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Pharmacokinetic drug interactions

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Milk thistle St John's wort (Silibinin) Garlic. Peppermint oil (Menthol) ... St John's wort may significantly reduce the effectiveness of the following by ... – PowerPoint PPT presentation

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Title: Pharmacokinetic drug interactions


1
Pharmacokinetic drug interactions
Phil Rowe Reader in Pharmaceutical
Computing Liverpool School of Pharmacy
2
Drug interactions Lecture 2
  • Interactions based upon
  • Distribution
  • Metabolism

3
Distribution
One drug changes the way in which another drug is
distributed around the body.
4
Alleged mechanism
Plasma
Tissue
Drug B
Drug A protein bound
Drug A free
Drug A free
Drugs A and B both bind to the same plasma protein
5
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.
6
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)
7
Clinical significance of displacement interactions
None Zero Zilch Not a sausage Absolutely sweet
Football Association
8
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
9
Metabolism (Induction)
Drug A speeds up the metabolism of Drug B. Blood
concentrations of B fall below normal
therapeutic levels. B becomes ineffective
10
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

11
Examples of drugs causing liver enzyme induction
  • Rifampicin
  • Griseofulvin
  • Carbamazepine
  • Barbiturates
  • Phenytoin

(Three anti-epileptics! Valproate is NOT inducer)
12
Examples of induction interactions
Inducer Drug with reduced effect Barbiturates
Warfarin Griseofulvin Warfarin Phenytoin
Oral contraceptives Rifampicin Theophylline
13
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
14
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
15
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

16
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.

17
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

18
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
19
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.
20
Significance of induction interactions
Real significance. Loss of effectiveness of
warfarin or theophylline could be fatal Loss of
effectiveness of oral contraceptives - even worse
21
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.
22
INHIBITION
23
INHIBITION
Not simple opposite of induction. Induction -
Additional P450 in the liver Inhibition - No
reduction in quantity of P450.
Existing P450 made less effective.
24
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.
25
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).
26
EXAMPLES OF INHIBITORS (Not exclusive)
  • Antifungals
  • e.g. Itraconazole
  • Cimetidine
  • Disulphiram
  • Fluvoxamine Fluoxetine
  • Macrolide antibiotics
  • e.g. Erythromycin
  • Phenylbutazone
  • (Powerful but limited use)
  • 4-Quinolones
  • e.g. Ciprofloxacin

27
THE TRUTH!!
This is the real explanation for the interaction
between phenylbutazone and warfarin. Phenylbutaz
one inhibits the hepatic metabolism of warfarin.
Especially the S isomer (the most
active). Nothing to do with binding
displacement.
28
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.
29
Herbal remedies
The fact that it's "natural" doesn't
automatically mean it's safe.
Inhibitors Inducers Milk thistle St John's wort
(Silibinin) Garlic Peppermint oil (Menthol)
30
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

31
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)

32
Terms with which you should be familiar
  • Induction
  • Inhibition

33
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
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