139 - Factors that complicate pharmacokinetics Flashcards
Zero order pharmacokinetics
Excreted at a constant rate
Effect of low bioavailability
If low, then variability will have a greater effect. Need to administer via different routes, EG nicotine patches, gaseous general anaesthetics, insufflation, rectal.
Types of unusual drug behaviour 1 2 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)
Rationale behind alternative administration routes for drugs with low bioavailability
Bypass first-pass hepatic metabolism
Drug reservoirs
Sites in the body where drug accumulates
Possible effects of drug reservoirs
• 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
Examples of drug reservoirs 1 2 3
• Plasma proteins • Cells • Fat
Plasma protein drug reservoirs 1 2 3
– only unbound drug gets from plasma to tissues –may get displacement from similar drugs – eg. aspirin can displace warfarin
Cellular drug reservoirs 1 2
– accumulation due to active transport or specific binding – eg. antimalarial quinacrine highly concentrated in liver
Fat drug reservoirs 1 2
– highly lipid-soluble drugs – blood supply is poor and capacity large, so may lead to slow distribution
Rapid iv administration of slow-distributing drug 1 2 3 4
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
*Rapid iv administration of slow-distributing drug
Effect of peak concentration in blood if a drug is absorbed quickly into a reservoir versus if it is absorbed slowly
Slowly-absorbed drugs have a higher initial concentration in blood (slowly-absorbed is initially confined to central compartment)
When is it a problem for a drug to be distributed slowly to reservoir?
If the drug has a narrow therapeutic window, as peak concentration can exceed maximum limit of therapeutic window
Example of a slowly-distributing drug
Digoxin
Calculation of peak concentration of a slowly-distributing drug from Vd at equilibrium
– peak concentration is higher than predicted from Vd (at equilibrium)
Digoxin administration 1 2 3 4
– Slowly distributes into reservoirs – Narrow therapeutic index – Long half life so requires loading dose – Loading dose must be divided to avoid toxic peak concentration
Type of drugs that normally display zero-order elimination
Those that are administered in high concentrations (elimination is saturated)
*Zero-order elimination of drugs
When do drugs with zero-order kinetics become problematic? 1 2 3
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
Examples of drugs with zero-order elimination
Aspirin Phenytoin
Phenytoin 1 2 3
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)
Things that can cause interpatient variability with pharmacokinetics
• Age • Genetic factors • Idiosyncratic reactions • Disease • Drug-drug interactions
Effects of age on kinetics 1 2 3
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
Renal clearance of newborns
~renal clearance rate is 20% of that of an adult
Effect of premature birth on renal clearance rate
Lowers renal clearance rate
How long does it take for newborn renal clearance rate to reach adult levels?
~1 week
When does renal function begin decreasing?
Age 20
Renal function at 50yo
~75%
Problem with renal function decreasing with age
Issue for drugs administered over years, EG digoxin
Issue with newborn drug metabolism 1 2 3
• Deficient in some drug metabolising enzymes (particularly phase II conjugation) • 6 weeks to reach adult levels • Increased plasma half life – eg. chloramphenicol, morphine
Metabolism in the early 1 2
• Reduced activity of cytochrome p450 • Increased half life – eg. diazepam
Why can’t morphine be given to a pregnant woman?
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.
Pharmacodynamic drug-drug interactions
• Drug A modifies effect of drug B without affecting its concentration
Pharmacokinetic drug-drug interactions
• Drug A modifies concentration of drug B at its receptor
When are drug-drug interactions clinically important? 1 2
• 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
Ways in which pharmacodynamic drug-drug interactions can come about 1 2
1) Receptor antagonism 2) Physiological effects
Ways in which pharmacokinetic drug-drug interactions can come about
Can affect • absorption • distribution • metabolism • excretion
In drug-drug interactions, how can absorption be affected? 1 2
• Gastric emptying rate – decreased by opiates – increased by metoclopramide • Formation of poorly-absorbed complex in gut – calcium (EG from milk) and tetracyclines
In drug-drug interactions, how can distribution be affected? 1 2
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
Example of plasma-protein displacement in drug-drug interactions 1 2 3
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
Example of drug-drug interactions altering drug metabolism 1 2 3
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
Examples of drugs that can inhibit cytochrome p450
Steroids, cimetidine. Causes problems with drugs that have a narrow therapeutic window, are metabolised by CYP450 (EG digoxin, phenytoin)
Examples of how drug-drug interactions can affect drug excretion in urine 1 2 3
• Protein binding – Affects filtration • Tubular secretion – Probenecid as a banned substance in sport • Urine flow/pH – Sodium bicarbonate in treatment of aspirin overdose
