Pharmacokinetics Flashcards
What is oral bioavailability of a drug?
Fraction or orally administered drug that reaches the systemic circulation.
What are some factors that affect the Oral Bioavailability of a drug?
Poor absorption in the gut
Breakdown of drug in the gut
First pass effect
What is the first pass effect in relation to absorption of drugs
When drugs are absorbed from the gut, they are taken to the liver via the hepatic portal vein to be metabolised.
Some drugs are completely metabolised in the liver therefore bioavailability is bad.
What are the factors that effect absorption of a drug across a membrane?
Lipid solubility - if highly lipid soluble the drug will easily diffuse across membrane.
pH/pKa - pH of solution and pKa of drug influence ionised/unionised ratio of drug
> The more unionised, easier diffusion across membrane
Will a weak acid like aspirin (pka 3.5) be mainly unionised or ionised in a the stomach where the pH is 3?
Mainly unionised - therefore it will easily cross the membrane
What is the Henderson Hasselbach equation for a weak acid?
pH = pKa + log [A-}/[HA]
ionised/unionised
What is the henderson hasselbach equation for a weak base?
pH = pKa + log [HA/A-}
unionised/ionised
What does the overall extent of distribution of a drug in the body depend on?
Lipid solubility (pKA/pH)
Plasma protein affinity - increased affinity for plasma proteins will be less likely to leave blood.
What is the main factor in the rate of distribution of a drug in the body?
Rate of blood flow to tissues/organs.
How can we measure drug distribution?
Vd- Volume of distribution expressed as volume or volume/mass.
Cp - plasma concentration
Vd= Amount of drug in body/plasma concentration.
What are the uses of Vd?
Partly determines plasma half life (t0.5) of a drug.
What is Volume of distribution
Volume of water in which drug would have to be distributed to give its plasma concentration.
What is clearance?
volume of plasma cleared of drug per unit time
Cl = [rate of elimination]/[Cp]
Why is clearance a useful measure ?
Because rate of elimination of most drugs varies with Cp. However clearance stays fairly constant.
What could be some situations where clearance could change?
Liver/renal disease
What is first order elimination?
Constant fraction of drug eliminated per unit time, t0.5 stays constant.
Clearance is not changing but the rate of elimination depends on how much drug is present and the higher the Cp the faster the rate of elimination.
What is zero order elimination?
Constant amount of drug eliminated per unit time
Rate of elimination stays constant.
t0.5 can vary.
What is the equation to work out t0.5 for first order elimination.
t0.5 = 0.693Vd/ Clearance
length of time that a drug persists in the blood is determined by both Vd and Clearance.
The equation says that if a drug has a high Vd then the t0.5 will be higher - it will take longer for concentration in blood to half.
The equation also shows that if the rate of clearance decreases then the t0.5 will also increase.
How can we calculate rate of elimination for intravenous infusion?
Rate of elimination = Css x Cl
CSS = concentration at which rate of infusion = rate of elimination
Time to reach CSS does not vary depending on the infusion rate.
How do we calculate CSS for oral dosing?
D = individual dose
F = oral bioavailability
T = time interval between doses in minutes
Cl = clearance
Css = D (individual dose) x F(oral bioavailability) / T (minutes between dose) x Cl. (clearance)
How do we calculate clearance?
Clearance = [rate of elimination] / [Cp]
How do we calculate intravenous infusion rate?
Rate of elimination = Cp x Cl.
As cp rises rate of infusion rises untill it is equal to the rate of elimination (CSS) ; therefore we can write the equation as ;
Rate of elimination = Css x Cl.
And as at Css Rate of elimination = Rate of infusion we can write the above equation as
Rate of infusion = Css x Cl.
Time taken to reach CSS is independant of rate of infusion/=.
What type of drugs are generally excreted by the kidney?
Drugs which are not lipid soluble
What are the 3 methods of renal excretion?
Glomerular filtration
Active secretion into nephron
Passive Reabsorption (all lipid soluble substances reabsorbed so non excreted in urine).
How Can changes in urinary pH alter drug expression
For a weak acid making the urine more alkaline can increase the amount of ionised form of the acid and increase renal excretion.
For a weak base making the urine more acidic can increase renal excretion.
What is phase I of hepatic drug metabolism?
Drug derivative formed by oxidation, reduction or hydrolysis into a more reactive form.
Drug is oxidised/reduced/hydrolysed by microsomal enzymes in the endoplasmic reticulum of the liver. Such as Cytochrome p450.
What is phase II or hepatic drug metabolism?
Conjugation of the species formed in Phase I with polar molecules, making the metabolites less lipid soluble and therefore easier to excrete in urine.
Occurs in the cytosol of the liver cells.
an example of a molecule which could be used in a conjugation reaction with a drug derivative is glucoronidea
What are some factors which effect the rate of drug metabolism in the liver?
Enzyme induction
- Some drugs and environmental pollutants cause an increase in the production of microsomal enzymes in the liver (such as cytochrome p450) which causes increased conjugation of drugs into polar derivatives leading to greater renal excretion. Hence this increases clearance and decreases the t0.5
Enzyme inhibition
Some drugs inhibit Cytochrome p450 enzymes, this in turn increases the t0.5 and can increase the likelihood of seeing increased adverse effects/toxicity in the body.
Genetic polymorphisms
- Some people may have poor ability to metabolise certain drugs due to genetic polymorphisms/
Disease
- Liver function for drugs mainly metabolised in liver
- Renal function for drugs mainly excreted unchanged in urine.
- Thyroid function (effects the liver metabolising enzymes)
- Cardiovascular disease (rate of delivery of drug to liver/kidney.
Age
- Generally drug metabolism is lower in the very young and the elderly.
How does paracetamol toxicity work?
Following overdose of paracetamol, the phase II reaction pathways become saturated, causing the paracetamol to undergo phase I metabolism into a toxic intermediate called NAPQI.
NAPQI can be conjugated with glutathione however if glutathione runs out NAPQI can react with cell proteins to cause hepatic cell damage and liver failure.
What can be a side effect of aspirin and warfarin?
Serious stomach bleeding, as Aspirin inhibits Cox-1 which is involved in the maintenance of the gastric mucosa and decreases platelet aggregation, which has a synergistic effect with the decreased clotting factors produced due to warfarin.
