PK PD Pharacokimetics And Pharmacodynamics

Question 1

What’s the difference between pharmacokinetics, pharmacogentics and pharmacodynamics?

Answer 1

Pharmacokinetics - what the body does to a drug

Pharmacogenetics - how individuals differences affect metabolism

Pharmacodynamics - what the drug is doing at receptor level

Question 2

What can happen to a free drug in the body?

Answer 2

Protein- bound drug

Metabolised -> active/ inactive

Excreted

Distributed to tissues reservoirs

Interact with receptors -> (therapeutic) effect

Question 3

Key factors affecting pharmacokinetics?

Answer 3

Bioavailability
Half-life
Drug elimination
Inter-subject variability (clinical trials)
Drug- drug interactions 

Renal function
Stress
Pyrexia
Alcohol
Smoking 
Occupational exposure
Lactation 
Albumin level
Circadian/ seasonal variations

Question 4

What is oral bioavailability? What affects it?

Answer 4

Measure of the amount of drug that gets into systemic circulation relative to IV route (=100%/ 1)

Measure of drug absorption where it can be used

<1 = lower bioavailability

Absorption
Formulation 
Age
Food
Vomiting/ malabsorption 
First pass metabolism (gut lumen, gut wall, liver)

Question 5

How to calculate bioavailability from a time, plasma concentration of drug graph

Answer 5

(Area under curve oral/ AUC IV) X 100%

Question 6

How does the rate of absorption dictate visibility of distribution and elimination phases?

Answer 6

Fast absorption means a more obvious distribution phase

Whereas slow absorption means gradual plasma conc increase

Question 7

Give an example of an extended release modified release preparation

Answer 7

Meteor in can be altered through tweeted preparation to change the pharmacokinetic parameters -> slower absorption so can be taken once a days rather than 3 but more expensive, less Gi discomfort, increased adherence

Question 8

What affects distribution of a drug?

Answer 8

Blood flow
Capillary structure
Lipophilicity
Hydrophilicity
Protein binding

Question 9

Which type drugs tend to bind to which proteins?

Answer 9

Albumin - acidic drugs
Globulins - hormones
Lipoproteins - basic drugs
Glycoproteins - basic drugs

Question 10

When is displacement of a drug from binding sites resulting in protein binding drug interactions important?

Answer 10

• highly protein bound
• narrow therapeutic index
• low Vd

Question 11

When is a sceond drug displacing a first drug from binding proteins important?

Answer 11

Results in more free first drug to elicit a response, potentially causing harm

• pregnancy (fluid balance)
• renal failure
• hypoalbuminaemia

Question 12

How to calculate Vd?

Answer 12

Dose/ drug plasma conc

Question 13

If you give a dose of 100mg, the plasma concentration is measured as 20mg/ L and the Vd as 5L what does this mean?

Answer 13

To achieve a plasma conc of 20mg with 100mg dose you need 5L for it to be dissolved into

Question 14

What does the Vd tell you about where the drug is in the body?

Answer 14

In general

A smaller apparent Vd suggests a drug confined to plasma and extracellular fluid

A larger apparent Vd suggests drug is distributed throughout tissues

Question 15

Compare where drugs are found if there Vd is <12L compared to >200L

Answer 15

<12L - found mostly in plasma

> 200L majority distributed, sequestered into other tissues

Question 16

Describe the stages of metabolism

Answer 16

Drug

Phase 1 enzymes

Oxidation/ dealkylation/ reduction/ hydrolysis

Phase 2 enzymes

Glucoronide/ sulphate/ glutathione/ N-acetyl

Conjugates

-> gall bladder -> bile
OR
-> kidney -> urine

Question 17

Explain how cytochrome P450 isoenzymes are affected by exogenous substances

Answer 17

CYP1A - induced by smoking 
CYP2C - many inhibitors 
CYP2D - metabolises many drugs 
CYP2E - alcohol metabolism 
CYP3A - 50% therapeutics

Majority of phase 1 catalysed reactions utilise the P450 system

Question 18

How do CYP450 enzymes work on most drugs and how else can they work?

Answer 18

Active -> inactive (most)

Inactive -> active (perindorpril -> perindoprilat/ levodopa -> dopamine)

Active -> active (codeine-> morphine/ diazepam -> oxazepam)

Induced/ inhibited by endogenous/ exogenous compounds affecting phase 1 metabolism e.g. age, hepatic disease, blood flow, alcohol (antibiotics), cigarette smoking

Question 19

What effect does grapefruit juice have on statin therapy?

Answer 19

CYP3A4 inhibition -> increased statin (simvastatin/ lovastatin) plasma concentration -> more likely time get side effects

Question 20

How is CYP 2D6 affected by genetic variations, substrates and other drugs?

