DRUG INTERACTIONS

Dr.Taita Towett.,M.P.S.
Introduction
 An interaction is said to occur when the effects of one drug are
changed by the presence of another drug, herbal medicine, food,
drink or by some environmental chemical agent.
 Drug interaction can therefore be defined as the modification of
the effect of one drug by the prior or concomitant administration
of another drug, food, drink or some environmental chemical
agent.
 The outcome can be harmful if the interaction causes an increase
in the toxicity of the drug.

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Outcomes of drug interactions
1) Loss of therapeutic effect.
2) Toxicity.
3) Unexpected increase in pharmacological activity.
4) Beneficial effects e.g. additive & potentiation (intended).
5) Chemical or physical interaction e.g. I.V incompatibility in fluid or
syringes mixture

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Risk Factors for Drug Interactions
 High Risk Patients
Elderly, young, very sick, multiple disease.
Multiple drug therapy.
Renal, liver impairment.

 High Risk Drugs

Low therapeutic index drugs e.g. Lithium, carbamazepine,
phenytoin, pheophylline (aminophylline), digoxin, cyclosporin,
phenobarbitone, warfarin.
Recognised enzyme inhibitors or inducers.
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Mechanisms of drug interactions
1. Pharmacokinetic Drug Interactions
2. Pharmacodynamic Drug Interactions
3. Pharmaceutical Interactions

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1. PHARMACOKINETIC DRUG
INTERACTIONS
 One drug alters the rate or extent of absorption,
distribution, metabolism or excretion (ADME) of another
drug.
 A change in blood concentration causes a change in the
drug’s effect.
 Pharmacokinetic interactions include: drug absorption
interactions, drug distribution interactions, drug metabolism
interactions and drug elimination interactions.

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i) Drug absorption interactions
 Most drugs are given orally for absorption through the mucous
membranes of the gastrointestinal tract, and the majority of
interactions that go on within the gut result in reduced rather than
increased absorption.
 Drug absorption interactions can result from:
(a)Changes in gastrointestinal pH:
 The passage of drugs through mucous membranes by simple passive
diffusion depends upon the extent to which they exist in the non-
ionised lipid-soluble form.

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 Absorption is therefore governed by the pKa of the drug, its lipid-
solubility, the pH of the contents of the gut and various other
parameters relating to the pharmaceutical formulation of the drug.
 E.g. the absorption of salicylic acid by the stomach is much greater
at low pH than at high. Alterations in gastric pH caused by drugs
such as the H2-receptor antagonists e.g. cimetidine decrease the
absorption of salicylic acid.
(b)Adsorption, chelation and other complexing
mechanisms:
 Activated charcoal is intended to act as an adsorbing agent within
the gut for the treatment of drug overdose or to remove other
toxic materials, but inevitably it can affect the absorption of drugs
given in therapeutic doses.

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 Tetracycline antibacterials can chelate with a number of divalent
and trivalent metallic ions, such as calcium, aluminium, bismuth and
iron, to form complexes that are both poorly absorbed and have
reduced antibacterial effects.
 Colestyramine, an anionic exchange resin intended to bind bile
acids and cholesterol metabolites in the gut, binds to a
considerable number of drugs (e.g. digoxin, warfarin, levothyroxine),
thereby reducing their absorption.
(c)Changes in gastrointestinal motility:
 Since most drugs are largely absorbed in the upper part of the
small intestine, drugs that alter the rate at which the stomach
empties can affect absorption.
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 E.g. propantheline delays gastric emptying and reduces
paracetamol absorption, whereas metoclopramide, has the
opposite effect.
(d)Induction or inhibition of drug transporter proteins:
 The oral bioavailability of some drugs is limited by the action of
drug transporter proteins, which eject drugs that have diffused
across the gut lining back into the gut.
 Digoxin is a substrate of P-glycoprotein, and drugs that induce
this protein, such as rifampicin, may reduce the bioavailability of
digoxin.
(e)Malabsorption caused by drugs:
 Neomycin causes a malabsorption syndrome that impairs the
absorption of a number of drugs.
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ii) Drug distribution interactions
(a)Protein-binding interactions:
 Depending on the concentrations and their relative affinities for the
binding sites, one drug may successfully compete with another and
displace it from the sites it is already occupying on the plasma
protein. This results into a rise in the plasma concentration of the
free drug of the displaced drug.
(b)Induction or inhibition of drug transport proteins:
 Distribution of drugs into the brain, and some other organs such as
the testes, is limited by the action of drug transporter proteins such
as P-glycoprotein. These proteins actively transport drugs out of
cells when they have passively diffused in.

