Pharmacokinetics

Question 1

What is oral bioavailability of a drug?

Answer 1

Fraction or orally administered drug that reaches the systemic circulation.

Question 2

What are some factors that affect the Oral Bioavailability of a drug?

Answer 2

Poor absorption in the gut

Breakdown of drug in the gut

First pass effect

Question 3

What is the first pass effect in relation to absorption of drugs

Answer 3

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.

Question 4

What are the factors that effect absorption of a drug across a membrane?

Answer 4

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

Question 5

Will a weak acid like aspirin (pka 3.5) be mainly unionised or ionised in a the stomach where the pH is 3?

Answer 5

Mainly unionised - therefore it will easily cross the membrane

Question 6

What is the Henderson Hasselbach equation for a weak acid?

Answer 6

pH = pKa + log [A-}/[HA]

ionised/unionised

Question 7

What is the henderson hasselbach equation for a weak base?

Answer 7

pH = pKa + log [HA/A-}

unionised/ionised

Question 8

What does the overall extent of distribution of a drug in the body depend on?

Answer 8

Lipid solubility (pKA/pH)

Plasma protein affinity - increased affinity for plasma proteins will be less likely to leave blood.

Question 9

What is the main factor in the rate of distribution of a drug in the body?

Answer 9

Rate of blood flow to tissues/organs.

Question 10

How can we measure drug distribution?

Answer 10

Vd- Volume of distribution expressed as volume or volume/mass.

Cp - plasma concentration

Vd= Amount of drug in body/plasma concentration.

Question 11

What are the uses of Vd?

Answer 11

Partly determines plasma half life (t0.5) of a drug.

Question 12

What is Volume of distribution

Answer 12

Volume of water in which drug would have to be distributed to give its plasma concentration.

Question 13

What is clearance?

Answer 13

volume of plasma cleared of drug per unit time

Cl = [rate of elimination]/[Cp]

Question 14

Why is clearance a useful measure ?

Answer 14

Because rate of elimination of most drugs varies with Cp. However clearance stays fairly constant.

Question 15

What could be some situations where clearance could change?

Answer 15

Liver/renal disease

Question 16

What is first order elimination?

Answer 16

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.

Question 17

What is zero order elimination?

Answer 17

Constant amount of drug eliminated per unit time

Rate of elimination stays constant.

t0.5 can vary.

Question 18

What is the equation to work out t0.5 for first order elimination.

Answer 18

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.

Question 19

How can we calculate rate of elimination for intravenous infusion?

Answer 19

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.

Question 20

How do we calculate CSS for oral dosing?

Answer 20

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)

Question 21

How do we calculate clearance?

Answer 21

Clearance = [rate of elimination] / [Cp]

Question 22

How do we calculate intravenous infusion rate?

Answer 22

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/=.

Question 23

What type of drugs are generally excreted by the kidney?

Answer 23

Drugs which are not lipid soluble

Question 24

What are the 3 methods of renal excretion?

Answer 24

Glomerular filtration

Active secretion into nephron

Passive Reabsorption (all lipid soluble substances reabsorbed so non excreted in urine).

Question 25

How Can changes in urinary pH alter drug expression

Answer 25

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.

Question 26

What is phase I of hepatic drug metabolism?

Answer 26

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.

Question 27

What is phase II or hepatic drug metabolism?

Answer 27

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

Question 28

What are some factors which effect the rate of drug metabolism in the liver?

Answer 28

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.

Question 29

How does paracetamol toxicity work?

Answer 29

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.

Question 30

What can be a side effect of aspirin and warfarin?

Answer 30

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.