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DR.Sugiarto, dr, SpPD, FINASIM

Sub-Bagian Endokrinologi dan Metabolik Ilmu Penyakit
Dalam FK Universita Sebelas Maret / RSUD Dr Moewardi
Drug Interaction
A drug interaction:
is a situation in which a substance (usually another drug) affects
the activity of a drug when both are administered together.
Action can be:
synergistic (drugs effect is increased) or
antagonistic (drugs effect is decreased) or
a new effect can be produced that neither.
Interactions between:
drugs and foods (drug-food interactions),
as well as drugs and
medicinal plants or herbs (drug-plant interactions).
Example :
antidepressant drugs such as monoamine oxidase inhibitors
should not take food containing tyramine as hypertensive crisis
may occur (drug-food interaction).
Interactions two drugs and one of them increases the
effect of the other it is possible that an overdose.
Interaction of the two drugs may also increase the risk
that side effects
Interaction will occur between a drug and another
substance present in the organism (foods or alcohol).
Interactions to occur outside an organism before
administration of the drugs. Example: two drugs are
mixed (saline solution prior to intravenous injection).
Synergy and antagonism
Synergistic effec:
interaction causes an increase in the effects of one or both
of the drugs.
Additive synergy:
when the final effect is equal to the sum of the effects of
the two drugs.
Enhanced synergy:
When the final effect is much greater than the sum of the
two effects.
opposite effect to synergy.
Two drugs are antagonistic when their interaction causes a
decrease in the effects of one or both of the drugs.
Underlying factors
Old age:
human physiology changes with age .
Genetic factor:
Genes synthesize enzymes that metabolize drugs (genotype
variations in the isozymes of cytochrome P450)
Hepatic and renal disease:
drugs that are metabolized in the liver and / or eliminated by
the kidneys.
Serious diseases.
Drug dependent factors:
Narrow therapeutic index, Steep dose-response curve and
Saturable hepatic metabolism.
Drug interactions
Also known as pharmacological
The reactions occur when two or more drugs
are mixed outside the body of the organism
for the purpose of joint administration.
Examples :
the mixing of penicillins and aminoglycosides
in the same serum bottle, which causes the
formation of an insoluble precipitate, or the
mixing of ciprofloxacin with furosemide.
Drug Interaction Mechanisms

A. Pharmacodynamic interactions.
B. Pharmaceutical interactions.
C. Pharmacokinetic interactions
Due to a combination of mechanisms.
A. Pharmacodynamic Interactions

Interactions are due to competition at

receptor sites or activity of the interacting
drugs on the same physiological system.
There is no change in the plasma
concentrations of interacting drugs.
Pharmacodynamic interactions..

Change in an organism's response on

administration of a drug.
Can occur on:
1.Pharmacological receptors.
Heterodynamic competitors.
2.Signal transduction mechanisms.
hypoglycaemia in an organism produces a release of
3.Antagonic physiological systems.
use of digoxin and furosemide
Drugs with opposing pharmacological actions acting on the
same receptor
E.g. salbutamol (a beta-2 agonist) with metoprolol (a beta-2
Drugs with a similar pharmacological action may have an
additive effect
E.g. Fluoxetine (an SSRI) with clomipramine (a tricyclic
antidepressant with serotonergic activity) can cause serotonin
syndrome in some patients.
Fluid/electrolyte imbalance
E.g. diuretics that cause hypokalaemia can increase the toxicity
of digoxin.
Indirect interactions
NSAIDs can reduce the effectiveness of antihypertensives by
causing salt and water retention.
B. Pharmaceutical Interactions
These can be classified as those interactions
that occur prior to systemic administration.
For example incompatibility between two
drugs mixed in an IV fluid.
These interactions can be physical (e.g. with a
visible precipitate) or chemical with no visible
sign of a problem.
C. Pharmacokinetic Interactions
Effect of a drug are caused by differences in the
absorption, transport, distribution, metabolization or
A change in blood concentration causes a change in the
drugs effect.
Most interactions result in reduced absorption rather
than increased absorption from the gut.
Interactions affecting the rate of absorption are
generally insignificant unless therapeutic plasma levels
are required quickly e.g. analgesics.
Interactions affecting the extent of absorption may
affect the efficacy of a drug.
Two drugs can be homergic if they have the same
effect in the organism and heterergic if their
effects are different.
1. Absorption interactions:
Changes in motility (prokinetic agents)
2. Transport and distribution interactions
mechanism is competition for plasma protein
3. Metabolism interactions
Cytochrome P450 is a very large family of
haemoproteins that are characterized by their
enzymatic activity and their role in the metabolism of
a large number of drug
1. Absorption interactions:
Factors affecting absorption (with examples):