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(iii) Drug metabolism (biotransformation)
interactions
 The greatest proportion of drug metabolism is carried out by
enzymes that are found in the membranes of the endoplasmic
reticulum of the liver cells.
 The majority of phase I oxidation reactions are carried out by the
haem-containing enzyme cytochrome P450.
 The most important isoenzymes are: CYP1A2, CYP2C9, CYP2C19,
CYP2D6, CYP2E1 and CYP3A4. Other enzymes involved in phase I
metabolism include monoamine oxidases and epoxide hydrolases.

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(a)Enzyme induction:
 usually caused by increased expression of CYP genes, resulting in a
net increase of enzyme protein synthesis.
 The metabolic pathway that is most commonly induced is phase I
oxidation mediated by the cytochrome P450 isoenzymes.
 E.g. Cyclosporin plasma levels are reduced when it is given with St
John’s wort (enzyme inducer). St John’s wort induces the
metabolism of cyclosporin by induction of CYP3A4 and possibly
also P-glycoprotein.
 Phase II glucuronidation can also be induced e.g. rifampicin induces
the glucuronidation of zidovudine (anti- HIV drug).

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 The extent of the enzyme induction depends on the drug and its
dosage, but it may take days or even 2 to 3 weeks to develop fully,
and may persist for a similar length of time when the enzyme
inducer is stopped.
 This means that enzyme induction interactions are delayed in
onset and slow to resolve.
(b)Enzyme inhibition:
 More common than enzyme induction is the inhibition of
enzymes.
 This results in the reduced metabolism of an affected drug, so
that it may begin to accumulate within the body, the effect usually
being essentially the same as when the dosage is increased.
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 Unlike enzyme induction, which may take several days or even
weeks to develop fully, enzyme inhibition can occur within 2 to 3
days, resulting in the rapid development of toxicity.
 The metabolic pathway that is most commonly inhibited is phase
I oxidation by the cytochrome P450 isoenzymes.
 Phase II conjugative metabolism can also be inhibited.
(c)Genetic factors in drug metabolism:
 Cytochrome P450 isoenzymes are subject to genetic
polymorphism, which means that some of the population have
a variant of the isoenzyme with different (usually poor) activity.

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 The best known example is CYP2D6, for which a small
proportion of the population have the variant with low activity
and are described as being poor or slow metabolisers.
 CYP2D6, CYP2C9 and CYP2C19 also show polymorphism,
whereas CYP3A4 does not.

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CYP 450 System Definitions
 Substrate: Drug is metabolised by the enzyme system.
 Inducer: Drug that increases the synthesis of CYP450 enzymes.
 Inhibitor: Drug that decreases metabolism of a substrate.

CYP450 Nomenclature
Family

CYP2D6
Sub-Family Individual Gene
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% drugs metabolized by enzymes
 CYP3A4 60%
 CYP2D6 25%
 CYP1A2 15%
 CYP2C9 Small no. but significant interactions
 CYP2C19 Small no. but significant interactions
 CYP2E1 ?

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Interactions During Metabolism
Interactions due to enzyme induction
Primary drug Inducing agent Effect of interaction
Warfarin Barbiturates Decreased anticoagulation
Ethanol (chronic use)
Rifampicin
Oral contraceptives Rifampicin pregnancy
Prednisolone/ciclosporin Anticonvulsants ↓immunosuppression (graft
rejection)
Theophylline Tobacco smoking Decreased plasma theophylline

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 Interactions due to CYP450 or other enzyme inhibition
Primary drug Inhibiting drug Effect of interaction
Phenytoin Isoniazid Phenytoin intoxication
Cimetidine
Chloramphenicol
Warfarin Allopurinol Haemorrhage
Metronidazole
Phenylbutazone
Co-trimoxazole
Azathioprine, 6-MP Allopurinol Bone-marrow suppression
Theophylline Cimetidine Theophylline toxicity
Erythromycin
Cisapride Erythromycin Ventricular tachycardia
Ketoconazole
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iv) Drug excretion interactions
 With the exception of the inhalation anaesthetics, most drugs are
excreted either in the bile or in the urine.
(a)Active tubular secretion:
 Occurs in the proximal tubules.
 Drug combines with a specific protein to pass through the
proximal tubules.
 When another drug competes for the same protein, decreased
drug excretion results leading to increase in plasma concentration
and hence its toxicity.

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(b)Passive tubular reabsorption:
 Excretion and reabsorption of drugs occur in the tubules by
passive diffusion which is regulated by concentration and lipid
solubility.
 Ionized drugs are reabsorbed lower than non-ionized ones
(effect of pH).
(c)Enterohepatic recirculation:
 A number of drugs are excreted in the bile, either unchanged or
conjugated (e.g. as the glucuronide) to make them more water
soluble. Some of the conjugates are metabolised to the parent
compound by the gut flora and are then reabsorbed.

