Individual variation, pharmacogenomics, personalised medicine and drug interactions

Question 1

what is inter-individual variation?

Answer 1

the same dose of drug does not produce the same response in different individuals

Question 2

what is intra-individual variation?

Answer 2

the same dose of drug does not produce the same response in the same individual

Question 3

what can happen if individual variation is not taken into account?

Answer 3

can lead to poor efficacy,
and unexpected harmful effects

Question 4

What is PK variability?

Answer 4

variability can be caused by diff concentrations at sites of drug action

something affecting A, D, M, E

eg one dose of a drug being ineffective in one patient, but potentially toxic with unwanted side effects in another

Question 5

What is PD variability?

Answer 5

same drug concentrations can produce different response

can be caused by genetics, drug interactions, pathological conditions

eg inter-individual differences in the response of receptors in equal concentrations of drug

Question 6

what are the causes of variability?

Answer 6

age

physiological (sex, preganncy, BMI)
disease

sociocultural factors (diet, habits)

drug interactions

genetic factors

ethnicity

Question 7

How does age affect drug action?

Answer 7

elimination ↓ efficient due to ↓ GFR

drug accumulating in plasma conc

more prolonged effect of drug

Question 8

what happens if digoxin is chronically administered in elderly pts?

Answer 8

chronic admin of same dose of digoxin levels in plasma conc

leads to glycoside toxicity

Question 9

what are 2 factors that change in body with age?

Answer 9

metabolism

body composition

Question 10

how does metabolism change with age?

Answer 10

hepatic enzyme activity ↓

overall ↓ clearance

drug accumulates eg benzodiazepines

Question 11

how does body composition change with age?

Answer 11

body fat composition ↑

Vd of lipid-soluble drugs ↑

Question 12

What is the relationship between half-life and lipid-soluble and water-soluble drugs?

Answer 12

Body fat composition ↑ the half-life of lipid-soluble drugs (eg benzodiazepines)

body fat composition ↑ serum level of water-soluble drugs (eg digoxin)

Question 13

What can the same dose of benzos cause in elderly pts?

Answer 13

benzos causes confusion, less sedation in elderly compared to young subjects

Question 14

what is polypharmacy?

Answer 14

concurrent use of several meds, mainly in elderly pts

Question 15

what can polypharmacy lead to?

Answer 15

can lead to ↑ risk of drug interactions and adverse drug effects

Question 16

how is renal excretion less effective in babies?

Answer 16

gfr is only 20% of the adult

therefore longer plasma elimination half life

more prolonged effects of drug

Question 17

how is metabolism less efficient in babies?

Give examples

Answer 17

low activity of liver enzymes (eg slow conjugation)

↑ drug accumulation in tissues causing toxic effects

eg ↑ doses of chloramphenicol → grey baby syndrome

morphine not given as analgesic in labour as transferred to foetus → prolonged resp depression

Question 18

How do physiological changes during pregnancy affect pharmacokinetics?

Answer 18

↓ plasma albumin conc → drug-protein binding altered

↑ CO → ↑ renal perfusion and GFR → ↑ elimination

↓ gastric motility →↓ GI absorption

Question 19

What does protein binding mean for drugs?

Answer 19

The less bound a drug is, the more efficiently it can traverse or diffuse through cell membranes.

Question 20

what does decreased protein binding lead to?

Answer 20

Decreased protein binding leads to ↑ concentrations of free drug and favours more distribution to tissues

Question 21

give an example of low protein binding in pregnancy

Answer 21

Eg phenytoin and tacrolimus, efficacy and toxicity are expected to be related to unbound drug concentration in plasma.

During pregnancy, both the drugs exhibit an increased unbound fraction due to lower albumin concentrations and increased clearance.

Question 22

how can drugs given to pregnant women affect the fetus?

Answer 22

drugs given to pregnant mum can affect fetus

eg LMWH can be given chronically as it is excluded from the placenta barrier

drugs transferred to fetus are eliminated more slowly due to immature liver kidney function

Question 23

Give examples of diseases which affect PK (A, D, M and E).

Answer 23

Absorption:
pancreatic disease, nephrotic syndrome -malabsorption

Distribution:
chronic renal failure - altered plasma protein binding
meningitis: altered BBB

Metabolism:
liver cirrhosis, portal HTN, hypothermia (elderly) - reduced clearance

Excretion;
renal failure - reduced excretion

Question 24

Give examples of diseases which affect PD

Answer 24

MG:
AI disease - inc sensitivity to drugs that influence neuromuscular transmission

familial hypercholesterolaemia:

LDL receptor deficiency - resistance to statins in homozygous indivduaals

Question 25

Define drug interactions?

Answer 25

clinically significant change in effect of 1 drug a result of co-administration of another drug

Question 26

what is the object drug?

Answer 26

the drug affected by interaction

Question 27

what is the precipitant drug?

