15.11 Pharmacology: Factors that complicate pharmacokinetics

Question 1

Factors that complicate drug use usually only pose a problem if….

Answer 1

If drug has low therapeutic index

Question 2

What are three ways a drug can behave unusually?

Answer 2

• Low bioavailability
• Slow distribution
• Drug saturates elimination processes

Question 3

What happens if there is low bioavailability of a drug?

Answer 3

Much greater variation of consequences

Question 4

What do we need to do with low bioavailablity drugs?

Answer 4

Administer by another route (avoid first pass hepatic metabolism-absorption still may be incomplete)

Question 5

What is a drug reservoir? What can this lead to (3)?

Answer 5

A site where the drug accumulates

• can prolong action
• can quickly terminate action
• can lead to slow distribution

Question 6

What are 3 examples of rdug resevoirs?

Answer 6

Plasma proteins (only unbound drug gets to tissues)

Cells (accumulation, active transport/binding)

Fat (lipid soluble drugs, large capacity)

Question 7

What is an example of a peripheral compartment? What is distribution like there?

Answer 7

E.g. fat and muscle, slow distribution

Question 8

What does the graph of a rapid iv administration of a slow-distributing drug look like?

Answer 8

• Initial rapid fall (distribution & elimination)
• Drug reaches equilibrium
• Flattening off, elimination only (from compartments)

Question 9

How does the IV (slow-distributing drug) differ to that of rapid distribution?

Answer 9

The peak concentration is higher in a slow distribution drug than a rapid distribution drug

Question 10

What can be a problem of a rapid IV administration of a slow distributing drug?

Answer 10

Peak concentration is high, may exceed therapeutic window (problem with drugs that have a low therapeutic index)

Question 11

What is an example of a slowly distributing drug? What do we need to do?

Answer 11

Digoxin

Need to divide loading dose to avoid toxic peak concentration

Question 12

What is zero order (saturable) distribution (in reference to rapid iv administration)?

Answer 12

Saturated: constand elimination
Not saturated: exponential elimination

(graph has a straight line then flattens)

Question 13

What occurs if we increase dose rate with zero order elimination multiple dosings? (why are zero order drugs special)

Answer 13

Disproportionate increase in concentration (steady state never reached)

Question 14

What are 2 examples of zero order elimination drugs? What do we need to do for long-term administration (2)?

Answer 14

Asprin, phenytoin

Adjust dose carefully, monitor concentration

Question 15

What is the renal clearance of a newborn?

Answer 15

20% of adult (size adjusted), increases to adult levels within one week

Question 16

What is renal excretion in the elderly like?

Answer 16

50yo. 75%

75yo. 50%

Question 17

What is important in metabolism in babies?

What is the clinical relevance of this?

Answer 17

Deficient in some drug metabolising enzymes (particularly phase II conjugation), increased plasma half life

Can’t women in childbirth morphine, crosses BBB

Question 18

How is metabolism different in the elderly?

Answer 18

Reduced CP450, increased half life

Question 19

How can migranes and pancreatic disease effect absorption of drugs?

Answer 19

Migraine: gastric stasis

Pancreatic disease: steatorrhoea=malabsorption

Question 20

What is an example of drug-drug interactions that are:
Pharmacodynamic

Pharmacokinetic

Answer 20

Dynamic: Drug A modifies effect of B (without affecting concentration)

Kinetic: Drug A modifies concentration of B at its receptor

Question 21

With drug drug interactions, what 2 characteristics must there be to be clinically important?

Answer 21

B must have narrow therapeutic index

Concentration-response curve to B should be steep (small change=large effect)

Question 22

What does displacement from plasma protein binding sites mean?

Answer 22

A transient increase in free (unbound) drug (toxicity?)
Increased elimination (reduced total drug, similar free drug prior to displacement)

Question 23

What is an example of plasma-protein displacement?

Answer 23

Asprin displacing phenytoin (tempting to erronoeously increase dose of phenytoin)

Question 24

What happens if CYP450 is induced?

Answer 24

Reduced half life/concentration in plasma (Warfarin) or increased bioactivation (increased toxicity-paracetamol)

Question 25

How can drug excretion be altered? (3)

Answer 25

Protein binding
Tubular secretion
Urine flow/pH