Individual variation, pharmacogenomics, personalised medicine and drug interactions Flashcards
what is inter-individual variation?
the same dose of drug does not produce the same response in different individuals
what is intra-individual variation?
the same dose of drug does not produce the same response in the same individual
what can happen if individual variation is not taken into account?
can lead to poor efficacy,
and unexpected harmful effects
What is PK variability?
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
What is PD variability?
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
what are the causes of variability?
age
physiological (sex, preganncy, BMI)
disease
sociocultural factors (diet, habits)
drug interactions
genetic factors
ethnicity
How does age affect drug action?
elimination ↓ efficient due to ↓ GFR
drug accumulating in plasma conc
more prolonged effect of drug
what happens if digoxin is chronically administered in elderly pts?
chronic admin of same dose of digoxin levels in plasma conc
leads to glycoside toxicity
what are 2 factors that change in body with age?
metabolism
body composition
how does metabolism change with age?
hepatic enzyme activity ↓
overall ↓ clearance
drug accumulates eg benzodiazepines
how does body composition change with age?
body fat composition ↑
Vd of lipid-soluble drugs ↑
What is the relationship between half-life and lipid-soluble and water-soluble drugs?
Body fat composition ↑ the half-life of lipid-soluble drugs (eg benzodiazepines)
body fat composition ↑ serum level of water-soluble drugs (eg digoxin)
What can the same dose of benzos cause in elderly pts?
benzos causes confusion, less sedation in elderly compared to young subjects
what is polypharmacy?
concurrent use of several meds, mainly in elderly pts
what can polypharmacy lead to?
can lead to ↑ risk of drug interactions and adverse drug effects
how is renal excretion less effective in babies?
gfr is only 20% of the adult
therefore longer plasma elimination half life
more prolonged effects of drug
how is metabolism less efficient in babies?
Give examples
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
How do physiological changes during pregnancy affect pharmacokinetics?
↓ plasma albumin conc → drug-protein binding altered
↑ CO → ↑ renal perfusion and GFR → ↑ elimination
↓ gastric motility →↓ GI absorption
What does protein binding mean for drugs?
The less bound a drug is, the more efficiently it can traverse or diffuse through cell membranes.
what does decreased protein binding lead to?
Decreased protein binding leads to ↑ concentrations of free drug and favours more distribution to tissues
give an example of low protein binding in pregnancy
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.
how can drugs given to pregnant women affect the fetus?
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
Give examples of diseases which affect PK (A, D, M and E).
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
Give examples of diseases which affect PD
MG:
AI disease - inc sensitivity to drugs that influence neuromuscular transmission
familial hypercholesterolaemia:
LDL receptor deficiency - resistance to statins in homozygous indivduaals
Define drug interactions?
clinically significant change in effect of 1 drug a result of co-administration of another drug
what is the object drug?
the drug affected by interaction
what is the precipitant drug?
the drug caused the altered interaction
what can drugs interact with?
other drugs
herbs
alcohol
chemical substances from diet
What are 3 overall mechs of drug interactions?
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
Give examples of drugs which interact to affect absorption.
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
Give examples of drugs which interact to affect distribution.
NSAIDs can displace MTX from plasma-binding proteins therefore it increases in systemic circulation → MTX toxicity
Phenylbutazone (NSAID) displaces warfarin from albumin → ↑ bleeding
Give examples of drugs which enhance CYP450 activity to affect metabolism.
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
Give examples of drugs which inhibit CYP450 activity to affect metabolism.
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
what effect do cyp450 inducers have on drug?
- induces CYP450 enzyme activity
- this leads to lower bioavailability of drug with high first pass metabolism
what effect do cyp450 inhibitors have on drug?
- inhibits cyp450 activity
- higher bioavailability of drug with high first-pass metabolism
Give examples of drugs which affect renal excretion.
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
Pharmacodynamic drug interactions examples
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
what effect does fast acetylation have on drug conc?
lower drug conc
quicker half-life
hepatotoxicity by metabolism products
what effect does slow acetylation have on drug conc?
higher conc
slower half life
toxicity due to high drug conc
what determines fast/slow acetylation?
a single gene, this can be influenced by ethnicity
What is pharmacogenomics?
study of variability in drug response determined by the genome
looks at how your genetics responds to drugs
What is personalised medicine?
targeted drugs to treat a variety of human diseases in individuals with different genotypes (max effect, min toxic effects)
what are SNPs?
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
How is codeine metabolism affected by CYPD6 gene?
- 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
What are haplotypes and how is it helpful when considering drug response?
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
give examples of pharmacogenomic tests?
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
