Drug distribution Flashcards
What must a drug do in the body to be active?
it must leave the blood stream and enter the inter or intracellular spaces
what does drug distribution mean?
the reversible transfer of a drug between the blood and the extra vascular fluids and tissues of the body (i.e fat, muscle and brain tissue)
Therapeutic range?
range over which they are active
drug elimination
the removal of active drug and metabolites from the body
determines length of action of the drug
what is bioavailability?
the proportion of a drug or other substance which reaches systemic circulation when introduced into the body and so is able to have an active effect
if 100mg of a drug are administered orally and 70mg of this drug are absorbed unchanged, the bioavailability is
0.7 or 70%
how is bio-availability determined?
comparing plasma levels of drug after a particular route of administration
factors that determine bio-availability
- drug formulation
- ability of drug to pass physiological barriers
- gastrointestinal effects- nausea, vomiting, abdominal pain, constipation, diarrhea, and gastritis
- first pass metabolism
Factors that determine drug distribution
chemical properties
plasma protein binding
clearance
half life
What is the distribution of drug between tissues dependent on?
vascular permeability blood flow cardiac output the ability of the drug to bind to tissue and plasma protein its lipid solubility
What do chemical properties of a drug determine?
where it is distributed (volume of distribution) e.g lipid solubility or ionisation? in membrane etc?
plasma protein binding
many drugs bind to proteins in the plasma such as albumin or alpha1-glycoprotein
- only unbound drugs are biologically active
define the term clearance
the theoretical volume from which a drug is completely removed over a period of time.
- It is the measure of elimination.
ie volume of urine (drug moves into kidney- removed by urine- so the vol. of urine taken until drug is removed from the body)
What does renal clearance depend on?
concentration and urine flow rate
What does biliary excretion depend on ?
biliary excretion for hepatic clearance (liver)
Define half-life
time taken for the drug concentration in the blood to decline to half of the current value.
What does a long half life indicate
Drug doesn’t need to be taken very often
What does the half life depend on?
volume of distribution rate of clearance
Blood brain barrier
and drug distribution
prevents the brain uptake of most pharmaceuticals due to the epithelial-like tight junctions within the brain capillary endothelium.
Blood-testes/ovary barrier and drug distribution
must be lipid soluble drugs or actively transported through membrane
Which organ is central to renal drug excretion
kidneys are the primary organ for drug excretion
What mechanisms are used in renal excretion?
- Glomerular filtration
- passive tubular reabsorption
- active tubular secretion
Glomerular filtration
the first step in making urine
filter excess fluid and waste products out of the blood into the urine collecting tubules of the kidney
the glomerular flow rate is the rate of filtered fluid through the kidney
Passive tubular re-absorption
solutes and water are removed from the tubular fluid and transported into the blood
Active tubular secretion
transfer of materials from peri-tubular capillaries (tiny ones used for absorption) to the renal tubular lumen
What can renal damage cause
drug toxicity- drug can’t be removed from the body so it accumulates
lipid soluble drugs
have high vol. of distribution as they move to tissues around the body
- can pass through membranes
- ie to the heart, brain and liver
Cannabis
highly lipid soluble
plasma protein binding
many drugs bind to proteins in the plasma such as albumin or alpha1-glycoprotein
An unbound drug is…
- biologically active
- more lipid soluble
- can cross membrane more efficiently
A bound drug…
is inactive- cannot be distributed around body- stays in blood stream
how can the amount of bound drug be changed?
renal failure hypoalbuminaemia ( level of albumin in the blood is abnormally low- protein in the blood) pregnancy other drugs saturability of binding
Apparent vol of distribution
the vol of distribution is the vol of plasma that would be necessary to account for the total amount of drug in a patient’s body, if that drug were present throughout the body at the same concentration as found in the plasma. Litres per kg
so basically how big a volume you would need to observe the blood plasma concentration actually measured
if you gave a patient 1000mg then waited for equilibrium- drug to distribute around the body and for there to be a balance between unbound and bound drug
a blood test then said there was only 50mg per litre in the blood
1000/50 = 20 litres so 20 litres is needed to contain the 1000mg of drug at a conc of 50 mg/l in the plasma
What does excretion by the kidney depend on?
glomerular filtration
passive tubular reabsorption
active tubular secretion
active tubular secretion
Some drugs are actively secreted into the proximal (top) tubules of the kidneys. This is the main method of excretion for protein bound cationic and anionic drugs.
passive tubular re-absorption
As the filtrate (This filtrate contains water, glucose, salts and urea) 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 drugs such as weak acids can be reabsorbed.
Can also be affected by renal failure.
Glomerular Filtration
All unbound drugs are filtered at the glomerulus (small tuft of capillaries at end of kidney tubule) provided their size or charge aren’t excessively large. Anything that affects the filtration rate will affect the clearance rate of a drug.
the higher the Vd means
greater the ability of the drug to diffuse into and through membranes ie be distributed around the body
how can Vd be increased
renal failure (fluid retention, more fluid for drug to be distributed to) liver failure (altered body fluid and plasma protein binding)
how can Vd be decreased
dehydration
drugs with a high lipid solubility (non-polar drugs), low rates of ionization, or low plasma protein binding capabilities have…
higher volumes of distribution
drugs which are more polar, more highly ionized or exhibit high plasma protein binding in the body’s environment
have lower volumes of distribution
What is the theoretical Vd
42 litres of fluid in the body
can you have a higher Vd than 42 litres?
yes just means the drug is highly distributed into tissue
Biliary secretion
the liver secretes 1 litre of bile a day
drugs may be passively or actively secreted into the bile
many drugs are reabsorbed from the bile into the circulation- entero- hepatic circulation
conjugation
metabolism in the liver often leads to conjugation of the drug- combination of drug and glucuronic or sulfuric acid
this conjugated drug is not reabsorbed from the intestine
damage to the liver may reduce the rate of conjucation and biliary secretion so allow the build up or reabsorption of the drug with resultant toxicity
