Science of Medicines Week 21 Flashcards
define elimination
the irreversible loss of drug by excretion and/or metabolism
define excretion
the irreversible loss of chemically unchanged drug
Where does excretion mostly happen?
in the kidneys - waste is excreted into the urine
define metabolism
the conversion of a drug into a different chemical product - also called ‘biotransformation’
Where does metabolism mostly occur?
in the liver
What does understanding the elimination of a drug help us to do?
- predict drug concentrations following uptake of a medicine
- predict how liver and renal disease may affect drug concentrations
- predict interactions modifying the elimination of drugs
- predict variability in drug therapy for age, genetic differences in enzymes
What do clearance and volume of distribution determine?
- the concentration that will be achieved after a dose, so the effects and toxicity
- how the concentration of a drug will evolve with time
- the body’s exposure to the drug
What is the 1st definition for clearance?
the proportionality factor that links the elimination rate of a drug with the drug concentration in blood (plasma)
What is the 2nd definition for clearance?
the volume of fluid (blood, plasma) that is completely cleared of drug per unit time
What are the units for clearance?
volume / time
What is the equation for rate of elimination?
clearance x C drug (concentration of drug in plasma)
What essentially is the clearance?
the body’s ability to eliminate a drug
What is the elimination rate of a drug proportional to?
BOTH the clearance and concentration of drug in plasma
What is the steady state?
rate in (dose/time) = rate out (Cl x Css)
What is the equation for total clearance of a drug?
total clearance = the sum of clearance by each organ EXCEPT the lungs
Which organ is the major site of drug metabolism?
the liver
What are the most common routes of drug metabolism?
- oxidation, reduction, hydrolysis (phase I)
- conjugation (phase II)
What may metabolites be?
- inactive
- toxic
- active
- exploited therapeutically, e.g. prodrugs
Can bound drugs enter the hepatocytes?
NO - only unbound drugs
What are the liver elimination processes?
metabolism + biliary excretion
What type of molecular does high biliary clearance work for?
- polar
- MW greater than 350
- actively selected
Are there specific enzymes for specific drugs?
YES, although some drugs can be metabolised by several enzymes
To be metabolised by one specific enzyme, what must a drug have?
- the correct 3D structure to interact with the enzyme site responsible for the reaction
- have a certain affinity for this site
What are enzyme-drug reactions usually described by?
the Michaelis-Menten equation
Are all drugs metabolised by the same enzyme metabolised at the time rate?
NO - drugs metabolised by the same enzyme can be metabolised at different rates
What is an advantage of a drug being metabolised by several different enzymes?
if one enzyme is affected by drug interactions, it won’t massively affect the metabolism of that drug
Which family of enzymes are MOSTLY responsible for the oxidation and reduction of drugs?
cytochrome P450 family
Why are the variations in how quick different people metabolise drugs?
there are HUGE variations in CYP enzymes due to alleles
What are the 5 main characteristics of drug metabolsim
- substrate specificity
- kinetics
- drug metabolism is saturable
- drug interactions
- variability
Which kinetics do enzymatic reactions follow?
Michaelis-Menten kinetics
How is drug metabolism saturable?
at high concentrations of drug, the rate of elimination becomes constant and equal to Vmax - for most drugs, this occurs at concentrations higher than those used in therapy
How may diet, drugs and chemicals impact enzymes?
enzyme induction and inhibition
What are examples of CYP enzyme inhibitors?
grapefruit and SSRIs
What are examples of CYP enzyme inducers?
smoking, insecticides, rifampin, phenoarbital
Which factors cause different activities of CYP enzymes among different individiuals?
genetic variations, age, disease etc
What is the Michaelis-Menten equation for drug metabolism?
-dC/dt = (Vmax x C) / Km + C
What is the equation for rate of drug presentation?
rate of drug presentation = Q x C entering
What is the equation for rate of drug elimination?
rate of drug elimination = Q x (C entering - C leaving)
What is the 1st definition for the hepatic extraction ratio?
the fraction of a drug passing by the liver which is eliminated
What is the 2nd definition for the hepatic extraction ratio?
the ratio between the rate of hepatic elimination and the rate of presentation of drug to the liver
What is the equation for hepatic extraction ratio?
