INTRODUCTION:
Drug Interaction is a
situation in which the effects of one
drug are altered by the prior or concurrent administration of another drug or by the presence of food,
drink or environmental
chemicals.
The drug whose activity
is affected by such an interaction is referred to as the object drug.
The agent which
precipitates such as interaction is referred to as the precipitant drug.
Drug interactions are
generally quantitative whereby the intensity of effect is changed (for example an increase or decrease) &
seldom qualitative.
v Most
interactions are specific types of adverse reactions with altered efficacy of
the body.
For
example:
An enhanced pharmacological activity (
eg: Haemorrhagic tendency of warfarin when phenylbutazone is given
subsequently.
Or
Decrease
in therapeutic activity resulting in loss of efficacy like that of tetracycline
when concomitantly administered with food, antacids or mineral supplements
containing heavy metal ions.
v In
some instances, drug interactions may be beneficial.
For
example: Enhancement of
activity of penicillins when administered with probenecid.
THE CAUSES OF DRUG
INTERACTIONS
- Administration of two or more
drugs simultaneously (Multiple pharmacological effects).
- Visiting of patients to many
doctors (Multiple prescribers).
- Concurrent use of prescribed
and non−prescribed drugs.
- Patient’s non−compliance.
- Drug abuse.
PATIENT VARIABLE
There are many factors that influence the response to a drug in man.
1. AGE
Ø
There is an increased incidence of drug interactions in both young and geriatric patients.
Ø
Drug-related problems in young patients are encountered most frequently in newborn infants. Newborn infants do not have fully developed enzyme
systems that are involved in the metabolism of certain drugs, and they also have
immature renal function.
Ø Several factors are responsible for increased risk of interactions
in the elderly. Most elderly patients have at least one chronic illness (eg, hypertension,
diabetes), and this is reflected in the prescribing of a larger number of medications for this
patient group. In addition, there may be aging-related changes in the absorption,
distribution,
metabolism, and excretion of certain drugs, which increase the possibility of adverse
events and drug interactions.
2. GENETIC FACTORS
Ø
These maybe responsible for the development of an unexpected drug response in a
particular patient.
Ø
Isoniazid is metabolized by an acetylation process, the rate of which appears to be under genetic control. Some individuals metabolize isoniazid rapidly,
whereas others metabolize it slowly, thus necessitating careful dosage adjustment, as the
dose that provides
satisfactory concentrations in rapid acetylators may cause toxicity in slow
acetylators.
Ø
Eg: Isoniazid causes peripheral neuritis in a number of patients, and this effect has been noted most frequently in
slow acetylators.
Ø It has been observed that isoniazid may inhibit the metabolism of phenytoin, possibly resulting in the development of adverse events (nystagmus, ataxia, lethargy) of
phenytoin.
3. DISEASE STATES
Ø
A number of disease states, other than the one for which a particular drug is being used
may influence patient response to a drug.
Ø
Impaired renal and hepatic function is the most important conditions that may
alter drug activity.
However, other disorders also may bring about a change in the activity of a drug.
4. RENAL FUNCTION
Ø
Renal function is one of the most important determinants of drug activity. If there is renal impairment and
the usual dose of a drug that is excreted by the kidney is given, there can be an increased and
prolonged effect, since it is not being excreted at the normal rate. As additional doses are given, serum concentrations will
increase, possibly resulting in toxicity.
Ø Therefore, a need exists for
careful dosage adjustment and particular
caution when other potentially interacting drugs are added to the therapeutic
regimen.
5. HEPATIC FUNCTION
Ø
Many drugs are metabolized in the liver by a number of mechanisms. Therefore, when
there is hepatic
damage, these drugs may be metabolized at a slower rate and exhibit a prolonged
effect.
Ø
Although each situation should be evaluated to determine whether a reduction in dosage
is necessary,
it should be recognized that some drugs will be metabolized at the normal rate even though
hepatic function is impaired.
Ø
Many therapeutic agents are metabolized by
hepatic enzymes.
If other drugs alter the amount and/or activity of these enzymes, a modified response to
the drugs that depend on these enzymes for their metabolism might occur.
Ø
Eg: many agents (eg. barbiturates,
rifampin) are known to stimulate the activity of hepatic enzymes (enzyme induction). This
results in rapid
metabolism and excretion of concurrently administered agents that
are metabolized by these enzymes.