Answer 20

CYP 2D6

• Absent in 7% Caucasians
• Hyperactive/ increased induction in 30% East Africans
• substrates include beta blockers, many SSRIs, some opioids
• inhibited by some SSRIs, other antiarrhythmic agents and other antidepressants

Question 21

How are drugs eliminated?

Answer 21

Primarily via kidney

Fluids (sweat, tears, genital secretions, saliva, breast milk)

Solids (faeces, hair)

Gases (volatile compounds e.g. alcohol)

Question 22

What Drugs are normally renally metabolised? What affects this?

Answer 22

Typically low molecular weight polar metabolites

Affected by: GFR, protein binding (gentamicin), competition for transporters (penicillin), lipid solubility/ PH/ flow rate (aspirin)

Question 23

What is clearance? How do you calculate it?

Answer 23

Clearance of drug from the body - clearance from all routes, both metabolism and excretion taken together (mL/ min), mostly GFR

• volume of blood cleared per unit time (mL/ min)

Rate of elimination from body (mg/min) / drug concentration in plasma (mg/ mL)

Question 24

What drugs are normally hepatically metabolised? What affects this?

Answer 24

Typically high molecular weight - conjugated with glucuronic acid (phase 2)

Bile -> faeces or reabsorbed -> enterohepatic circulation

Antibiotic drug interactions (manipulate gut biome, change rate of reabsorption)

Question 25

How does elimination rate constant relate to Vd and clearance? Therefore how can that be displayed in an equation?

Answer 25

Elimination is inversely proportional to Vd (1/Vd)

Elimination is directly proportional to clearance

K (rate constant) = CL/ Vd
K = 0.693/t1/2
Substitute K for CL/ Vd

t1/2 = (0.693 X Vd) / CL

Question 26

What type of elimination kinetics do most drugs exhibit? What about alcohol, salicylic acid and phenytoin? What does this mean needs considering?

Answer 26

Most drugs first order kinetics at therapeutic doses (t1/2 constant)

High doses, alcohol, salicylic acid and phenytoin - zero order so dose change can produce unpredictable change in plasma concentration as t1/2 not calculable - important consideration for toxicity and dosing

Question 27

What is the steady state? When is it normally reached?

Answer 27

The steady state concentration (CSS) is when the amount going into the body equals the amount leaving the body and it’s used as the maintenance dose for patients

It’s reached about 5t1/2
Reaches new steady state after another 5t1/2

After 5t1/2 almost complete elimination (negligible drug concentration)

Therapeutic benefit optimal at steady state

Question 28

What equations are true once steady state is reached?

Answer 28

Normally : rate of elimination = CL X [plasma]
At Steady state: [plasma] = CSS
So rate of elimination = CL X Css

At steady state: Rate of elimination = rate of infusion so
Rate of infusion = CL X Css

Css = rate of infusion/ CL
CL = rate of infusion/ Css

Question 29

What do the symbols in this equation mean: rate of administration = (DXF)/ t ? What about this one: rate of elimination = CL X Css? How can these be combined at steady state? From that equation what can you do to change the Css?

Answer 29

D = maintenance dose
F = bioavailability correction 
t = dose interval (how often drug is given) 

CL = clearance
Css = steady state concentration 

At steady state rate of administration = rate of elimination so:
(DXF)/ t = CL X Css
OR
Css = (DXF)/ (tXCL)

Can only change t (dose interval) and D (maintenance dose) as F (bioavailability) and CL (clearance) are constant

Question 30

What is the loading dose? When is it used? How can we calculate loading dose?

Answer 30

Accelerates getting to steady state (large initial dose) single dose to achieve desired concentration apparent Vd

Used if rapid onset required or drug with long t1/2 (e.g. Digoxin large Vd and large t1/2)

If Vd = dose/ [plasma] then
[plasma] = dose/ Vd
At steady state:
Css = loading dose/ Vd

Loading dose = Css X Vd

Question 31

If a drug has a long t1/2 what’s important to consider?

Answer 31

Long period before drug is fully eliminated from body - may be months so consider interactions with other drugs
E.g. amiodarone t1/2 50-60 days and increased [plasma] of other cardiac drugs

Question 32

What’s important to consider for dosing schedules?

Answer 32

Maintain dose within therapeutic range

Safe

Achieve adherence

Initiating and terminating treatment - titrations up and down

Question 33

How can we measure response to drug therapy?

Answer 33

Physiological measurements

Feeling

Appearance

Primary and secondary prevention

Question 34

Examples of drug actions and examples for those

Answer 34

Agonist (binds to receptor and causes response) e.g. adrenaline

Partial agonist (partial response) sub- maximal e.g. formoterol

Inverse agonist (prevents response happening, some receptors have basal activity in R state) e.g. propranolol

Competitive antagonist e.g. naloxone on opioid receptors

Non- competitive antagonist (causes functional changes to receptor) e.g. some alpha blockers

Functional antagonist (agent acts at different receptor but causes opposite response)