considered that steady state is reached when a time of 4 to 5 times the half-life for a drug after regular dosing is started.
What processes carry out drug elimination?
Drug metabolism - liver
Drug excretion - kidneys
What drugs are removed in glomerular filtration?
All small unbound drugs will be filtered at the glomerulus as long as their molecular size, charge or shape are not excessively large.
What drugs are removed by active tubular secretion?
This is the most important system for eliminating protein bound cationic and anionic drugs.
What drugs are reabsorbed in passive tubular reabsorption?
Only un-ionised drugs such as weak acids are reabsorbed.
Describe entero-hepatic circulation
- The liver secretes 1 litre of bile a day.
- Drugs may be passively or actively secreted into the bile.
- Biliary secretion accounts for 5-95% of drug elimination for many drugs.
- Many drugs are then reabsorbed from the bile into the circulation. This is called entero-hepatic circulation.
- Continues until drug is metabolised in the liver or excreted by kidneys
