3. Pharmacokinetics

Question 1

What is pharmacokinetics?

Answer 1

‘What the body does to the drug.’

Study of the movement of a drug into and out of the body.

Question 2

What is pharmacodynamics?

Answer 2

‘What the drug does to the body.’

Study of the drugs effects and mechanism of action. (Think d for drugs first)

Question 3

Name some factors that influence drug pharmacokinetics

Answer 3

• age
• sex
• pregnancy/lactation
• infection/disease
• nutritional status - overweight, malnourished
• smoking/drugs/alcohol
• renal/hepatic/CVS/GI function

Question 4

What is Cmax and Tmax in single dosing?

Answer 4

Cmax - is the peak plasma concentration of a drug

Tmax - is the time taken to reach that peak plasma concentration (Cmax)

Note that in single dosing ADME, A and D are short, M is longer and most of the time is E.

Question 5

What is meant by therapeutic window and what constitutes the boundaries?

Answer 5

It is the range of the plasma concentration of which the drug has its desirable effects ie. does what it says but doesn’t cause harm.

The lower limit is the minimum effective concentration - ie. the lowest concentration for it to work and the upper limit is the maximum concentration after which there is an increased risk of toxicity.

Question 6

What is bioavailability (F)?

Answer 6

The fraction of a dose which finds its way into a body compartment, usually the circulation.

For an IV bolus the bioavailability is always 100%.

Question 7

How do you calculate oral bioavailability?

Answer 7

F= AUCoral/AUCiv

Question 8

What factors can affect bioavailability?

Answer 8

Absorption:

• drug formulation: e.g. slow release
• age: don’t have as effective uptake when older
• food: lipid soluble is greater than water soluble
• vomiting/malabsorption e.g. crohn’s

First pass metabolism (extraction ratio)

• any metabolism occurring before the drug reaches the systemic circulation (first pass effect).
• can occur in gut wall due to efflux pumps (p-glycoproteins)
• can be inactivated in gut lumen due to gastric acid, proteolytic enzymes
• can be inactivated in the liver - first pass

Question 9

What is meant by distribution of the drug and what are the 2 key factors involved?

Answer 9

The ability of the drug to ‘dissolve’ in the body.depends on:

• volume of distribution
• protein binding

Question 10

What is meant by protein binding?

Answer 10

Many drugs are bound to circulating proteins:

• albumin: acidic drugs (think A)
• globulins: hormones (e.g. SHBG)
• lipoproteins: basic drugs
• glycoproteins: basic drugs

Usually, only free drug can have a pharmacological effect and bind to receptors pass across tissue membranes etc.

Question 11

In which 3 cases can a change in protein binding become significant?

Answer 11

• high protein binding
• low volume distribution- doesn’t get very far in tissues
• narrowing therapeutic ratio - can easily find yourself in toxic/ineffective zone

Question 12

What factors/states can affect protein binding?

Answer 12

• hypoalbuminaemia e.g. in malnutrition/severe liver disease
• pregnancy: change in fluid balance
• renal failure
• displacement by other drugs - if another drug is more protein bound it can displace the first drug increasing its free concentration

Question 13

What is meant by the volume of distribution?

Answer 13

It is a measure of how widely a drug is distributed in the tissues of the body. It is a hypothetical measure.

Vd = dose/concentration of drug in plasma

E.g. 100mg gentamicin dose, peak plasma concentration of 5mg/L then Vd will be: 100mg/5mg/L = 20L

Question 14

What is the relationship between half life and volume of distribution?

Answer 14

The Half life is proportional to Vd and clearance.

If a drug has a large volume of distribution ie. has spread more in the body, it will take longer to be eliminated, and have a longer half life.

Question 15

Give 1 example of a drug with a small volume of distribution and 1 with a large…

Answer 15

Small Vd: warfarin

Large Vd: digoxin

Question 16

What is a pro drug?

Answer 16

A pharmacologically inactive drug which can be metabolised to one with pharmacological activity.

Question 17

What are the cytochrome p450 isoenzymes?

Answer 17

• family of isoforms responsible for 90% of drug metabolism through oxidative reactions
• metabolise toxins such as carcinogens and pesticides
• genetic differences in metabolism

Question 18

What factors can influence the activity of the CYPs?

