139 - Factors that complicate pharmacokinetics

Question 1

Zero order pharmacokinetics

Answer 1

Excreted at a constant rate

Question 2

Effect of low bioavailability

Answer 2

If low, then variability will have a greater effect. Need to administer via different routes, EG nicotine patches, gaseous general anaesthetics, insufflation, rectal.

Question 3

Types of unusual drug behaviour 1 2 3

Answer 3

• bioavailability is low – if low, more sensitive to variability • slow distribution – some drug eliminated during distribution • drug in sufficiently high concentration to saturate elimination process(es) – elimination rate is constant (zero order kinetics)

Question 4

Rationale behind alternative administration routes for drugs with low bioavailability

Answer 4

Bypass first-pass hepatic metabolism

Question 5

Drug reservoirs

Answer 5

Sites in the body where drug accumulates

Question 6

Possible effects of drug reservoirs

Answer 6

• can prolong action – released from store as concentration falls • can quickly terminate action – if stored drug has high capacity • can lead to slow distribution – if capacity of store is great

Question 7

Examples of drug reservoirs 1 2 3

Answer 7

• Plasma proteins • Cells • Fat

Question 8

Plasma protein drug reservoirs 1 2 3

Answer 8

– only unbound drug gets from plasma to tissues –may get displacement from similar drugs – eg. aspirin can displace warfarin

Question 9

Cellular drug reservoirs 1 2

Answer 9

– accumulation due to active transport or specific binding – eg. antimalarial quinacrine highly concentrated in liver

Question 10

Fat drug reservoirs 1 2

Answer 10

– highly lipid-soluble drugs – blood supply is poor and capacity large, so may lead to slow distribution

Question 11

Rapid iv administration of slow-distributing drug 1 2 3 4

Answer 11

1) Drug rapidly distributes to central compartment (well-perfused organs) 2) Slowly distributes to peripheral organ (where it is stored in a reservoir, EG in fat, muscle) 3) Distribution equilibrium is established, according to volume of distribution 4) Elimination occurs from central compartment (blood, kidneys, liver), changing equilibrium, pulling drug out of reservoir

Question 12

*Rapid iv administration of slow-distributing drug

Answer 12

Question 13

Effect of peak concentration in blood if a drug is absorbed quickly into a reservoir versus if it is absorbed slowly

Answer 13

Slowly-absorbed drugs have a higher initial concentration in blood (slowly-absorbed is initially confined to central compartment)

Question 14

When is it a problem for a drug to be distributed slowly to reservoir?

Answer 14

If the drug has a narrow therapeutic window, as peak concentration can exceed maximum limit of therapeutic window

Question 15

Example of a slowly-distributing drug

Answer 15

Digoxin

Question 16

Calculation of peak concentration of a slowly-distributing drug from Vd at equilibrium

Answer 16

– peak concentration is higher than predicted from Vd (at equilibrium)

Question 17

Digoxin administration 1 2 3 4

Answer 17

– Slowly distributes into reservoirs – Narrow therapeutic index – Long half life so requires loading dose – Loading dose must be divided to avoid toxic peak concentration

Question 18

Type of drugs that normally display zero-order elimination

Answer 18

Those that are administered in high concentrations (elimination is saturated)

Question 19

*Zero-order elimination of drugs

Answer 19

Question 20

When do drugs with zero-order kinetics become problematic? 1 2 3

Answer 20

1) When multiple dosings are required. 2) Steady state is never reached, concentration just increases as elimination rate is constant. 3) Changing dose rate can disproportionately increase rate of concentration increase

Question 21

Examples of drugs with zero-order elimination

Answer 21

Aspirin Phenytoin

Question 22

Phenytoin 1 2 3

Answer 22

1) Anti-epileptic drug, anticonvulsant. 2) Zero-order kinetics. 3) Taken over long periods, any changes to dose rate gives big changes in drug concentration, so need to monitor dosing regime very carefully (EG take regular blood samples to monitor blood concentrations)