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 This recycling process prolongs the stay of the drug within the
body, but if the gut flora are diminished by the presence of an
antibacterial, the drug is not recycled and is lost more quickly.
 This may possibly explain the rare failure of the oral
contraceptives that can be brought about by the concurrent use
of penicillins or tetracyclines.

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Competitive interactions for renal tubular transport

Primary drug Competing drug Effect of interaction

Penicillin Probenecid Increased penicillin blood
level
Methotrexate Salicylates Bone marrow suppression
Sulphonamides
Salicylate Probenecid Salicylate toxicity
Indometacin Probenecid Indometacin toxicity
Digoxin Spironolactone Increased plasma digoxin
Amiodarone
Verapamil

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2. PHARMACODYNAMIC DRUG INTERACTIONS

 One drug causes a change in patient’s response to another drug

without altering that drug’s pharmacokinetics.
 Drugs may act on the same or different receptors or processes,
mediating similar biological consequences.
Alcohol + benzodiazepine (to produce sedation)
Morphine + naloxone (to reverse opioid overdose)
Rifampicin + isoniazid (effective antituberculosis combination).
Beta-blocker given with beta-agonist
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 Drug-Drug interaction may alter drug effect by
(a)Antagonism (1 - 1 = 0 or 0.5):
 Two drugs have opposite pharmacodynamic effects,
e.g. histamine & adrenaline on the bronchi
 or they compete reversibly for the same drug receptor
e.g. flumazenil & benzodiazepines exhibit competitive
antagonism.
(b)Synergism (1 + 1 > 2):
 Combined effect of two drugs exceeds the sum of the effects
of each agent given alone
E.g. thiazides + loop diuretics
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(c)Potentiation effect (1 + 0 = 2):
 The effect of the combination is greater than the effects of the
individual drugs.
i.e. Effect of Drug A + B > Effect of drug A + Effect of drug B.
 This is always true when one component drug given alone
produces no effect but enhances the effect of the other e.g.
Amoxicillin + clavulanic acid.
(d)Additive effect (1 + 1 = 2):
 The effect of the two drugs is in the same direction and simply
adds up e.g. effect of drugs A + B = Effect of drug A + Effect of
drug B.
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 3. Pharmaceutical Interactions
 Occur by chemical reaction or physical interaction when drugs
are mixed prior to systemic administration
Mixture Result
Thiopentone + suxamethonium Precipitation
Diazepam + infusion fluids Precipitation
Phenytoin + infusion fluids Precipitation
Heparin + hydrocortisone Inactivation of heparin
Gentamicin + hydrocortisone Inactivation of gentamicin
Penicillin + hydrocortisone Inactivation of penicillin
Protamine zinc insulin + soluble insulin ↓Immediate effect of the dose

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Prevention of drug interaction
1) Monitoring therapy and making adjustments.
2) Monitoring blood level of some drugs with narrow therapeutic
index e.g., digoxin, anticancer agents…etc.
3) Monitoring some parameters that may help to characterize the
early events of interaction or toxicity e.g., with warfarin
administration, it is recommended to monitor the
prothrombin time to detect any change in the drug activity.
4) Increase the interest of case report studies to report different
possibilities of drug interaction.

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DRUG-HERB INTERACTIONS
 There has been increase in the use of herbal medicines over the
decades.
 Such products (herbal medicines) often contain pharmacologically
active ingredients which can give rise to clinically significant
interactions when used inadvertently with other conventional
drugs.
 Extracts of Glycyrrhizin glabra (liquorice) used for treating
digestive disorders may cause significant interactions in patients
using digoxin or diuretics. It may exacerbate hypokalaemia induced
by diuretic drugs and precipitate digoxin toxicity.
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 A number of herbal products like garlic, Ginkgo (Ginkgo biloba)
have anti-platelet and anticoagulant properties and may increase
the risk of bleeding when used with aspirin or warfarin.
 St John's wort (Hypericum perforatum) extract used for
treatment of depression is associated with a variety of drug
interactions. The herb can induce the cytochrome P450
isoenzyme CYP3A4, and can also induce P-glycoprotein. Hence St
John’s wort decreases the levels of ciclosporin and digoxin
respectively.

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FOOD – DRUG INTERACTIONS
 Food can cause clinically important changes in drug absorption
through effects on gastro-intestinal absorption or motility, hence
the advice that certain drugs should not be taken with food, for
example, iron tablets and antibiotics.
 Cruciferous vegetables, such as brussels sprouts, cabbage, and
broccoli, contain substances that are inducers of the cytochrome
P450 isoenzyme CYP1A2.
 Grapefruit juice inhibits intestinal CYP3A4, and only slightly affects
hepatic CYP3A4.

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THANKS FOR LISTENING

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