2. LEARNING OUTCOMES
• Define drug interaction
• Describe the types of drug interactions
• Outline the basic mechanisms of drug-drug
interactions
• Describe drug-food interactions
• Describe the consequences of drug interaction
3. Introduction
• Drug interaction refers to chemical reaction
that occurs when more than one drug or drug
and food are administered together
• Some interactions are both intended or
desired as when drugs are combined to treat
hypertension
• Some interactions are unintended and
undesired
• Interactions occur because patients take more
than one drug due to multiple conditions
4. Consequences of drug interactions
• One drug may intensify the effects of the
other
• One drug may reduce the effects of the other
• The combination may produce a new
response not seen with either drug alone
5. Intensification of effects
• Commonly called “potentiative effect”
• Increased therapeutic effects
• Increased adverse effects
6. Increased therapeutic effects
• Sulbactam administered together with
ampicilin increases effects of ampicillin
• When administered alone, ampicilin
undergoes rapid inactivation by bacteria
enzymes.
• Sulbactam inhibits these enzymes and
prolongs and intensifies the effects of
ampicillin
7. Increased adverse effects
• The interaction between aspirin and Warfarin
• Warfarin suppresses clot formation
• If the dose is too high, it leads to spontaneous
bleeding
• Ironically, the dose has to be high enough to
significally supress clot formation
• Aspirin also suppresses clot formation.
• If administered together with Warfarin, severe
bleeding can occur
8. Reduction of the effects
• Such effects are called inhibitory effects
• Can be beneficial or detrimental
• Inhibitory effects that reduce toxicity are
beneficial
• Inhibitory effects that reduce therapeutic
effects are detrimental
9. Reduced therapeutic effects
• Interaction between propranolol and
Albuterol is such an example
• Albuterol is an antiasthmatic drug which
dilates bronchi
• Propranolol is an antihypertensive
• When taken together, propranolol blocks the
effects of Albuterol
10. Reduced adverse effects
• The use of naloxone to treat
morphine/pethidine overdose is an example
• Naloxone completely blocks the effects of
morphine or pethidine
11. Creation of a unique response
• Rarely combination of drugs produce a new
response
• Alcohol and Disulfiram (antiabuse), a drug
used to treat alcoholism
• A range of responses can occur that are not
seen when either drug is administered alone
12. Basic mechanisms of drug-drug
interactions
• Direct chemical or physical interaction
• Pharmacokinetic interaction
• Pharmacodynamic interaction
• Combined toxicity
13. Direct chemical or physical
interaction
• Usually render both drugs inactive
• Occur when drugs are combined in IV or
injectable solutions
• Frequently but not always, the interaction
produces a precipitate
• Discard such a solution
• NB: not all chemical interactions produce a
precipitate
• Never combine two or more drugs in one
container unless you are sure of their nature
14. Chemical or physical interaction
• Interactions can also occur within a human
body
• BUT the body fluids helps to dilute the drugs
and reduce the effects of chemical interaction
• Hence effects are much less likely than in IV
solutions
15. Pharmacokinetic interactins
• Drugs can affect all the 4 pharmacokinetic
processes
• Altered absorption: mechanisms
– By elevating gastric pH- antiacids can decrease the
ionization of basic drugs in the stomach,
increasing the ability of some drugs to cross
membranes. Acidic drugs have the opposite effect
on
– Laxatives-can accelerate passage of other oral
drugs through the intenstines
16. • Altered absorption
– Suppress peristalsis e.g morphine, atropine-
increasing time of absorption
– Inducing vomiting-leading to decreased
absorption
– Drugs that themselves are not absorbed e.g
cholestyramine, can absorb other drugs onto
themselves leading to decreased absorption of
those drugs
– Reduction of regional blood flow-e.g epinephrine
injected together with anesthesia
17. • Reduced absorption
– Epinephrine cause vasoconstriction leading to
decreased/delayed absorption of the anesthesia
18. Altered distribution
• Competition for protein binding
– When 2 drugs bind to the same albumin,
coadministration of such drugs leads to
competition
– Binding of one or both drugs is reduced
– Plasma levels of free drug increase-
– Theoretically, increase in free plasma drug leads to
increased effect
– However, since the newly freed drug rapidly
undergoes metabolism and elimination, sustained
increased free drug level rarely occur
19. Altered distribution
• Alteration of extracellular pH
– Increased pH in ECF- such a drug will increase
ionization of acidic drug in ECF.