EH = rate of elimination / rate of presentation
What does an extraction ratio of 1 tell you?
all the drug is eliminated by the liver
What does an extraction ratio of 0 tell you?
the drug is not eliminated at all by the liver
What is the 1st definition for hepatic clearance?
the volume of blood entering the liver from which all the drug is removed per unit of time
What is the 2nd definition for hepatic clearance?
the ratio between hepatic elimination rate and the incoming concentration
Which equation links clearance to the extraction ratio?
ClH = Q x EH
Why might drugs have a HIGH extraction ratio?
the time need for…
- leaving blood cells
- dissociating from plasma proteins
- diffusing across hepatic membranes
- being metabolised by enzymes
- being transported to bile
is SO SHORT that most of the drug being delivered by the blood is removed by the liver
What is the rate-limiting factor for clearance for drugs with a high extraction ratio?
blood flow
In practical terms, what value of extraction ratio is considered high?
0.7-1
What is the hepatic clearance of drugs with a high hepatic extraction ratio sensitive to?
changes in blood flow - e.g. surgery, disease
What do drugs with high extraction ratios usually have?
low oral bioavailability as they are highly metabolised by hepatic first pass
Why may drugs have a low extraction ratio?
- slow dissociation from red blood cells
- slow dissociation from plasma proteins
- slow diffusion into hepatocytes
- slow enzymatic reaction - most frequent
- slow transport into bile
What is considered a low extraction ratio?
less than 0.3
What is hepatic clearance for drugs with a low extraction ratio sensitive to?
changes in plasma binding, enzymatic interactions as these majorly influence clearance - INSENSITIVE to changes in blood flow
What is the 1st definition of renal clearance?
the proportionality factor that relates the renal elimination rate of a drug with the drug concentration in the plasma
What is the equation for the ‘rate of renal elimination’?
rate of renal elimination = renal clearance x Cdrug (concentration of drug in plasma)
What are the units for the equation ‘rate of renal elimination’?
mass/time = volume/time x mass/volume
What is the 2nd definition for renal clearance?
the volume of fluid that is completely cleared of drug by the kidneys per unit time
What does a renal clearance of 100 mL/min mean?
the kidneys can completely clear all the drug present in 100 mL of plasma every minute
What is the equation for the total clearance of a drug?
Total clearance = sum of clearance for all organs
What is the equation for the rate of drug elimination?
rate of drug elimination = QR x (C entering - C leaving)
blood flow x (concentration of drug in blood entering kidney - concentration of drug in blood leaving the kidney)
What is the equation for the rate of drug presentation?
rate of drug presentation = QR x C entering
blood flow x concentration of drug in blood entering the kidney
What is the 1st definition for the renal extraction ratio?
the fraction of a drug passing by the kidneys which is eliminated by the kidneys, normally excreted into the urine
What is the 2nd definition for the renal extraction ratio?
the ratio between the rate of renal elimination and the rate of drug presentation to the kidneys
What is the equation for the renal extraction ratio?
ER = rate of elimination / rate of presentation
ER = (QR x (C entering - C leaving)) / QR x C entering
ER = (C entering - C leaving) / C entering
What does the renal clearance measure?
the loss of drug across the kidney
What is the 1st definition for renal clearance?
the ratio between the elimination rate by the kidney and the incoming concentration
What is the 2nd definition for renal clearance?
the volume of blood entering the kidney from which all the drug is removed per unit time
What is the equation for renal clearance?
CLR = rate of elimination / C entering
CLR = (QR x (C entering - C leaving)) / C entering
CLR = QR x E
What numbers does the renal extraction ratio vary between?
0-1
What does a renal extraction ratio of 0 indicate?
the drug is not eliminated by the kidneys at all
What does a renal extraction ratio of 1 indicate?
the drug is completely eliminated by the kidney
What essentially is the renal extraction ratio?
a measure of the efficiency with which the kidneys eliminate a drug from the systemic circulation over a single pass through them
What is classed as a high renal extraction ratio?
equal to or greater than 0.7 - renal clearance will approach blood flow
What is classed as a low renal extraction ratio?
equal to or less than 0.3
Which 3 processes contribute to renal excretion?