Change in gastrointestinal pH
Ketoconazole is a poorly soluble base and has to be changed to the
more soluble hydrochloride salt by gastric acid. H2-antagonists (such
as ranitidine, cimetidine), and antacids all raise gastric pH thus
reducing the absorption of ketoconazole.

Drug binding in gastrointestinal tract (adsorption, chelation,

complex formation)
Calcium binds to tetracycline and reduces absorption

Change in gastrointestinal flora.

Short-term use of antibiotics may alter gut flora and thus reduce the
reabsorption of oestrogens from the combined OC.
Possible reduction in effectiveness.
Change in gastrointestinal motility
Metoclopramide increases gut motility and
prevents complete absorption of slow dissolving
digoxin preparations

Malabsorption caused by other drugs.

Orlistat (Xenical) can reduce absorption of fat-
soluble vitamins by reducing fat absorption from
the gut.
2. Transport and distribution interactions
Displacement of one drug by another from binding sites on
plasma proteins was previously put forward as the
mechanism for many drug interactions.
For example, phenylbutazone displaces warfarin from
plasma proteins and this was thought to be the mechanism
for the increased anticoagulant effect.
However, it is now known that the mechanism is due to
phenylbutazone inhibiting the metabolism of warfarin.
Although warfarin is displaced from plasma proteins the
increase in free drug is only transient as there is a
compensatory increase in metabolism.
In general, due to a compensatory increase in elimination,
protein binding displacement interactions are not usually
significant and other mechanisms are responsible.
3. Metabolism interactions

Most drugs undergo metabolism (usually hepatic)

to more water-soluble compounds, before being
excreted in the urine.
Drug interactions affecting metabolism are often
clinically significant and can involve induction
(increased metabolism) or inhibition (reduced
metabolism) of enzymes.
Most clinically significant metabolic interactions
involve either inhibition or induction of
cytochrome P-450 enzymes in the liver.
The cytochrome P-450 (CYP450) enzyme system
The CYP450 enzyme system is one of several metabolic
systems, which evolved to enable organisms to deal with
lipid-soluble environmental chemicals.
The CYP450 system performs this function by oxidizing,
hydrolyzing or reducing the chemicals.
This enables another group of enzymes (conjugation
enzymes), to attach polar groups to make the metabolites
water-soluble so they can be excreted in the urine.
CYP450 system is important because it is involved in most
clinically relevant metabolic drug interactions.
To date, about 55 human isoforms (varieties) of CYP450
have been discovered.
The known clinically relevant cytochromes are CYP3A4,
CYP2D6, CYP1A2, CYP2C9, CYP2C19 and CYP2E1. CYP3A4 is
the most abundant enzyme.
Metabolism interactions
Cytochrome P450
these interactions the function of the enzymes can either
be stimulated (enzyme induction) or inhibited (enzyme

Enzymatic inhibition:
enzymatic inhibition will cause an increase in the
drugs effect and cause a wide range of adverse
Enzymatic induction:
enzymatic induction will cause a decrease in the
drugs effect
Where are these enzymes ?
These CYP enzymes are present in every cell, but are
primarily located in the endoplasmic reticulum of
hepatocytes in the liver and in the small intestine, with
smaller quantities in the kidneys, lungs and brain.
The liver is the main site of drug metabolism.
However, isoenzymes occur in many tissues and CYP3A4, in
particular, is found at quite high concentrations in the
mucosa of the small intestine.
CYPs in the gut are also involved in drug interactions.
For example constituents of grapefruit juice are known to
inhibit the metabolism of some drugs in the gut wall.
Most of the clinically significant interactions with grapefruit
juice involve drugs that are CYP3A4 substrates.
Substrates, Inhibitors and Inducers

