Transcript drug interactions - Liverpool John Moores University

Pharmacokinetic drug
interactions
Phil Rowe
Reader in Pharmaceutical Computing
Liverpool School of Pharmacy
Pharmacokinetic Drug Interactions
Drug interactions
Lecture 2
Interactions based upon:
• Distribution
• Metabolism
Pharmacokinetic Drug Interactions
Distribution
One drug changes the way in which
another drug is distributed around the
body.
Pharmacokinetic Drug Interactions
Alleged mechanism
Drug B
Plasma
Tissue
Drug A
protein bound
Drug A
free
Drug A
free
Drugs A and B both bind to the same plasma protein
Pharmacokinetic Drug Interactions
What would really happen?
More drug will be driven into all tissues including
eliminating organs such as liver and kidney
Clearance increases and so total drug levels in blood fall.
Can be shown mathematically that this effect will exactly
cancel out the effect of displacement into tissues.
Concentration of free drug in tissues is not altered.
Pharmacokinetic Drug Interactions
Why did anybody ever believe
in displacement interactions?
Commonly quoted example was Warfarin
+ Phenylbutazone
This combination did kill patients ...
But mechanism is not displacement.
(Truth will be revealed later)
Pharmacokinetic Drug Interactions
Clinical significance of
displacement interactions
None
Zero
Zilch
Not a sausage
Absolutely sweet Football Association
Pharmacokinetic Drug Interactions
Metabolism
One drug changes the rate of
metabolism of another drug
A increases the rate of metabolism of B = Induction
A reduces the rate of metabolism of B = Inhibition
Pharmacokinetic Drug Interactions
Metabolism
(Induction)
Drug A speeds up the metabolism of Drug B.
Blood concentrations of B fall below normal
therapeutic levels.
B becomes ineffective
Pharmacokinetic Drug Interactions
General increase in hepatic
function
• Liver grows larger and blood flow increases
• Drug metabolising enzymes (inc Cyt P450)
increased
• Increased clearance of a wide range of drugs,
environmental chemicals and endogenous
substances
Pharmacokinetic Drug Interactions
Examples of
drugs causing
liver enzyme
induction
•Rifampicin
•Griseofulvin
•Carbamazepine
•Barbiturates
•Phenytoin
(Three anti-epileptics! Valproate is NOT inducer)
Pharmacokinetic Drug Interactions
Examples of induction
interactions
Inducer
Drug with reduced effect
Barbiturates
Warfarin
Griseofulvin Warfarin
Phenytoin
Oral contraceptives
Rifampicin
Theophylline
Pharmacokinetic Drug Interactions
Withdrawal of inducer
Patient taking barbiturates and warfarin
Barbiturates cause induction - warfarin clearance increased
Warfarin dose titrated above normal dose (Blood levels normal)
Barbiturates suddenly withdrawn and replaced by valproate
Warfarin clearance falls - blood levels rise above normal
Patient dies
Pharmacokinetic Drug Interactions
Beneficial use of induction
New born infants have poorly developed hepatic
metabolic enzymes.
Conjugate bilirubin inefficiently - some become
jaundiced
Small doses of barbiturates can be used to induce
the liver enzymes and clear the bilirubin
Pharmacokinetic Drug Interactions
Monitoring induction
How do find out whether a drug or environmental
chemical is an inducer?
• Measure hepatic Cyt P450
• Pharmacokinetics of a model substance
• Endogenous metabolites
Pharmacokinetic Drug Interactions
Measure Cyt P450
Expose animals/humans to substance
Controls exposed to placebo
Obtain liver tissue and measure P450
• Most definitive test of induction.
• Extremely difficult in humans.
• No guarantee that humans and an animal model
will respond in same way.
Pharmacokinetic Drug Interactions
Kinetics of model substance
Antipyrine commonly used because:
• Not strongly protein bound
• Almost exclusively eliminated by hepatic
metabolism
• Has no sig. inducing/inhibiting properties of
its own
Pharmacokinetic Drug Interactions
Antipyrine
Compare t½ or clearance (Cl better) with/without
exposure to the suspect substance.
e.g. Comparison of workers exposed to insecticides with
controls:
Mean antipyrine t½
Controls
13.1 h
Exposed
7.7 h
Pharmacokinetic Drug Interactions
Endogenous metabolites
e.g. 6b-hydroxycortisol
Hormone cortisol - small % normally metabolised
to 6b-hydroxycortisol (6HC) by hepatic Cyt P450.