Question 23

Things that can cause interpatient variability with pharmacokinetics

Answer 23

• Age • Genetic factors • Idiosyncratic reactions • Disease • Drug-drug interactions

Question 24

Effects of age on kinetics 1 2 3

Answer 24

Relates to • Renal excretion • Hepatic metabolism Reduced in • Neonates • Elderly Leads to increased half life of some drugs • May require reduced dose if multiple dosing

Question 25

Renal clearance of newborns

Answer 25

~renal clearance rate is 20% of that of an adult

Question 26

Effect of premature birth on renal clearance rate

Answer 26

Lowers renal clearance rate

Question 27

How long does it take for newborn renal clearance rate to reach adult levels?

Answer 27

~1 week

Question 28

When does renal function begin decreasing?

Answer 28

Age 20

Question 29

Renal function at 50yo

Answer 29

~75%

Question 30

Problem with renal function decreasing with age

Answer 30

Issue for drugs administered over years, EG digoxin

Question 31

Issue with newborn drug metabolism 1 2 3

Answer 31

• Deficient in some drug metabolising enzymes (particularly phase II conjugation) • 6 weeks to reach adult levels • Increased plasma half life – eg. chloramphenicol, morphine

Question 32

Metabolism in the early 1 2

Answer 32

• Reduced activity of cytochrome p450 • Increased half life – eg. diazepam

Question 33

Why can’t morphine be given to a pregnant woman?

Answer 33

Babies can’t metabolise morphine initially (is metabolised with phase II conjugation, which babies can’t do). Baby has a dose of morphine that it can’t metabolise.

Question 34

Pharmacodynamic drug-drug interactions

Answer 34

• Drug A modifies effect of drug B without affecting its concentration

Question 35

Pharmacokinetic drug-drug interactions

Answer 35

• Drug A modifies concentration of drug B at its receptor

Question 36

When are drug-drug interactions clinically important? 1 2

Answer 36

• Affected drug must have narrow therapeutic index – small reduction in concentration will lead to loss of effect – small increase in concentration will lead to toxicity • Concentration-response curve to affected drug should be steep – small change in concentration gives large change in effect

Question 37

Ways in which pharmacodynamic drug-drug interactions can come about 1 2

Answer 37

1) Receptor antagonism 2) Physiological effects

Question 38

Ways in which pharmacokinetic drug-drug interactions can come about

Answer 38

Can affect • absorption • distribution • metabolism • excretion

Question 39

In drug-drug interactions, how can absorption be affected? 1 2

Answer 39

• Gastric emptying rate – decreased by opiates – increased by metoclopramide • Formation of poorly-absorbed complex in gut – calcium (EG from milk) and tetracyclines

Question 40

In drug-drug interactions, how can distribution be affected? 1 2

Answer 40

Displacement from plasma protein binding sites • Transient increase in free (unbound) drug – Transient toxicity • Increased elimination to give reduced total drug but similar free drug prior to displacement – Altering of target therapeutic range

Question 41

Example of plasma-protein displacement in drug-drug interactions 1 2 3

Answer 41

Aspirin displacing phenytoin • Normally measure total phenytoin in plasma • Aspirin will reduce total phenytoin, but leave free phenytoin unchanged • Tempting to erroneously increase dose of phenytoin – toxicity

Question 42

Example of drug-drug interactions altering drug metabolism 1 2 3

Answer 42

Induction of cytochrome p450 system by eg. • Rifampicin • Ethanol Leads to • Reduced half life/reduced concentration in plasma – eg. Warfarin • Increased bioactivation leading to increased toxicity – eg. Paracetamol

Question 43

Examples of drugs that can inhibit cytochrome p450

Answer 43

Steroids, cimetidine. Causes problems with drugs that have a narrow therapeutic window, are metabolised by CYP450 (EG digoxin, phenytoin)

Question 44

Examples of how drug-drug interactions can affect drug excretion in urine 1 2 3

Answer 44

• Protein binding – Affects filtration • Tubular secretion – Probenecid as a banned substance in sport • Urine flow/pH – Sodium bicarbonate in treatment of aspirin overdose