Pharmacokinetics Flashcards
Absorption Distribution Excretion
What is drug pharmacokinetics?
How drugs move around the body
What 4 factors determine drug pharmacokinetics?
ADME
Absorption
Distribution
Metabolism
Elimination
In pharmacokinetics, what does absorption refer to?
Process of movement of an unchanged drug from the site of administration to the systematic circulation
What is Tmax?
Time until drug concentration in circulation is at its peak, from when it was administrated
What is the Cmax?
Peak concentration of the drug in circulation
The area under the concentration time graph of a drug in circulation gives what information?
The amount of drug that has been absorbed and not excreted
What effect does dosage have on Cmax and Tmax?
No effect on rate of absorption so no affect on Tmax
Dosage determines Cmax
What is the therapeutic range?
Range of concentrations of the drug that will be effective over
What is bioavailability?
Amount of drug that reaches circulation
compared to how much was administered
Which method of administration of a drug has the highest bioavailability?
Intravenous
100% bioavailability
Bioavailability of other methods compared to IV
What factors affect bioavailability of a drug?
Formulation
Ability to pass physiological barriers
Gastrointestinal effects
First pass metabolism
What is first pass metabolism?
Drug metabolism, prior to reaching systematic circulation
Liver, gut lumen, gut wall
What might affect a patients gastrointestinal ability to absorb a drug?
Gut motility
Food they’ve eaten
Illness
Why is it important that oral drugs must be in an un-ionised state in the stomach?
So they can pass through the plasma membrane of cells lining the stomach
What is the effect of ion trapping?
Drugs trapped in cells they are trying to diffuse through
“An acidic drug will be more concentrated in the compartment with a ____ pH due to ion trapping”
High (alkaline)
What is the lipid-water partition coefficient?
Ability for a drug to diffuse across a lipid barrier
If a drug is easily metabolised by the body, what methods of administration are suitable to use?
IV
Subcutaneous /Intra-muscular
Sublingual/buccal (under tongue)
Rectal
Transdermal
What effect does plasma protein binding have on drug distribution?
When a drug is bound to in the blood plasma, it can not be diffuse out ∴ can not be distributed to other sites in the body
What are the main proteins that bind to drugs in the plasma?
Albumin
alpha1-glycoprotein
What factors affect the amount of drug that is bound to by proteins? (5)
Renal failure
Hypoalbuminaemia
Pregnancy
Saturability of binding
Other drugs
Describe the drug distribution of a 95% protein bound drug, and how this would be affected by a 5% decrease in the amount of protein binding.
Drug distribution is quite low, only 5% isn’t bound to ∴ 95% remains in blood
5% decrease means a 100% increase in the amount of drug that is biologically available and leaves the circulation
What is the apparent volume of distribution?
The volume of plasma that would be necessary to account for the total amount of drug in a patient’s body, at the same concentration as found in the plasma
If a patient is given 1000mg of a drug, and the plasma drug concentration found in a plasma sample is 50mg/L, what is the apparent volume of distribution?
1000/50 = 20L
20L
(should be expressed as L/kg)
What does a high apparent volume of distribution value mean?
High Vd ∴ higher the ability for the drug to diffuse out and through membranes
What apparent volume of distribution value would a lipid soluble drug have and why?
High
Lipid soluble ∴ diffuses easily across membranes
What is the ‘clearance’ of a drug?
Theoretical volume from which a drug is removed over a period of time
It is a measure of the rate of elimination
ml/min
The clearance rate is basically a combination of two clearing ‘systems’, what are they, and what affects each?
Renal - urine concentration and flow rate
Hepatic - billiary secretion and metabolism rate
What is the half life of a drug?
Time taken for concentration in the blood to drop to 50% of it’s original value
What is half life proportional and inversely proportional to?
Proportional to A. Volume of distribution
Inversely proportional to clearance rate
As a rule of thumb, how many half lives does it take for a drug to (pretty much) be removed from the system?
5 half lives
Pathologies can often prolong the half life of a drug. What are the problems with this?
Reduction in clearance / large VOD
∴ abnormally high amount of drug remains in the body ∴ toxicity
Define the elimination of a drug .
Removal of the active drug, and it’s metabollites from the body
Governed by the metabolism and excretion of the drug
Where does metabolism usually take place?
Liver
What organ is mainly responsible for excretion of a drug?
not bladder
Kidneys
Biliary system/gut, lung and milk are also involved with excretion
What are the 3 mechanisms that affect excretion rate, at the kidneys?
Glomerular filtration - most important
Passive tubular reabsorption
Active tubular excretion
Which excretion system is responsible for eliminating protein bound cationic and anionic drugs?
Active tubular secretion
What happens with passive tubular re-absorption?
Drugs move from renal tubule back into circulation
Down concentration gradient (passively)
Only un-ionised drugs can do this
Sum up the stages entero-hepatic circulation, of a drug.
Intestine to blood
Blood to liver
Liver to bile
Bile to intestine
(will repeat unless the drug is conjugated)
Describe what conjugation of a drug is.
Metabolism in liver leads to conjugation
When secreted into bile, then into intestine, the drug is not absorbed again
If the liver is damaged, and conjugation does not take place effectively, how could this cause toxicity?
No conjugation ∴ drug re-absorbed more
Hepatic elimination rate decreases
Drug build up
Toxicity
True or false
Most excretion takes place in the kidneys
True
Define drug metabolism
The biochemical modification of pharmaceutical substances by living organisms
What type of organic molecule is key in drug metabolism?
Enzymes
Why must lipid-soluble substances be converted to water-soluble substances by the body?
So they can be excreted
Lipid soluble substances would be constantly re-uptook and pass back into blood circulation
What is the purpose of metabolism of drugs?
Make them more water-soluble, so they can be excreted
Deactivate the compounds (except from prodrugs which are activated by metabolism)
What potential problem is associated with metabolism of drugs?
Production of toxic metabolites
- Direct toxicity
- Teratogenesis
- Carcinogenesis
What is teratogenesis?
the process by which congenital malformations are produced in an embryo or fetus
What is carcinogenesis?
the initiation of cancer formation
What are the 2 phases of drug metabolism?
Inactivation / activation (if prodrug)
Conjugation
What type of reactions can take place in phase 1 metabolism of drugs?
Oxidation
Reduction
Hydrolysis
What group of enzymes are important in phase 1 metabolism?
Cytochrome P-450 enzymes
These are often called CYP1A2, for example
What is the effect of Phase 1 metabolism?
Increases polarity of compound and provides an active site for phase 2 metabolism
In phase 2 metabolism, there is conjugation of the drug.
What are the effects of this?
Increase water solubility (for excretion)
Usually involves in-activation of the drug (a small number of active metabolites may remain however)
Chemical groups that are made in phase 1 metabolism, can be added onto the metabollite in phase 2.
Give examples of some of these groups.
Glucuronic acid, glutathione, suplhate, acetate
List some factors that effect metabolism of drugs.
Other drugs/herbals/natural substances Genetics Hepatic blood flow Liver disease Age Sex Ethnicity Pregnancy
What effect can other substances, such as herbal medicines, have on enzymes involved with drug metabolism?
Induction (increased metabolism of drug = less drug effect)
Inhibition (drug isn’t metabolised effectively = build up of active drug, often toxicity)
What age category of people are most effective at metabolising drugs?
Adolescents
