Tutorial: Drug variability Flashcards
What determines the amount of drug reaching the end organ
ADME
What might be reasons for variabulity
Absolute differences in dose administered
Relative overdose or underdose
Reasons for absolute difference in dose administered
This may be deliberate or accidental eg. due to:
a) error in prescription or dispensing
b) patient non-compliance
c) drug formulation
Reasons for relative underdose or overdose
Environmental exposure to chemicals, including other drugs
Food intake – drugs may interact chemically with components of food; this may alter their absorption
Fluid intake
Age
Disease
How can Environmental exposure to chemicals, including other drugs affect overdose or underdose
enzyme induction
enzyme inhibition
Why would a patient be told to take a drug with food
foods delay gastric emptying and alter gastric pH.
means that drug is absorbed in the stomach
In which case would a patient take drug with water
most drugs are better absorbed if taken with water eg may dissolve better
fluids may stimulate gastric emptying. (so taken for drugs absorbed in intestine)
How might age affect relative underdose or overdose
NEWBORNS:
- more body water than adults
- poorer renal function, with immature tubular secretion
- an immature blood brain barrier
- lower capacity for drug metabolism
ELDERLY
deterioration n physiological function
How might absorption in elderly influence relative underdosing or overdosing
- ABSORPTION
- decreased absorptive surface of small intestine
- altered gastric and gut motility
- increased rate of gastric emptying
How might distributionin elderly influence relative underdosing or overdosing
- DISTRIBUTION: reduced lean body mass and body water, relative increase in fat
- lipid soluble drugs have increased Vd and decreased blood levels
- water soluble drugs have decreased Vd and increased blood levels
- reduced plasma albumin, so fewer plasma protein binding sites so increased amount of drug
How might metabolism in elderly influence relative underdosing or overdosing
- METABOLISM:
- splanchnic and hepatic blood flow decrease by 0.3 – 1.5%/year
- liver size and hepatocyte number decrease
- hepatic enzyme activity and induction capacity decrease
How might excretion in elderly influence relative underdosing or overdosing
reduced renal mass
reduced renal perfusion
reduced glomerular filtration rate
reduced tubular excretion
These changes are normal – the situation may be compounded if the patient has renal disease
REDUCED EXCRETION OF DRUG AND ACCUMULATION
What is the most important affecting drug handling in elderly
changes in renal function are probably the most important factors affecting drug handling in the elderly
How might organ sensitivity in elderly influence relative underdosing or overdosing
the elderly tend to be more sensitive to CNS active drugs
How might general nutritional status affect overdosing or underdosing
unbalanced diets may lead to deficiency states and enzyme abnormalities
starvation – decreased plasma protein binding and metabolism
obesity – increased lipid fraction
How might GI status affect overdosing or underdosing
altered drug absorption
eg achlorhydria (lack of HCl in stomach… affects gastric pH and absorpton) , coeliac and Crohn’s
How might congestive heart failure affect overdosing or underdosing
reduced splanchnic blood flow
intestinal mucosal oedema
reduced hepatic clearance
How might kidney failure affect oversdosing or underdosing
decreased drug excretion leading to toxicity
water overload leading to changes in drug concentrations in different body fluid compartments
How might liver failure affect oversdosing or underdosing
reduced metabolism
reduced first pass metabolism (hence increased bioavailability)
decreased biliary secretion and hence decreased removal
decreased albumin synthesis and hence reduced plasma protein binding
Why would it be bad for patients to take bisphosphonates with milk
They are used osteoporosis.
Patients might think good to take with milk
But ions in milk chelate the bisphosphonates and affect the absorption
What type of antibiotic is clarithryomycin
Macrolide
What does the warfarin dose depend on
ADME…. it is standarised for each patient in relation to this
How does clarithromycin affect warfarin
Warfarin metabolised by CYTP450
Clarithromycin inhibits CYTP450 which inhibits the warfarin metabolism and incrases plasma levels of it
Which other drugs might reduce warfarin metabolism
Other amcrolide ABs
CYTP450 inhibitors:
ABs of other classes e.g. quinolones
Some systemic antifungals
PPIs
Some anti-HIV drugs
What is INR
International normalised ration
INR=(pro-thrombin time (TEST)/ pro-thrombine time (CONTROLLED SAMPLE))^ISI
What is ISI
International sensitivity index
(the tissue factor used in the clotting assay can be different and this also affects prothrombin time)…
between 1-1.4
it is standardised
What is the normal INR
0.9-1.2
What does reduced INR mean
increased INR?
Reduced INR= Increased propensity for clotting
Increased INR= increased propensity to bleed
What might INR be in clotting and bleeding
Clotting=0.5
Bleedng=4
How might St John’s wort affect warfarin
Upregulates CYTP450 to increase metabolism of the warfarin (hypericin)
more metabolism of warfarin so less of it so increased clotting
What else might upregulate the warfarin metabolisn
CYTP450 inducers
Rifampicin (TB)
Griseofulvin (a systemic antifungal drug)
Anti-epilepsy drugs
Which molecule in st johns wort induces CYTP450
Hypericin
What would you want to do to INR if they have AF
You want to increase the INR (but be careful to not increase bleeding)
Action of digoxin
Increases FoC and slows heart
By reducing the Na+/K+ ATPase
What is the effect of hyperkalaemia and hypokalaemia for digoxin
Hyperkalaemia (renal problem?, so digoxin not cleared well, so more digoxin than you would expect
Hypokalamia- well digoxin competes with K+ for the Na/+K+ATPase, so digoxin will have a hige effect here and slow the heart
Would you change the digoxin dose for increased ventricular rate
No, unless normokalaemic
If hypo or hyperkalaemic then no
Why might effect of benzodiazapine for depression be greater on Mr Jones than his daughter
- ADME differences meanin worse metabolism and excretion so increased bioavailability
- OLDER PEOPLE HAVE INCREASED SENSITIVITY TO CNS DRUGS
If Mr Jones had become anxious and lost lots of weight why might INR change
It may increase (increased bleeding)
Because malnutrition reduces CYTP450 activity so increased bioavailability of warfarin and increased propensity to bleed