- glomerular filtration
- active tubular secretion
- passive and active reabsorption
What are the 3 main reasons for variability in the renal excretion of a drug?
- renal disease
- age
- drug interactions
What are the 4 main roles of the kidney?
- water and electrolyte balance
- hormone secretion
- blood pressure maintenance
- removal of waste
How much blood do the kidneys receive per minute (on average)?
1.2 L/min
How much of the blood received by the kidneys is filtered?
120 mL/min - 10%
What is the reabsorption of water the driving force for?
solutes (including drugs) to reabsorb passively
How is active reabsorption done?
transporters at the proximal convoluted tubule
What is filtered by the glomerulus?
ONLY unbound drugs
What are the steps of passive reabsorption of a drug?
- when the plasma is filtered, the free C drug is the same in the filtrate as in the plasma - an equilibrium is achieved
- 99% of water in the filtrate is reabsorbed back into the blood, therefore the C drug increases in the filtrate as water is removed, concentrating the drug
- a drug concentration gradient is formed across the membrane which drives the passive diffusion of the drug back into the body
What is tubular renal secretion carried out by?
carriers (transporters)
What are the 2 main factors affecting transporters in active tubular secretion?
- interactions
- saturation
How do interactions impact active tubular secretion?
two drugs may compete for the same transporter, so this decreases the active secretion and renal clearance of the drug
How does saturation affect active tubular secretion?
transporters can become saturated - this gives non-linear kinetics
How does tubular secretion affect renal clearance?
it increases renal clearance - drugs are secreted into the nephron tubules
How does tubular reabsorption affect renal clearance?
it decreases renal clearance - moves drug back into the blood
Which equation describes the link between renal clearance, renal perfusion (blood flow) and the efficiency of the renal elimination process?
ClR = Q x ER
renal clearance = blood flow x renal extraction ratio
How can we apply the ‘additivity’ of mechanisms of renal excretion?
ClR = Cl filtration + Cl secretion - Cl rebasorption
What is creatinine?
a waste product produced int he body as a byproduct of muscle metabolism
How does creatinine exist in the plasma?
it is completely unbound
What does the rate of production of creatinine depend on?
muscle metabolism, so:
- age
- sex
What do healthy people have for creatinine?
a balance - rate of production of creatinine = rate of elimination of creatinine
How can we asses renal function using creatinine?
- we need to know the rate of creatinine production for a person
- measure the creatinine concentration in the serum
- this can be used to predict the clearance of creatinine - assessing renal function
What is the equation for the creatinine elimination rate?
creatinine elimination rate = ClCR (clearance of creatinine) x C creatinine (concentration of creatinine in serum)
How can we estimate the renal clearance using creatinine?
ClR = Cl filtration
= f unbound x GFR
= f unbound x Cl CR
What is the creatinine clearance equal to?
the GFR
What is the equation for the renal clearance of a drug that is partially bound to plasma proteins?
ClR = f unbound x ClCR
How do you know if a drug is affected by tubular secretion?
the renal clearance for the drug will exceed its renal filtration clearance
What is the equation for the renal clearance of a drug that undergoes tubular secretion?
ClR = Cl filtration + Cl secretion
= (f unbound x ClCR) + Cl secretion
What will happen to the total clearance of a drug that is filtered then reabsorbed?
the renal clearance will be LESS than the rate of filtration
What is the equation for the renal clearance of a drug that is reabsorbed?
ClR = Cl filtration - Cl reabsorption
= )f unbound x ClCR) - Cl reabsorption
What are the 2 main factors that determine passive reabsorption?
- the gradient established
- the passive permeability properties of the drug
How does the gradient formed affect the reabsorption of a drug?
for a large urine flow, less water is reabsorbed, so the drug is more diluted (smaller concentration of drug in the urine) - the gradient is smaller, so there is less reabsorption
How do the passive permeability properties of a drug affect its reabsorption?
- MW
- partitioning
- the fraction ionised
How does urine pH affect the reabsorption of basic drugs?
- increase pH of urine
- less drug is ionised
- there is greater reabsorption of the drug
- lower renal clearance
How does urine pH affect the reabsorption of acidic drugs?
- increased pH
- drug becomes more ionised
- less drug is reabsorbed as it can’t pass over plasma membrane
- higher renal clearance