6. ALCOHOL CONSUMPTION
Ø
Chronic use of alcoholic
beverages may increase the rate of metabolism of drugs such as warfarin and phenytoin by increasing the activity of
hepatic enzymes.
Ø
Acute use of alcohol by
nonalcoholic individuals may cause an inhibition of hepatic enzymes.
7. SMOKING
Ø
Smoking increases the activity of drug-metabolizing enzymes in the liver, with the
result that certain therapeutic agents (eg, diazepam, propoxyphene, theophylline,
olanzapine) are
metabolized more rapidly, and their effect is decreased.
8. DIET
Ø
Food often may affect the rate and extent of absorption of drugs from the
gastrointestinal (GI) tract. For example, many antibiotics should be given at least 1 hr before
or 2 hr after meals to achieve optimal
absorption.
Ø
The type of food is important with regard to the absorption of concurrently administered
drugs. Eg: 1.Interaction of milk and other dairy products with tetracycline and
Ø
fluoroquinolone derivatives. 2. Certain dietary items contain an appreciable amount of
vitamin K. A change in dietary habits that would
significantly alter the intake of these foods could cause problems in patients
on warfarin therapy.
Ø Diet also may influence urinary
pH values. One study has compared the excretion of amphetamine in two groups of patients maintained on different
diets. One group was placed on a balanced protein diet that provided an acidic
urine (average pH of 5.9), whereas the other group was put on a low-protein diet that provided an alkaline
urine (average pH of 7.5). Each group was given a dose of
amphetamine, and those with the acidic urine excreted 23 to 56%
of unchanged amphetamine in the first 8
hr and 5 to 13% in the next 8 hr. In comparison, in those with alkalinized urine, there was a 2 to 6% excretion in the first 8 hr, followed by a 0.5 to 3%
excretion in the next 8 hr.
9. INDIVIDUAL VARIATION
Ø Plasma concentrations of certain
drugs may vary widely among individuals using the same dosage regimen over the
same time period.
TYPES OF DRUG INTERACTIONS
Drug
Interactions are of following types:
1. Drug − Drug Interactions.
A)
Beneficial Drug Interactions.
B)
Adverse Drug Interactions.
2. Drug − Food Interactions.
3. Drug − Herbal Interactions.
4. Drug − Laboratory Tests Interactions.
DRUG – DRUG INTERACTIONS
BENEFICIAL DRUG
INTERACTIONS
Ø
Some drug interactions
may be desirable and intended because of beneficial effects they produce when a
combination of medications is given.
Ø
Such a combination
produces,
1. Improved
therapy,
2. A
greater margin of safety,
3. More
appropriate onset or duration of action,
4. Lowered
toxicity or enhanced potency with diminishing side effects.
Ø
Such an interaction is
also termed as Rational Drug Interaction.
DRUG INTERACTION
LEADING TO INCREASE IN THERAPEUTIC EFFECTS :
- In the treatment of Urinary
Tract Infections & Pneumocystosis (due to microorganism
pneumocystis carini ).
- In the treatment of Parkinsonism,
use of Levodopa & Carbidopa.
- In the treatment of Angina,
use of Nitrates + β−blockers.
- In the treatment of Angina,
use of Nitrates + calcium channel blockers.
- In the treatment of
Hypertension, use of Thiazide diuretics + potassium supplements +
β−blockers.
- In the treatment of
Hypertension, use of Thiazide diuretics + potassium supplements + α−methyldopa.
- In the treatment of
Hypertension, combination of diuretics (Hydrochlorthiazide + Triamterene) is used to minimise the K+
loss.
- Use of probenecid to ↑ the
serum concentration & prolong the activity of penicillins & some
cephalosporins.
- Amoxicillin with a β−lactamase
inhibitor (clavulanic acid or sulbactam) to prevent degradation of
Amoxicillin by β−lactamase producing bacteria & to increasing its antimicrobial spectrum.
DRUG INTERACTIONS
PROVIDING ADVANTAGE IN THE MANAGEMENT OF POISIONING & DRUG OVERDOSAGE :
- In the treatment of Morphine Poisoning
& Morphine addiction Naloxone is used.
- In the treatment of Heparin
toxicity, Protamine sulphate (heparin antagonist) is used.
- In the treatment of Atropine poisoning,
physostigmine is used.
- To reverse the skeletal muscle
relaxant effects of d−tubocurrarine, Neostigmine is used.
- In the treatment of Methyl
alcohol poisoning, Ethyl alcohol is used.
- In the treatment of Iron poisoning,
Deferoxamine is used.
