Drug-drug and drug-disease interactions Flashcards
what is drug interaction?
modification of one drug’s action by another drug
what do drugs include?
prescribed drugs herbal remedies OTC medications dietary factors lifestyle factors - smoking and alcohol
what do drugs interact with?
drugs
disease
variation in drug response
physiological changes
genetics
drug-drug interactions
disease state
variation in drug response - physiological changes
age sex pregnancy size weight
variation in drug response - genetics
ethnicity
enzymatic
variation in drug response - disease state
hepatic renal GI cardiac CNS
individual variations to drugs
variability in the effect of a drug can occur in different individuals or the same individual on a different occasion
what can variability cause?
loss of efficacy
unexpected side effects
what are the types of drug response variability?
different concentrations of drug reaching site of action - pharmacokinetic
different degree of response to the same drug concentration - pharmacodynamic
different unpredictable response - idiosyncratic
the effects of youth
drug metabolism is slower - immature organ function
renal excretion is less efficient
drug sensitivity changes - receptor numbers
physiological factors
effects of elderly
drug metabolism is slower - failing organ function renal excretion is less efficient drug sensitivity changes poly-pharmacy co-morbidities body fat to mass
pregnancy and drug response
decrease in plasma protein binding
increased plasma volume and ECF
increased cardiac output
increased renal blood flow and GFR (increased renal drug elimination)
pharmaco-genetics
how different individual genotypes relate to different drug responses
pharmaco-genomics
pharmacogenetics applied to the whole human genome
ethnicity and drug responses
genetic differences account for some variations
ACE inhibitors in Afro-caribbeans
reduced hypotensive effect
increased angioedema
alcohol
some groups less tolerant of alcohol
altered ethanol metabolism
idiosyncratic reactions
usually harmful reaciton in tiny % of patients
unexpected and unusual
often genetic and immunological basis
beneficial drug interactions/ combinations
enhanced effect
reduce metabolism
minimise side effects/ toxicity
harmful drug interactions
15% of adverse drug reactions
certain groups at high risk
who are at high risk of harmful drug interactions?
elderly
hepatic/ renal disease
polypharmacy
patients taking drugs with narrow therapeutic ranges
combos - enhanced drug effect
triple therapy for TB reduces development of resistance
combos - reduced metabolism of drugs
L-dopa and peripheral dopa decarboxylase inhibitor reduces peripheral breakdown to maximise CNS effect in parkinson’s
combos - minimise side effects/ toxicity
loop diuretics cause potassium loss, prescribed with potassium sparing diuretic
or antagonists in overdose
opiate overdose
naloxone
where do drug interactions occur?
pharmaceutical level - chemical interaction when mixed
pharmacokinetic level - interference with absorption, distribution, metabolism and excretion
pharmacodynamic level -drugs may interfere with others at site of action
what are the stages of pharmacokinetics
absorption
distribution
metabolism
excretion
pharmacodynamic interactions
agonism
antagonism
non-selective nature of drug
enhanced effect by other means
agonism
2 drugs of same/ similar class
antagonism
given the antagonist and agonist
beta blockers and beta 2 agonists
opiate analgesics and naloxone
non-selective nature of drug
interact with many receptor sub types
antidepressants
enhanced effect by other means
digoxin toxicity increased by hypokalaemia caused by a loop diuretic for example
absorption
changes in gut motility
interfere with absorption and enterohepatic circulation
altered P-glycoprotein activity
changes in gut motility
slow or speed it up e.g. opiates or metoclopramide
altered P-glycoprotein activity
transporter - alters how much is absorbed
metoclopramide
increases gastric emptying
delivers drugs to small bowel quickly
absorbed more rapidly
distribution
many drugs alter distribution by displacing another from plasma or tissue binding sites
causes transient increase in unbound drug
corrected by increased elimination
hepatic drug metabolism
2 phase metabolism
phase 1
CYP450
low substrate specificity
metabolises wide range of drugs
phase 2
increases solubility and allows easier renal elimination
INR
ratio of pro-thrombin time compared between patient and normal
liver enzyme induction
enzyme inducing drug which increase CYP450 activity (anticonvulsants)
break down more of the drug and increase drug metabolism
anticonvulsants
carbamezepine increases metabolism of warfarin so it is no longer effective
drugs that induce CYP450
increase metabolism of certain other drugs
may increase their own metabolism
CYP450 induction
200+ drugs induce CYP450
relatively slow onset
new enzyme production required
induction can persist after withdrawal whilst enzyme levels normalised
removing an inducer will disturb equilibrium and so may reduce CYP450 activity, causing build up of drug
st Johns Wort
effective herbal remedy for depression
induces CYP3A4 and increases metabolism of certain drugs
what does St Johns wort increase metabolism of?
oral contraceptives
digoxin
phenytoin (anticonvulsant)
warfarin
CYP450 inducers
anticonvulsants antibiotics steroids alcohol weed cigarettes st johns wort HIV therapies
melaena
black poo caused by upper GI bleeding
macrolide antibiotics and warfarin
kill bacteria in gut vitamin K synthesis falls increases anticoagulant effect increased INR inhibit CYP450 enzyme system warfarin metabolism reduced and increased INR
CYP 450 inhibition
quick onset
reduced metabolism of drugs
increased effect and toxicity
CYP450 inhibitors
anti-arrhythmics antibiotics - erythromycin antidepressants HIV drugs statins
treatment failure or toxicity
CYP450 inducers = treatment failure and inhibitors = toxicity
QTc interval prolongation
people with elongated QT intervals are more prone to arrhythmias
torsade des pointes
QT interval
between start of QRS complex to end of P wave
what causes prolonged QT intervals?
congenital malformations
drugs
genetic and acquired forms
what drugs prolong QTc interval?
anti-arrhythmics
any drug that impairs metabolism of a QTc prolonging drug
terfenadine
anti-histamine in body rapidly changed to fexofenadine
another drug - anti-fungal for example blocks conversion to fexofenadine, causing build up of terfenadine which is a potent calcium channel blocker in heart which causes cardiac effects.
drugs and long QT syndrome
anti-arrhythmics antibiotics anti-fungals anti-histamines psychotropic drugs motility agents
drugs which often cause interactions
anticonvulsants anti-arrhythmics antidepressants antibiotics anticoagulants
hepatic disease
decreased clearance of hepatically metabolised drugs
renal disease
reduced clearance of renally excreted drugs
cardiac disease
reduced metabolism of drugs dependent on hepatic blood flow
cannot reach site of metabolism/ excretion
what foods commonly cause drug interactions?
grapefruit and cranberry juice
grapefruit juice
inhibits CYP450 isoenzymes reduces clearance of drugs amiodarone terfenadine simvastatin increases drug exposure
cranberry juice
used for treatment of urinary sepsis
inhibits bacterial adherence to urothelium
inhibits CYP2C9 isoform
decreases clearance of warfarin
increases risk of haemorrhage
dont drink excessive amounts when on warfarin