A drug, which is metabolised by a particular

isoenzyme, is a substrate for that enzyme.
A drug can be a substrate for several different
isoenzymes or an active metabolite can be a
substrate for a different isoenzyme to the
parent drug.
Enzymatic inhibition:
Enzyme inhibition occurs when the inhibitor drug binds to the CYP
isoenzyme and prevents binding (and therefore metabolism) of the
substrate drug.
For most drug interactions the inhibition is due to reversible,
competitive binding.
The onset and time to maximal drug interaction are determined by
the half-life and time to steady state of theinhibitor drug, and the
time required for the substrate to reach a new steady state.
Most inhibition interactions occur rapidly but maximal effect will
take several weeks if the drug has long half-life (e.g. Fluoxetine).
When the inhibitor is stopped it is released from the binding sites
as it is cleared from the body so inhibition interactions usually
resolve quite quickly unless the drug has a long half-life.
Some inhibition interactions are due to irreversible or non-
competitive binding but these are generally less important.
Some clinically significant examples:
Ciprofloxacin inhibits theophylline metabolism by inhibiting CYP1A2 enzyme
and leads to elevated theophylline plasma levels with possible cardiac
arrhythmias and convulsions. Erythromycin, however, increases theophylline
plasma level through inhibiting CYP3A4, however erythromycin needs to be
given for several days for this effect to appear.
Protease Inhibitors (saquinavir, ritonavir and indinavir) are metabolised by
CYP450 in the liver, in particular CYP3A4. Protease Inhibitors (PI) also act as
inhibitors of the CYP enzyme system, with ritonavir being the most potent.
When PI are prescribed concurrently with CYP3A4 inducers (rifampicin)
reduced plasma levels of PI and therapeutic failure will occur.
Grapefruit and grapefruit juice can inhibit intestinal CYP3A4 and can affect
the oral bioavailability of some drugs, such as cyclosporin, amiodarone and
dihydropyridine calcium channel blockers
Enzymatic induction
An inducer is a drug that causes increased activity of a CYP
isoenzyme by causing increased synthesis and therefore
an increased amount of the induced enzyme.
The metabolic capacity of the isoenzyme is therefore
The enzyme-inducing agent increases the velocity of the
drug metabolic reaction.
The process of enzyme induction requires new protein
synthesis, so its maximum effect is not reached for 2-3
weeks after starting the enzyme-inducer; likewise, the
effect may take some weeks to wear off when the enzyme-
inducer is stopped.
Rifampicin is such a potent enzyme inducer that significant
induction occurs in just a few days and takes several weeks
to wear off.
Some clinically significant examples:

Rifampicin :
Rifampicin induces the metabolism of oral
contraceptives (OCs) and can lead to
contraception failure. Rifampicin also increases
the metabolism of itraconazole, which can lead to
subtherapeutic blood concentrations.
Cigarette smoke and consumption of charcoal
grilled beef induces CYP1A2, which leads to
accelerated metabolism of theophylline and
reduced blood concentrations in smokers.
Genetic Polymorphism
A major characteristic of CYP enzymes is the large
range of interindividual variation in the expression of
enzyme protein.
Some of the isoenzymes exhibit genetic
The frequency of these polymorphisms differs
markedly between ethnic groups.
These genetic differences mean some people have an
enzyme with reduced or no activity.
One isoenzyme, CYP2D6, also has alleles that result in
super fast metabolisers.
This factor contributes to whether a person is classified
as a poor metaboliser or and extensive metaboliser.
Poor metabolisers may achieve toxic drug
concentration levels when usual doses of certain
Active drug is actually the metabolite (as in the
case of a pro-drug), they may not achieve the
desired pharmacological effect from the drug.
These people are a minority in the population
but the prevalence varies between ethnic groups.
The proportion of individuals classified as poor
metabolisers for isoenzyme CYP2D6 is about 8%
for Caucasians , 4% for African-Americans and
<1% for Asians.
Summary characteristics of the main CYPs with
CYP3A4 :
CYP3A4 is the most common and the CYP3A family is responsible for the
metabolism of about 60% of all drugs.
As well as being present in the liver there is a significant quantity in the
gut mucosa and so this isoenzyme is responsible for the metabolism of
some drugs in the gut.
There is no evidence that this isoenzyme is polymorphic.
Inducers: Phenytoin, carbamazepine and rifampicin.
Inhibitors: Erythromycin, itraconazole and saquinavir.