– As a result the administered acidic drug will be
drawn from within cell where the pH was low to
ECF where the pH is high
– Changing the distribution of the drug
– Clinical use in management of poisoning
– E.g aspirin poisoning- give sodium bicarbonate.
20. Altered metabolism
• The most important and most complex
mechanism of drug interaction
• Some drugs increase while others decrease
metabolism of other drugs
• Drugs that increase metabolism of other drugs
do so by inducing synthesis of hepatic drug-
metabolizing enzymes
• Drugs that decrease metabolism of other
drugs inhibit hepatic enzymes
21. Altered metabolism
• The majority of drug metabolism is catalyzed
by CYP450 group of enzymes which is
composed of a a large number of isoenzymes
• Of the P450 isoenzymes, 5 are responsible for
the metabolism of most drugs
• CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4
22. Altered metabolism
• Drugs that stimulate the synthesis of CYP
isoenzymes are referred to as inducing agents
• E.g is phenobarbital, a member of barbiturate
family
• They induce metabolism of themselves and
other drugs by as much as 2-3 fold
• The increase develops over 7-10 days & rate
returns to normal 7-10 days after withdrawal
of the drug
23. Altered metabolism
• When taken with other drugs, dosage of other
drugs should be adjusted e.g oral
contraceptives dosage should be increased to
protect the woman from pregnancy-or go for
double protection; later decrease when the
inducer is terminated
24. Altered metabolism
• Inhibition of CYP isoenzymes
– If drug A inhibits metabolism of drug B, free level
of drug B rises
– The result may be beneficial or detrimental
– E.g of ketaconazole (antifungal) and cisapride (GI
stimulant) and cyclosporine (immunosuppressant)
– Ketaconazole inhibits CYP3A4 that metabolizes
cisapride and cyclosporine
– Results: cisapride (fatal cardiac dysarhythmias);
cyclosporine (allows clinicians to achieve
therapeutic effects with smaller doses of the drug
which is very expensive)
25. Altered elimination
• Altered renal excretion:
– all 3 phases of renal excretion can be altered
– Filtration; reabsorption and active secretion
– Drugs that reduce cardiac output can reduce
glomerular filtration because less blood flow goes
to the renal system.
27. Interactions at the same site
• These are almost always inhibitory in nature
• Agonist-antagonist interaction
• E.g morphine and naloxone
28. Interactions at different sites
• If the drugs influence the same system, they
can influence the effect/response of the other
• E.g morphine and Diazepam(valium)
• Both of these drugs work on CNS-depressant
effect
• Administration of these together influence the
response of the other
• Reason /rationale behind lytic cocktail
previously used for pre-eclampsia
29. Combined toxicity
• If drug A and drug B are both toxic to the liver,
then giving them together would increase the
toxicity
• E.g isoniazid and rifampicin-both are
hepatotoxic
• However, in treating for TB the combination is
essential
• Be cautious with dosages
30. Minimizing drug-drug interactions
• Minimize polymedicine when possible
• Take a thorough drug history-patients taking
illicit drugs and over-the-counter drugs might
not mention them-so be detailed enough
• Consider dosage readjustments when a
metabolite inducer is added or removed.
• Closely monitor side effects of drugs
32. Food-drug interactions
• Altered metabolism-the grape fruit effect
– Inhibits metabolism of certain drugs
– Drug levels are increased
– HOW?- inhibits CYP3A4 found in the liver and
intestine
– Since inhibition of CYP3A4 in liver is minimal,
grapefruit has less effect on drugs after they have
been absorbed
– Less effect on IV administered drugs-because
intestinal metabolism is not involved
33. The grape fruit juice effect
• Chemicals in grape fruit
– Bargapten & 6’.7’-dihydroxybergamottin are
furanocoumarins
– Naringin & naringenin are flavenoids
• The inhibitory effect persists after grape
fruit juice has been taken
• It does not necessarialy has to be taken
together
• Even up to 3 days post last glass of juice
34. Grape fruit juice effect
• E.gs
– Nifedipine
– Caffeine
– Carbamazepine
– saquinavir
35. Timing of drug administration and
food/meals
• Consider the interactions if any
• Consider the effects of the drug on an empty
tummy if any
• The effects need to be weighed for one to
make a decision
36. Drug-food interactions
• They can lead to drug toxicity or therapeutic
failure
• Decreased absorption
– Food reduces drug absorption hence reduced
onset and peak of effect
– Calcium containing foods decrease absorption of
tetracycline-Tetracycline binds to calcium and
forms an insoluble substance
– High fiber foods decrease absorption of digoxin
