Pharmacokinetics - ME Flashcards
What is drug elimination?
Refers to the processes of drug metabolism and excretion
How is it possible for drugs to be removed from the body?
Body regulates concentrations of endogenous molecules
these regulatory processes also recognise drug molecules
What are the Phase 1 CYP450 enzymes?
Large group of isoenzymes
that metabolise drugs
Where are Phase 1 CYP450 enzymes located?
Hepatocytes
surface of ER
How many different drugs to Phase 1 CYP450 enzymes metabolise?
Different types of CYP450s metabolise different types of drugs
but fair amount of overlap because CYP450s are generalists
What is meant by Phase 1 CYP450 enzymes being generalists?
Metabolise a wide range of drug molecules
What is a disadvantage of Phase 1 CYP450 enzymes being generalists?
Take longer to metabolise some drug molecules
What do Phase 1 CYP450 enzymes do?
Carry out redox reactions, hydrolysis reactions to the drug molecule
What is the purpose of redox and hydrolysis reactions carried out by phase 1 CYP450 enzymes?
To introduce polar groups into the drug molecule
Where are Phase 2 conjugating enzymes located?
Hepatocytes
cytosol
What do Phase 2 conjugating enzymes do?
Add chemical groups to the drug molecule
What happens to the drugs metabolised by Phase 1 CYP450 enzymes?
Either elimindated directly
or go on to Phase 2 conjugating enzymes
What is the most common chemical group added to drug molecules by Phase 2 conjugating enzymes?
Glucoronate
What is the purpose of adding chemical groups to drug molecules by Phase 2 conjugating enzymes?
To increase the polarity of the drug molecule
To inactivate the drug
What is the purpose of increasing polarity of drug molcules?
To make them hydrophilic
so they are excreted more easily in the kidneys, because they won’t be able to diffuse back into the blood once filtered out
What are the factors affecting drug metabolism?
Age
Gender
Genetic status
State of health or illness
CYP450 inducton or inhibition
How does genetic status affect drug metabolism?
CYP450 enzymes show genetic polymorphism
affects their metabolic activity
What is genetic polymorphism?
Refers to when a gene has more than allele in a population
How are CYP450 enzymes induced?
Increased transcription or translation
Slower degradation
How does CYP450 induction affect drug metabolism?
Faster elimination of drug from the body
build up of metabolites, may be toxic
What is the clinical significance of CYP450 induction?
Dose of drug needs to be adjusted
Levels of drug in body need to be monitored
How long does CYP450 induction usually take?
1-2 weeks
What are the types of CY450 inhibition? What do they each mean?
Competitive - inhibitor and drug both metabolised at same site
Non-competititve - inhibitor binds away from active site and inactivates CYP450
How does CYP450 inhibition affect drug metabolism?
Slow drug elimination from the body
increased plasma drug concentration, may be toxic
What is the clinical significance of CY450 inhibition?
Avoid giving different drugs at the same time
Dose of drug needs to be adjusted
Levels of drug in body need to be monitored
How long does CYP450 inhibition usually take?
Few days
What are pro-drugs?
Refer to drugs that are metabolised in the body to produce their active form
How are pro-drugs metabolised to their active form?
By Phase 1 CYP450 enzymes
What happens to drugs after they are metabolised?
They are excreted from the body
completing their elimination
Where does drug excretion largely take place?
Kidneys
What are some examples of other places where drug excretion takes place? How?
Intestines - faeces
Lungs - exhalation
Skin - sweat
What are the three stages of drug excretion in the kidneys?
Glomerular filtration
Proximal tubular secretion
Distal tubular reabsorption
What happens in glomerular filtration of drug excretion?
Free drug molecules diffuse through capillaries into Bowman’s capsule
What happens in proximal tubular secretion of drug excretion?
Large hydrophilic drug molecules are actively transported into the proximal tubule by organic anion and cation transporters
What happens in distial tubular reabsorption of drug excretion?
Water is reabsorbed along length of tubule
leads to increase in concentration of drug molecules in tubule
if lipophilic or unionised, it diffuses back into the blood
What is clearance?
The rate of elimination of a drug from the body
What is the symbol of clearance?
CL
What are the over-simplifications made by clearance?
That there is just one big fluid compartment in the body
That this fluid compartment is the plasma
That defines volumes of plasma become and remain drug-free
What is clearance, taking into account its over-simplifications?
Volume of plasma cleared of drug per unit time
What is the reference volume used when calculating clearance?
The volume of distribution
What are the units of clearance?
ml/min
What are the different groups of factors affecting clearance?
Hepatic factors affecting metabolism
Renal factors affecting excretion
Cardiovascular factors affecting blood flow to eliminatory organs
What is the clinical significance of clearance?
Influences dosages required, when required
because it tells us how long the drug will stay in the body
What are both volume of distribution and clearance used to calculate?
Drug half-life
What is drug half-life?
The amount of time taken for the plasma drug concentration to decrease to half of what was initially measured
What is the symbol of drug half-life?
t 1/2
How is drug half-life calculated?
0.7 x Vd
_______
CL
How does volume of distribution relate to drug half-life?
Proportional
as Vd changes, drug half-life changes in the same direction
How does clearance relate to drug half-life?
Inversely proportional
as clearance increases, drug half-life decreases
and as clearance decreases, drug half-life increases
What are the groups of factors affecting drug half-life?
Factors affecting volume of distribution
Factors affecting clearance
What is first order kinetics in the context of drug elimination?
The rate of drug elimination is proportional to the plasma drug concentration
What does a graph of x axis-time against y axis-plasma drug concentration with first order kinetics look like? Why?
Downhill curve
Rate of drug elimination shown by the gradient is higher at higher plasma drug concentrations
What does a logarithmic graph of x axis-time against y axis-drug concentration with first order kinetics look like?
Straight line
What are the conditions of first order kinetics in the context of drug elimination?
Enough Phase 1 CYP450 and Phase 2 conjugating enzymes
Enough organic anion and cation transporters
What is zero order kinetics in the context of drug elimination?
The rate of drug elimination is not afected by the plasma drug concentration
What is the cause of zero order kinetics in the context of drug elimination?
Phase 1 CYP450 and Phase 2 conjugating enzymes are saturated
Organic anion and cation transporters are saturated
What does a graph of x axis-time against y axis-plasma drug concentration in the context of drug elimination look like? Why?
Downhill straight line
Rate of elimination shown by the gradient is the same for all plasma drug concentration values
When is drug elimination more likely to show zero order kinetics?
At high concentrations of the drug
or taking multiple drugs at once that occupy similar sites
Reduced metabolism, excretion of the drug due to age, ill health etc.
What are the risks of drug elimination by zero order kinetics?
More likely to reach higher concentrations which may be toxic
More likely to have drug-drug interactions as their binding sites are taken up
What shape does a graph of x axis-plasma drug concentration against y axis-rate of elimination look like?
Rectangular hyperbola
Which regions of the rectangular hyperbola x axis-plasma drug concentration against y axis-rate of elimination show first order and zero kinetics? Why?
Uphill part of curve is first order kinetics
because rate of elimination increases with plasma drug concentration
Flat part of curve is zero order kinetics
because increasing plasma drug concentration has no effect on rate of elimination