CYP2D6 :
About 25% of all drugs used today are substrates for this isoenzyme.
It exhibits polymorphism and there are extensive and poor metabolisers.
Not inducible.
Inhibitors: Paroxetine, fluoxetine, cimetidine, ritonavir
This enzyme metabolizes approximately 15% of all drugs used
No genetic polymorphism.
Inducers: Cigarettes, barbecued food
Inhibitors: Cimetidine, omeprazole, quinolones (e.g. ciprofloxacin)

CYP2C Family
This family consists of 2C9, 2C10, 2C19 plus others.
These enzymes metabolize a smaller number of drugs, however
many of these are involved in clinically significant drug interactions.
Genetic polymorphism plays a major role with the CYP2C subfamily.
Inducers: phenobarbitone, rifampicin, griseofulvin (2C9)
phenytoin, carbamazepine, rifampicin (2C19)
Inhibitors: azole antifungals, cimetidine, omeprazole (2C9 and
2C19) lansoprazole, fluoxetine (2C19)
Drugs related to CYP1A2:
Enzyme found in the human liver.
The table shows the substrates (drugs metabolized by this
enzyme) and the inductors and inhibitors of its activity.

Substrates. Inhibitors. Inductors.

Caffeine Omeprazole Phenobarbital
Theophylline Nicotine Fluvoxamine
Phenacetin Cimetidine Venlafaxine
Clomipramine Ciprofloxacin Ticlopidine
Certain medicines can interact pharmacologically and
affect the activity of others if they are mixed during
their administration.
Foods and their influence on drug metabolism:
Some foods also act as inductors or inhibitors of enzymatic activity
Food. Mechanism. Drugs affected.
Avocado Enzymatic inductor Acenocoumarol, warfarin
Brassicas (brussel
sprouts, broccoli,
Grapefruit juice Enzymatic inhibition Calcium channel blockers: Nifedipine,
Felodipine, Nimodipine, Amlodipine
Cyclosporine, tacrolimus.Terfenadine,
astemizole,Cisapride, Pimozide
Carbamazepine, Saquinavir,
Midazolam, Alprazolam, Triazolam
Soya Enzymatic inhibition Clozapine, Haloperidol, Olanzapine,
caffeine, NSAIAs, Phenytoin,
Zafirlukast, warfarin
Hypericum perforatum Enzymatic inductor Warfarin, Digoxin, Theophylline,
(St Johns wort) (CYP450) cyclosporine, phenytoin and
Grapefruit juice can act as an enzyme inhibitor.
Grapefruit Juice Interactions

Grapefruit juice contains various components known as bioflavonoids,
which have the ability to inhibit CYP450 isoenzymes found in the gut wall.
This can impair the oxidative metabolism of some drugs.
Grapefruit juice (fresh and frozen) has been demonstrated to inhibit first
pass metabolism of drugs metabolised by CYP3A4, CYP1A2, and CYP2A6.
CYP3A4 is the main isoenzyme affected, and one proposed mechanism for
the interaction is selective down regulation of CYP3A4 in the small
The inhibiting constituents have been found in the flesh, core and peel of
the grapefruit.
The maximum inhibitory effect due to grapefruit juice occurs within 1 hour,
however the duration of effect is at least 24 hours.
One study has estimated the half-life of the effect of grapefruit juice on
CYP3A4 to be 12 hours.
Drugs affected by grapefruit juice

Amiodarone Itraconazole
Astemizole* Lovastatin*
Methadone Midazolam
Carbamazepine* Nifedipine Quinidine
Cisapride* Saquinavir Sertraline
Clomipramine Simvastatin* Sirolimus
Ciclosporin Tacrolimus*
Felodipine Triazolam Verapamil
Hypericum perforatum can act as an enzyme
4. Interactions due to changes in drug excretion

