2.1 Pharmacokinetics

Question 1

What is pharmacokinetics?

Answer 1

What the body does to a drug

Question 2

What key factors should you consider with a drug?

Answer 2

Drug- drug interactions
Bioavailability 
Half life
Drug elimination
Intra-subject variability
Patient specific pharmacokinetic parameters allows tailored dosing regimens to be initiated

Question 3

What should you consider with pharmacokinetics?

Answer 3

Renal function
Stress
Pyrexia
Alcohol
Smoking
Age
Sex
Diet
Infection
Liver function
GI function

Etc.

Question 4

What is bioavailability?

Answer 4

A measure of drug absorption into body compartment where in can be used - typically circulation

(F)

Drugs administers via IV is said to be 100%
Other routes referenced as a fraction of IV

Question 5

What is bioavailability affected by?

Answer 5

Absorption
E.g due to formula, age, food, vomiting/malabsorption (Crohn’s)

First pass metabolism (shunted via hepatic portal vein into liver for metabolism)
E.g metabolism before reaching systemic circulation

Question 6

What determines how well a drug dissolves and is distributed through interstitium from circulation?

Answer 6

Blood flow and capillary structure
Highly vascularised Vs poorly vascularised tissue
Lipophilicity and hydrophilicity
(Lipophilic drugs will readily cross through call membranes whereas hydrophobic drugs require junctions in the endothelium)
Protein binding
(Albumin - acidic drugs, globulins, glycoproteins

Question 7

What type of drugs will be able to afford a response and/or be eliminated?

Answer 7

Only free drugs typically

Displacement of a drug from a binding site can result in protein binding drug interaction

Clinically important if

• highly protein bound
• narrow therapeutic index
• low Vd

Question 8

How can increased free drug illicit a response?

Answer 8

Second drug displaces first drug from binding proteins
More free first drug to elicit a response through receptor
Potentially causing harm = entering toxic dose conc
E.g in pregnancy. Renal failure, hypoalbuminemia among others

Question 9

What is Vd?

Answer 9

Volume distribution. A measure of how widely a drug is distributed in the body.

Vd = DOSE / (DRUG)plasma

The amount of fluid required to contain the total amount (dose) of drug in the body at the same conc as in the plasma (DRUG)plasma.

Question 10

What does a large/small Vd indicate?

Answer 10

Large = drug is distributed throughout tissue

Small = drug is confined to plasma and extracellular fluid.

Question 11

What processes do phase 1 enzymes in the liver carry out on drugs?

Answer 11

Oxidation
Dealkylation
Reduction
Hydrolysis

Convert drugs into lipophilic metabolites

Question 12

What processes do phase 2 enzymes carry out on drugs in the liver?

Answer 12

Glucuronide
Sulphate
Glutathione
N acetyl

Before its excreted

Question 13

What effects the route and mechanism of metabolism?

Answer 13

Size, lipophilicity, hydrophilicity, structural complexity

Question 14

What are the modes of activation in drugs?

Answer 14

Active to inactive
Inactive to active
Active to active

Question 15

What can influence phase 1 metabolism?

Answer 15

Age, hepatic disease, blood flow, alcohol and cigarette smoking

Question 16

What routes allow drug elimination from the body?

Answer 16

Primarily via the kidney
Also
- pulmonary
- biliary
- faecal sweat
- genital secretions 
- saliva 
- breast milk

Question 17

What is drug elimination affected by?

Answer 17

1) GFR and protein binding (e.g gentamicin)
2) competition for transporters (e.g penicillin)
3) lipid solubility, pH, flow rate (aspirin)

Question 18

What is clearance of a drug?

Answer 18

The rate of clearance from all routes - both metabolism and excretion taken together by definition (mL/min)

Mostly GFR

Question 19

What is half life? T1/2 and what is its relation to clearance?

Answer 19

The time in which concentration of a drug in the plasma decreases by half

If GFR is reduced them clearance is reduced and t1/2 increases

Reasoned that t1/2 is inversely proportional to clearance
Half life will increase when clearance is compromised, renal or hepatic stenosis, haemorrhage, reduced metabolism, reduced plasma drug extraction and drug-drug interactions

-metabolism and excretion are rate limited by physiological processes

Question 20

What s the rate of elimination proportional to in

• 1st order kinetics
• 0 order kinetics

Answer 20

1st = rate of elimination is proportional to drug conc
0 = rate of elimination is constant (receptor/enzyme saturation)

Question 21

What order of kinetics do most drugs exhibit

Answer 21

First order kinetics (t1/2 is constant)

Ethanol, aspirin and phenytoin exhibit zero order = unpredictable half life

Question 22

What is the clinical importance of drug monitoring?

Answer 22

Pharmacokinetics 
Zero order kinetics
Long half life
Narrow therapeutic window
Drug-drug interactions
Reported or expected toxic effects
Therapeutic effect - response

Question 23

What is the aim of half life considerations?

Answer 23

To maintain a minimum effective conc of drug

T1/2 alone does not give us info about duration of therapeutic effect

Question 24

When plasma concentration has been reached, how should dosing be altered?

Answer 24

Dosing should match clearance to maintain the desired therapeutic effect
Only amount of drug that has been eliminated needs to be replaced in subsequent doses - incorporating bioavailability