Answer 18

• enzyme-inducing/enzyme-inhibiting drugs
• sex: women slower ethanol metabolisers
• age: reduced in elderly and children
• liver disease
• hepatic blood flow
• cigarettes and alcohol consumption

Question 19

Example: the CYP 2D6 is absent in 7% of Caucasians and hyperactive in 30% of East Africans. It is responsible for metabolising Beta blockers, codeine and TCAs. It is inhibited by fluoxetine, haloperidol and quinidine.

Predict what will happen in someone prescribed a beta blocker who is normal, hyperactive and absent for this CYP family.

Answer 19

• if someone has a normal CYP you will give a predicted dose and get a predicted response

Hyperactive CYP: the beta blocker will be metabolised faster even at higher doses and will have less of an impact

Absent: cannot metabolise the drug or it will be metabolised slowly, so it will be around for longer and this could lead to bradycardia (as there’ll be too much beta blocker around)

Question 20

What happens if GFR is reduced?

Answer 20

If GFR is reduced, then clearance is reduced.

Half life is inversely proportional to clearance. A reduction in clearance (or GFR) increases half life.

Think about like this: if you halve renal function it’s like doubling the concentration of drug so be aware when prescribing in patients with renal problems.

Question 21

Explain the difference between first order and zero order kinetics

Answer 21

first order kinetics are considered as a linear process because the rate of elimination is proportional to the drug concentration. This means that the higher the drug concentration, the higher its elimination rate. In other words, the elimination processes are not saturated and can adapt to the needs of the body, to reduce accumulation of the drug. 95% of the drugs in use at therapeutic concentrations are eliminated by first order elimination kinetics.

A few substances are eliminated by zero-order elimination kinetics, because their elimination process is saturated. Examples are Ethanol and Phenytoin. Because in a saturated process the elimination rate is no longer proportional to the drug concentration but decreasing at higher concentrations, zero-order kinetics are also called “non-linear kinetics.”

Question 22

In repeated drug administration, how long for a new steady state (CpSS) to be achieved?

Answer 22

3-5 half lives.

From a steady state, it also takes 4-5 half lives to eliminate most of the drug.

Example: to reach a steady state with an antibiotic which has a half life of 5 hrs, a steady state will be achieved the next day (5 x 5 = 25hrs).

If a drug has a half life of 30 hours then a steady state will be achieved in a weeks time. This is because 30 x 5 = 150. 150/24 is 6.25 days. Not good if you need immediate action.

Question 23

What is meant by a loading dose?

Answer 23

A loading dose is an initial higher dose of a drug that may be given at the beginning of a course of treatment before dropping down to a lower maintenance dose.

A loading dose is most useful for drugs that are eliminated from the body relatively slowly, i.e. have a long systemic half-life (also will have a large Vd because t1/2 is proportional to Vd). Such drugs need only a low maintenance dose in order to keep the amount of the drug in the body at the appropriate therapeutic level, but this also means that, without an initial higher dose, it would take a long time for the amount of the drug in the body to reach that level.

Drugs which may be started with an initial loading dose include digoxin.

Question 24

Do we always need to give a loading dose?

Answer 24

• no!
• just because a drug has a large Vd and therefore a long half life doesn’t mean we always need to give a loading dose
• only when you need to give it in an acute situation

Question 25

What might we see in a patient with digoxin toxicity and what can we do? (Digitoxic)

Answer 25

• bradycardia
• xanthopsia (yellow vision)
• vomiting

Give something which binds to digoxin and therefore it will become inactive and be eliminated.

Question 26

How do you calculate a loading dose?

Answer 26

Vd = dose/concentration of drug in plasma at t0

Loading dose = Vd x concentration of drug target

1) so if you have a 100kg patient you want to treat for epilepsy and you want to give him phenytoin you need to multiply his body weight by the Vd phenytoin (0.7l/kg) to get Vd. His Vd would therefore be 70L.
2) we want to achieve a steady state dose of 20mg/L (desirable dose for treating epilepsy). So 70L x 20mg/L = 1400mg. (Times the Vd by steady state dose)
3) but phenytoin is a salt which is 92 % phenytoin. So we need to give a slightly higher dose. So we convert the 1400 mg to grams (becomes 1.4g) and divide by 0.92 to get 1.5g.

Question 27

How do we calculate a half life?

Answer 27

Half life = 0.693/k

K = clearance/vd

Answer should be in minutes