Changes in active excretion in the kidney

Changes in biliary excretion.
Changes in renal blood flow.
Changes in urine pH
Excretion interactions
Renal excretion:
Only the free fraction of a drug that is dissolved
in the blood plasma can be removed through the
drugs that are tightly bound to proteins are not
available for renal excretion.
excretion of drugs :
passive filtration,
reabsorption and
active secretion.
Changes in active excretion in the kidney tubule:
Drugs that have the same active transport
mechanism can compete for excretion in the
kidney tubules.
Probenecid acts in this way to reduce the
excretion of penicillins and increase blood
concentrations of the latter.
In a similar way salicylates and some NSAIDs can
increase methotrexate concentrations possibly
leading to serious toxicity.
Changes in renal blood flow:
If renal blood flow is reduced the excretion of some drugs may be
Vasodilatory renal prostaglandins partly control renal blood flow.
Indomethacin inhibits the synthesis of renal prostaglandins
reducing renal blood flow and thus reducing lithium excretion.

Changes in urine pH :
Many drugs are reabsorbed to some extent in the kidney tubules.
Only the non-ionised, lipid soluble form can be reabsorbed.
Therefore a change in urinary pH may change the ionisation status
of some drugs For example, weakly acidic drugs will be mainly
ionised in highly alkaline urine and reabsorption will be prevented.
Very few of these interactions are clinically significant as most drugs
appear in the urine as inactive metabolites.
Bile excretion:
Bile excretion is different from kidney excretion as
it is always involves energy expenditure in active
transport across the epithelium of the bile duct
against a concentration gradient.
drugs mainly takes place where their molecular
weight is greater than 300 and they contain both
polar and lipophilic groups.
drug excreted in the bile duct can occasionally be
reabsorbed by the intestines (in the entero-
hepatic circuit), which can also lead to interactions
with other drugs.
Changes in biliary excretion :
Some drugs are excreted in the bile as water-soluble
These conjugates can be broken down by bacteria in the gut
to liberate the free drug, which can then be reabsorbed.
This is a proposed mechanism for the interaction between
antibiotics and oestrogen containing oral contraceptives.
Normally a significant amount of oestrogen is reabsorbed
after the conjugate is cleaved by gut bacteria.
The antibiotic prevents this reabsorption by killing the
bacteria that are responsible for breaking down the
Side effects frequently go unnoticed or are not always
caught in older people for the following reasons:

Drug reactions sometimes act like signs or

symptoms of disease (e.g., dementia).
Symptoms of a drug reaction are thought to
be caused by an existing illness or the start of
a new health problem.
Physical reactions to medication, such as
being tired, falling, or weight loss, may be
mistakenly labeled as normal aging.
Physical Signs That Can Happen Due To A Side Effect

fatigue (being tired)

constipation or diarrhea
incontinence (not being able to control your bladder
or frequent urination)
frequent falls
depression (feeling sad or blue)
weakness or tremors
excess drowsiness or dizziness
agitation or anxiety
decreased sexual behavior
Drug-drug interaction occurs when the effect of one
drug is altered by the presence of another drug in the

One drug might reduce or increase the effects

of another drug.
Two medications taken together may produce
a new and dangerous interaction.
Two medications that work the same way may
produce an effect that is greater than would
be expected from taking just one drug if they
are taken at the same time.
the-counter medications can interact with each
Taking a cough medication with alcohol at the
same time as an antihistamine medication can
increase drowsiness and decrease alertness.
Mineral oil taken with fat-soluble vitamins (A, D,
E, K) can decrease the absorption of the vitamins.
Aspirin can significantly increase the effect of
blood thinning medications (anticoagulants), thus
increasing the risk of excessive bleeding.
Antacids can interfere with drug absorption of
antibiotics (i.e., tetracycline), thereby reducing
the effectiveness of the drug in fighting infection.
Antihistamines, often used for allergies and colds, can
increase the sedative effects of barbiturates,
tranquilizers, and some prescription pain relievers.
Decongestants in cold and cough medications can
interact with diuretics or water pills to aggravate high
blood pressure.
Iron supplements taken with antibiotics can reduce or
stop the ability of the antibiotics to fight infection.
The chemicals in the supplement and the antibiotic
bind together in the stomach, instead of being
absorbed into the bloodstream.
Drug and Food Interactions

