Drug Distribution Flashcards
What must a drug do to be active
Leave the blood stream and enter the inter or intracellular spaces
What is drug distribution
The Reversible Transfer of a Drug between the Blood and the Extra Vascular Fluids and Tissues of the body (e.g. fat, muscle, and brain tissue)
What factors determine tissue distrubution
Plasma protein binding Tissue perfusion Membrane characteristics Transport mechanisms Diseases and other drugs (esp renal failure, liver disease, obesity) Elimination
What type of membrane characteristics are there
Blood-brain barrier
Blood-testes/ovary barrier
Give examples of drugs which bind to proteins in plasma
Many drugs do this
Albumin
Alpha 1-glycoprotein (e.g. phenytoin)
In what sate are drugs biologically active
Unbound
Is plasma protein binding reversible
Yes
How can the amount of bound drug be changed
By: Renal failure Hypoalbuminaemia Pregnancy Other drugs Saturability of binding
What parameters need to be characterised when considering therapeutic range
Volume of distribution
Clearance
Half-life
What is Vd
Apparent volume of distribution
What is volume of distribution
The volume 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 (L/kg)
What does it mean if the Vd is high
A high ability of the drug to diffuse into and through membranes
What is Cl
Clearance
The theoretical volume from which a drug is completely removed over a period of time
How is clearance measured
Measure of elimination in units of time (ml/min)
What is renal clearance dependent on
Concentration and urine flow rate
What is hepatic clearance dependent on
Metabolism and biliary excretion
What is half life (t1/2)
The time taken for the drug concentration in the blood to decline to half of the current value
Give an example of drug half life
If it takes 4 hours for the concentration of a drug in the blood stream to drop from 10mg/L to 5 mg/L then the half life is 4 hours
What does half life depend on
The volume of distribution and rate of clearance
What does the prolongation of the half life of a drug do
Increase toxicity of a drug because of a:
Reduction in clearance
Large volume of distribution (e.g. amiodarone)
What does the formula, t1/2 = 0.693Vd/Cl link together
The chemical properties of the drug, i.e. lipophilicity, and the ability of the body to metabolise and excrete the drug
How does knowledge of the half life of a drug help us clinically
Helps us to work out how often a drug needs to be administered
How should drugs be administered to have a therapeutic benefit
Depends on the half life
Long half life = less doses required
Short half life = more doses required
What can chronic administration cause
The plasma levels of a drug to take many doses before they stabilise, usually 4-5 half-lives
This may necessitate a loading dose
What is drug elimination
The removal of active drug and matabolites from the body
It determines the length of action of the drug
What is drug elimination made up of
Drug Metabolism
Drug Excretion
Where does drug metabolism normally take place
Liver
Where does drug excretion normally take place
Mainly kidney but also biliary system/gut, lung and breast milk
What mechanisms are used for drug excretion
Glomerular filtration
Passive tubular reabsorption
Active tubular secretion
About how many liters of fluid does the glomerulus filter a day
190
What happens to all unbound drug
It’s filtered at the glomerulus as long as their molecular size, charge or shape are not excessively large
What effect will the factors that affect the glomerular filtration rate have on the clearance of a drug
Reduce the clearance of a drug
Which system is important for eliminating protein bound cationic and anionic drugs
The active secretion of some drugs into the proximal tubule (acidic and basic compounds)
What does the active secretion into the proximal tubule eliminate
Protein bound cationic and anionic drugs
What does passive diffusion along the concentration gradient allow
The drug to move back through the renal tubule into the circulation
Describe the features of passive tubular reabsorption
Occurs in the distal tubule and collecting duct
Only un-ionised drugs such as weak acids are reabsorbed
Can also be affected by renal failure
How much bile is secreted a day
1 liter by the liver
In what ways can drugs be secreted into bile
Passively or actively
How much drug elimination does biliary secretion account for
5-95%
What happens to the drugs after they have been secreted into the bile
Many are then reabsorbed from the bile into the circulation
This is called entero-hepatic circulation
What is entero-hepatic circulation
Drugs being reabsorbed from the bile into the circulation
How long does entero-hepatic circulation last for
Continues until the drug is metabolised in the liver or excreted by the kidneys
What can metabolism of the drug in the liver lead to
Conjugation of the drug
What happens to conjugated drugs
They are not reabsorbed from the intestine
What can damage to the liver cause
May reduce the rates of conjugation and biliary secretion, so allow the build up or reabsorption of the drug with resultant toxicity
Name some drugs which undergo enterohepatic recirculation
Chlordecone
Morphine
Phenytoin
Methadone