DRUG COMBINATIONS WITH
POTENTIAL ADVANTAGES :
|
Sl.NO
|
EXAMPLES
|
POTENTIAL ADVANTAGE
|
|
1
|
Anti−tubercular
drugs
(Rifampicin
& Isoniazid), Ferrous sulphate & Folic acid
|
Improved
compliance
|
|
2
|
Triple
vaccine
(Diptheria
, pertussis & tetanus)
|
Ease
of administration
|
|
3
|
Trimethorprim
+ sulfamethoxazole .
Aspirin
+ codeine.
|
Synergistic
effect
|
|
4
|
Levodopa+
carbidopa
|
Increased
effect
|
|
5
|
antacids
(Aluminium salt & magnesium salts)
|
|
ADVERSE
DRUG INTERACTIONS
An adverse drug
interaction occurs due to error of the patient or physician. And these interactions are undesirable & unintentional.
The drug interaction
may be Hetergic or Homergic.
Hetergic
: This type of drug interaction occurs
when two drugs producing different types of effects are administered.
Homergic
: This type of drug interaction occurs
when two drugs producing similar types of effects are administered.
Adverse Drug − Drug Interactions can happen Invitro or
Invivo.
INVITRO ADVERSE DRUG - DRUG
INTERACTIONS :
These
interactions occur outside the body and are precisely the “pharmaceutical
Interactions” where no pharmacokinetic / pharmacodynamic principles are
involved except for chemistry.
|
Sl.NO
|
DRUGS
|
MIXED
INTO
|
RESULT
|
|
1
|
Thiopental
+ succinyl choline
|
In
the same syringe
|
Precipitation
(or) Inactivation
|
|
2
|
Hydrocortisone
+ Heparin
|
In
the same syringe
|
Inactivation
of Heparin.
|
|
3
|
Hydrocortisone
+ Penicillin
|
In
the same syringe
|
Inactivation
of penicillin.
|
|
4
|
Penicillin
+ Gentamycin
|
In
the same syringe
|
Mutual
Inactivation.
|
|
5
|
Sodium
salts of phenytoin, Barbiturates, sulfonamides, Heparin & Penicillins.
|
In
I.v infusion fluid such as 5% dextrose.
|
Drugs
are precipitated in the acidic pH of dextrose solution.
|
IN VIVO ADVERSE DRUG −
DRUG INTERACTIONS:
In vivo drug-drug interactions
occur either due to pharmacokinetic or pharmacodynamic reasons.
Pharmacokinetic interactions are those in which one agent (the precipitant drug) alters the absorption, distribution, metabolism, or excretion (ADME)
of a second agent (the object drug), with a resultant change in the plasma concentration of
the latter agent.
pharmacodynamic interactions are those in which drugs having
similar ((or) opposing) pharmacological effects are administered concurrently and situations in which the
sensitivity or responsiveness of the tissues to one drug is altered by another. Simply
Pharmacodynamic interactions are situations in which there is a change in drug effect
without a change in drug plasma concentration. Although the pharmacokinetic interactions often
present challenging clinical
problems widely, the pharmacodynamic
interactions are encountered more frequently.
PHARMACOKINETIC INTERACTIONS
A. ABSORPTION
1. ALTERATION OF Gl ABSORPTION
Due to Interactions, absorption of a drug from the GI tract may change.
In some situations the absorption of the drug may be reduced, and its therapeutic activity
compromised. In others, absorption may
be delayed, but the same amount of
drug is absorbed eventually.
A delay in drug absorption can be undesirable when a rapid effect is needed to relieve acute
symptoms, such as pain. The slower absorption rate also may prolong the effects of a drug
and may present difficulty.
Eg:- If Effects Hypnotic Drugs are prolonged -
the patient may experience excessive sedation or hangover in the morning.
A slower rate of absorption may preclude achievement of effective plasma and tissue concentrations of drugs
that are metabolized rapidly and excreted.
2. ALTERATION OF pH
Since many drugs
are weak acids or weak bases, the pH of the GI contents may influence the
extent of absorption.
The non-ionized
form of a drug (the more lipid-soluble) will be absorbed more readily than the
ionized form. Acidic drugs exist primarily in the non-ionized form in the upper
region of the GI tract (having a lower pH).
