15.11 Pharmacology: Factors that complicate pharmacokinetics Flashcards
Factors that complicate drug use usually only pose a problem if….
If drug has low therapeutic index
What are three ways a drug can behave unusually?
- Low bioavailability
- Slow distribution
- Drug saturates elimination processes
What happens if there is low bioavailability of a drug?
Much greater variation of consequences
What do we need to do with low bioavailablity drugs?
Administer by another route (avoid first pass hepatic metabolism-absorption still may be incomplete)
What is a drug reservoir? What can this lead to (3)?
A site where the drug accumulates
- can prolong action
- can quickly terminate action
- can lead to slow distribution
What are 3 examples of rdug resevoirs?
Plasma proteins (only unbound drug gets to tissues)
Cells (accumulation, active transport/binding)
Fat (lipid soluble drugs, large capacity)
What is an example of a peripheral compartment? What is distribution like there?
E.g. fat and muscle, slow distribution
What does the graph of a rapid iv administration of a slow-distributing drug look like?
- Initial rapid fall (distribution & elimination)
- Drug reaches equilibrium
- Flattening off, elimination only (from compartments)
How does the IV (slow-distributing drug) differ to that of rapid distribution?
The peak concentration is higher in a slow distribution drug than a rapid distribution drug
What can be a problem of a rapid IV administration of a slow distributing drug?
Peak concentration is high, may exceed therapeutic window (problem with drugs that have a low therapeutic index)
What is an example of a slowly distributing drug? What do we need to do?
Digoxin
Need to divide loading dose to avoid toxic peak concentration
What is zero order (saturable) distribution (in reference to rapid iv administration)?
Saturated: constand elimination
Not saturated: exponential elimination
(graph has a straight line then flattens)
What occurs if we increase dose rate with zero order elimination multiple dosings? (why are zero order drugs special)
Disproportionate increase in concentration (steady state never reached)
What are 2 examples of zero order elimination drugs? What do we need to do for long-term administration (2)?
Asprin, phenytoin
Adjust dose carefully, monitor concentration
What is the renal clearance of a newborn?
20% of adult (size adjusted), increases to adult levels within one week
What is renal excretion in the elderly like?
50yo. 75%
75yo. 50%
What is important in metabolism in babies?
What is the clinical relevance of this?
Deficient in some drug metabolising enzymes (particularly phase II conjugation), increased plasma half life
Can’t women in childbirth morphine, crosses BBB
How is metabolism different in the elderly?
Reduced CP450, increased half life
How can migranes and pancreatic disease effect absorption of drugs?
Migraine: gastric stasis
Pancreatic disease: steatorrhoea=malabsorption
What is an example of drug-drug interactions that are:
Pharmacodynamic
Pharmacokinetic
Dynamic: Drug A modifies effect of B (without affecting concentration)
Kinetic: Drug A modifies concentration of B at its receptor
With drug drug interactions, what 2 characteristics must there be to be clinically important?
B must have narrow therapeutic index
Concentration-response curve to B should be steep (small change=large effect)
What does displacement from plasma protein binding sites mean?
A transient increase in free (unbound) drug (toxicity?) Increased elimination (reduced total drug, similar free drug prior to displacement)
What is an example of plasma-protein displacement?
Asprin displacing phenytoin (tempting to erronoeously increase dose of phenytoin)
What happens if CYP450 is induced?
Reduced half life/concentration in plasma (Warfarin) or increased bioactivation (increased toxicity-paracetamol)
How can drug excretion be altered? (3)
Protein binding
Tubular secretion
Urine flow/pH