Answer 27

the drug caused the altered interaction

Question 28

what can drugs interact with?

Answer 28

other drugs

herbs

alcohol

chemical substances from diet

Question 29

What are 3 overall mechs of drug interactions?

Answer 29

PK interactions: precipitant drug affects object drug by interfering with ADME therefore altering the conc

PD interactions: (precipitant drug affects object drug - without changing conc)

In vitro (outside body) interactions: when drugs interact with each other when outside the body - they mix in the vial or syringe before entering the body

Question 30

Give examples of drugs which interact to affect absorption.

Answer 30

GI pH: GI alkalinisation by omeprazole (used to treat XS stomach acid) may decrease absorption of ketoconazole (antifungal)

GI flora: abx decreases GI bacterial flora, which decreases vit K (helps clots) production thereby augmenting anticoag effect of warfarin

Question 31

Give examples of drugs which interact to affect distribution.

Answer 31

NSAIDs can displace MTX from plasma-binding proteins therefore it increases in systemic circulation → MTX toxicity

Phenylbutazone (NSAID) displaces warfarin from albumin → ↑ bleeding

Question 32

Give examples of drugs which enhance CYP450 activity to affect metabolism.

Answer 32

The mnemonic CRAP GPs can be used to easily remember common CYP450 inducers:

Carbamazepine
Rifampicin - reduces warfarin efficacy
Alcohol
Phenytoin - increases clearance of ciclosporin
Griseofulvin
Phenobarbital - warfarin
Sulphonylureas

Question 33

Give examples of drugs which inhibit CYP450 activity to affect metabolism.

Answer 33

The mnemonic SICKFACES.COM can be used to easily remember common CYP450 inhibitors:

Sodium valproate
Isoniazid
Cimetidine
Ketoconazole
Fluconazole
Alcohol & Grapefruit juice
Chloramphenicol
Erythromycin
Sulfonamides
Ciprofloxacin
Omeprazole
Metronidazole

Question 34

what effect do cyp450 inducers have on drug?

Answer 34

• induces CYP450 enzyme activity
• this leads to lower bioavailability of drug with high first pass metabolism

Question 35

what effect do cyp450 inhibitors have on drug?

Answer 35

• inhibits cyp450 activity
• higher bioavailability of drug with high first-pass metabolism

Question 36

Give examples of drugs which affect renal excretion.

Answer 36

inhibiting tubular secretion: amiodarone (antiarrhythmic) can block renal excretion of digoxin (glycoside-positve ionotrope) , causing digoxin toxicity

alteration of urine flow/pH:
loop and thiazide diuretics inc Li reabsorption , causes toxicity

Question 37

Pharmacodynamic drug interactions examples

Answer 37

warfarin and antithrombotic drugs: increases the risk of bleeding by 2 mechs; anti coag and inhibition of platelet function

promethazine and alcohol: H1 receptor antagonist causes drowsiness - enhanced by alcohol

NSAIDs and anti-HTN drugs: block hypotensive effects of anti-HTN drugs by inhibiting synthesis of renal vasodilator

Question 38

what effect does fast acetylation have on drug conc?

Answer 38

lower drug conc
quicker half-life
hepatotoxicity by metabolism products

Question 38

what effect does slow acetylation have on drug conc?

Answer 38

higher conc
slower half life
toxicity due to high drug conc

Question 39

what determines fast/slow acetylation?

Answer 39

a single gene, this can be influenced by ethnicity

Question 39

What is pharmacogenomics?

Answer 39

study of variability in drug response determined by the genome

looks at how your genetics responds to drugs

Question 39

What is personalised medicine?

Answer 39

targeted drugs to treat a variety of human diseases in individuals with different genotypes (max effect, min toxic effects)

Question 40

what are SNPs?

Answer 40

single nucleotide polymorphisms

varying genetic sequences at a genetic locus.

They arise by mutations and may increases or die out, depending on if they confer a selective advantage

Question 41

How is codeine metabolism affected by CYPD6 gene?

Answer 41

• CYP2D6 gene is highly polymorphic, metabolises analgesics
• codeine metabolised to morphine by CYP2D6
• if pt has fast CYP2D6 metabolism: avoid codeine due to toxic morphine levels (as it will metabolise it rapidly to morphine)
• if pt has slow CYP3D6 metabolism: avoid codeine due to toxic accumulation

Question 42

What are haplotypes and how is it helpful when considering drug response?

Answer 42

set of DNA variants along a single chromosome that tends to be inherited together

SNPs and haplotypes (a combination of SNPs at a locus) in genes involved in drug action may predict drug response

Question 43

give examples of pharmacogenomic tests?

Answer 43

carbamazepine and HLA-B*1502 allele - highly associated with the outcome of carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis (asian patients)

5fu (chemo drug) - metabolised by DYPD - not recommended in DYPD deficiency as it has unpredictable toxicity