Inducer - more P450 - greater % of cortisol
converted to 6HC.
Measure 6HC in urine to monitor induction.
Pharmacokinetic Drug Interactions
Significance of induction
interactions
Real significance.
Loss of effectiveness of warfarin or theophylline
could be fatal
Loss of effectiveness of oral contraceptives even worse
Pharmacokinetic Drug Interactions
Metabolism
(Inhibition)
Drug A slows down the metabolism of Drug B.
Blood concentrations of B increase above normal
therapeutic levels.
Increased chance of toxicity from B.
Pharmacokinetic Drug Interactions
INHIBITION
Drug A
Cyt
P450
NADPH
O2
Pharmacokinetic Drug Interactions
INHIBITION
Not simple opposite of induction.
Induction - Additional P450 in the liver
Inhibition - No reduction in quantity of P450.
Existing P450 made less effective.
Pharmacokinetic Drug Interactions
A problem ???
Same substance may appear in lists of both inducers
and inhibitors!!!
Explanation - May both increase the quantity of
P450 and inhibit it as well.
Actual effect seen depends upon the balance of the
two effects.
Pharmacokinetic Drug Interactions
Example
e.g. Alcohol usually seen as an inducer,
but acute intoxication may not give
enough time for new enzyme to be
synthesised. We only see inhibitory
effect (instant).
Pharmacokinetic Drug Interactions
 Antifungals
– e.g. Itraconazole
 Cimetidine
EXAMPLES OF
INHIBITORS
 Disulphiram
 Fluvoxamine
& Fluoxetine
 Macrolide antibiotics
– e.g. Erythromycin
 Phenylbutazone
– (Powerful but limited use)
 4-Quinolones
– e.g. Ciprofloxacin
Pharmacokinetic Drug Interactions
(Not exclusive)
THE TRUTH!!
This is the real explanation for the
interaction between phenylbutazone and
warfarin.
Phenylbutazone inhibits the hepatic
metabolism of warfarin. Especially the
S isomer (the most active).
Nothing to do with binding displacement.
Pharmacokinetic Drug Interactions
Significance of interactions
based upon inhibition
Probably the most significant interactions
of all. Several potentially FATAL.
If you want to kill a patient, this is
probably best way.
Pharmacokinetic Drug Interactions
Herbal remedies
The fact that it's "natural" doesn't
automatically mean it's safe.
Inhibitors
Inducers
Milk thistle
(Silibinin)
St John's wort
Garlic
Peppermint oil
(Menthol)
Pharmacokinetic Drug Interactions
Herbal remedies
Example. St John's wort may significantly reduce
the effectiveness of the following by induction of
hepatic Cyt P450 and intestinal P-Glycoproteins
• Anticonvulsants
• Cyclosporin
• Digoxin
• Protease inhibitors
• Oral contraceptives
• Theophylline
• Warfarin
Pharmacokinetic Drug Interactions
Fruit juices
• Grapefruit juice contains antioxidants (probably
flavonoids) that inhibit CYP3A4 in the gut wall and liver.
Leads to increased blood levels of terfenadine and some
calcium channel blockers (Appendix 1 of BNF gives
details).
• Cranberry juice contains various antioxidants including
flavonoids, which are known to inhibit cytochrome P450.
Warfarin levels may rise significantly. (See Pharm.J. 27th
Sept 2003)
Pharmacokinetic Drug Interactions
Terms with which you should
be familiar
• Induction
• Inhibition
Pharmacokinetic Drug Interactions
What you should be able to do
• Explain why interactions do not arise due to
displacement from protein binding
•Describe the mechanisms of induction and inhibition
• Cite examples of drugs that may induce or inhibit
metabolism
• Describe the consequences of induction or inhibition
• Recognise the danger of sudden withdrawal of an inducer
• Describe methods for monitoring induction
Pharmacokinetic Drug Interactions