Food can speed up or slow down the action of

a drug.
Some medications may cause vitamins and
minerals to not work properly in the body.
Stimulation or suppression of the appetite.
Medications may alter how nutrients are used
in the body.
Herbs may interact with many medicines.
Factors Affecting the Extent of Interaction
Between Foods and Medications
Dosage of the drug.
A persons age, size, and state of health.
When the food is eaten and when the
medication is taken.
Alcohol and Medication Interactions
Many medications can interact with alcohol, thereby altering the metabolism or effects
of alcohol and/or the medication.
Some of these interactions can occur even at moderate drinking levels and result in
adverse health effects for the drinker.
Two types of alcoholmedication interactions exist:
(1) Pharmacokinetic interactions, in which alcohol interferes with the metabolism
of the medication, and
(2) Pharmacodynamic interactions, in which alcohol enhances the effects of the
medication, particularly in the central nervous system (e.g., sedation).
Pharmacokinetic interactions generally occur in the liver, where both alcohol and many
medications are metabolized, frequently by the same enzymes.
Numerous classes of medications can interact with alcohol :
antibiotics, antidepressants, antihistamines, barbiturates, benzodiazepines,
histamine H2 receptor antagonists, muscle relaxants, nonnarcotic pain medications
and anti-inflammatory agents, opioids, and warfarin.
In addition, many over-the-counter and herbal medications can cause negative
effects when taken with alcohol.
Herb-drug interactions
Use of herbs
mimic, magnify, or oppose the effect of drugs.
Bleeding when warfarin is combined with ginkgo (Ginkgo
biloba), garlic (Allium sativum), dongquai (Angelica sinensis), or
danshen (Salvia miltiorrhiza);
Mild serotonin syndrome in patients who mix St Johns wort
(Hypericum perforatum) with serotonin-reuptake inhibitors;
Decreased bioavailability of digoxin, theophylline,cyclosporin,
and phenprocoumon when these drugs are combined with St
Johns wort;
Induction of mania in depressed patients who mix
antidepressants and Panax ginseng;
Exacerbation of extrapyramidal effects with neuroleptic drugs
and betel nut (Areca catechu);

Herb-drug interactions..

Increased risk of hypertension when tricyclic

antidepressants are combined with yohimbine
(Pausinystalia yohimbe);
Potentiation of oral and topical corticosteroids by liquorice
(Glycyrrhiza glabra);
Decreased blood concentrations of prednisolone when
taken with the Chinese herbal product xaio chai hu tang
Decreased concentrations of phenytoin when combined
with the Ayurvedic syrup shankhapushpi.
Decrease the absorption of drugs when anthranoid-
containing plants and cascara [Rhamnus purshiana]) and
soluble fibres (including guar gum and psyllium) .
Smoking and Drug Interactions
Several studies have shown that smokers require and
are prescribed higher doses of psychotropic medication
than non-smokers.
Increased metabolism and faster clearance of
medication implies that higher doses are required to
achieve desired therapeutic effects.
When smoking is reduced or stopped, enzyme
induction reduces or ceases, the rate of metabolism
decreases, leading to a rise in serum drug levels.
Dose adjustments may be required for certain drugs.
Stopping smoking, a person may experience increased
side effects despite taking the same dose of medication
as that prescribed while smoking.
Risk factors for drug interactions

High risk patients :

The elderly are more prone to drug
interactions, as they are more sensitive to
some pharmacodynamic effects and also tend
to be on more drugs.
Patients on > 6 drugs have an 80% chance of a
drug interaction.
Many hospital inpatients are on 6 drugs or
High risk drugs:
Narrow therapeutic index, i.e. a relatively small change in the
plasma concentration can cause drug toxicity or subtherapeutic
Pharmacokinetic interaction which changes the plasma
concentration (up or down) will cause a change in effect.
Warfarin and the other oral anticoagulants fall in to a special high-risk
warfarin is measured from the prothrombin time or INR and the dose
is titrated to provide a sufficient degree of anticoagulation without
causing bleeding.
Agents that change the supply or synthesis of vitamin K can also alter
the pharmacodynamic effect of warfarin.
Antidepressants, antiarrhythmics, antipsychotics, hypoglycemic
Drugs cimetidine and erythromycin are potent enzyme inhibitors
Some drugs with a low therapeutic

Lithium Digoxin
Carbamazepin Cyclosporin
Phenytoin Phenobarbital
Theophylline Warfarin
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