If a drug such
as an antacid is ingested, which will raise the pH of the GI contents,
it is possible that the absorption of such acidic drugs can be delayed and/or
inhibited partially.
v KETOCONAZOLE - ANTACIDS
When
ketoconazole is administered orally, an acidic medium is required for
dissolution of ketoconazole. Drugs like an antacid, a histamine H2-
receptor antagonist (eg, cimetidine,
ranitidine) or a proton pump inhibitor (eg, lansoprazole, omeprazole) is
likely to reduce the dissolution, absorption, and effectiveness of the
antifungal agent.
v BISACODYL
- ANTACIDS
Laxative
bisacodyl when administered orally they cause Gastric Irritation, so formulated
as enteric-coated dosage form.
If concurrent
administration of antacid or ingestion of milk leads to increase in the pH of
the GI contents and may cause disintegration of the enteric coating in the
stomach, resulting in release of
the drug in the stomach, which cause irritation and vomiting.
3. COMPLEXATION & ABSORPTION
v
TETRACYCLINES-METALS
Tetracycline can combine with metal ions such as calcium, magnesium, aluminum, iron, bismuth, and zinc in the GI tract to form complexes that are
absorbed poorly.
Thus, the simultaneous administration of certain dietary items (eg. milk, other products containing calcium) or drugs (eg.
antacids, iron preparations, products containing calcium salts) with tetracycline could result in a significant
decrease in the amount of antibiotic absorbed.
v
FLUOROQUINOLONES-METALS
Aluminum and
magnesium-containing antacids, as well as certain dietary items (eg. milk,
yogurt), reduce the absorption and serum concentrations of fluoroquinolones, as
a result of the metal ions complexing with the anti-infective agent.
Eg: Labeling
for Moxifloxacin - is recommended that
Moxifloxacin be taken at least 4 hours before or 8 hours after antacids
containing magnesium or aluminum, as well as sucralfate, metal cations such as iron, and
multivitamin preparations with zinc.
v
CHOLESTYRAMINE AND COLESTIPOL
cholestyramine
and colestipol, the resinous materials which are not absorbed from the GI tract and also bind with bile acids, thyroid hormone, warfarin,
digoxin. And thiazide diuretics and
prevent their reabsorption.
The naturally
occurring human bile acid, ursodiol is used in the dissolution of gallstones
composed primarily of cholesterol.
Prolonged
administration of cholestyramine and colestipol can decrease the absorption of
fat-soluble vitamins such as vitamin K leading to increased bleeding
tendencies in some patients in whom the vitamin K intake is not increased.
A newer bile
acid-binding agent, colesevelam, appears less likely than cholestyramine and
colestipol to interact with other medications or fat-soluble vitamins.
For the
treatment of Rheumatoid arthritis Leflunomide is used. Leflunomide can cause
fetal harm if administered during pregnancy, and it has an active metabolite that can
persist in the system for up to 2 years. If a woman of childbearing potential discontinues use of Leflunomide. It is recommended
that cholestyramine (e g. three times
a day. for 11 days) be used to accelerate the elimination of the drug and its active
metabolite.
v PENICILLAMINE-METALS
Aluminum and iron salts reduce
the absorption of penicillamine through chelation and/or adsorption mechanisms.
4. ALTERATION OF MOTILITY / RATE OF GASTRIC EMTYING
v
CATHARTICS
A cathartic, increases GI motility, enhance the rate of drug passage
through the GI tract which leads to
decreased absorption of certain drugs.
Drugs which are absorbed slowly and require prolonged contact with the absorbing
surface or those that are absorbed
only at a particular site along the GI tract. Similar problems might be noted with
enteric-coated and controlled-release formulations.
v ANTICHOLINERGICS
Anticholinergics
decreases GI motility, which causes reduced peristalsis which inturn retards the dissolution and finally
absorption is decreased. And slowing of gastric emptying may delay absorption from the
small intestine.
If a drug is
retained for a longer period of time in the area from which it is optimally absorbed,so absorption is increased.
METOCLOPRAMIDE
Metoclopramide
increases motility of the upper GI tract, and may influence the absorption of other drugs administered
concurrently.
5.
ALTERATION OF METABOLISM IN G.I. TRACT
The absorption of certain agents is influenced by the extent to which they are metabolized in the GI tract.
MAOIs-TYRAMINE:
Tyramine is a pressor substance,
which is metabolized by MAO (Mono Amino Oxidase ) enzyme present in the intestinal wall of the liver
and protects against the pressor actions of amines in foods.
MAO Inhibitors (eg. Isocarboxazid, phenelzine, tranylcypromine) inhibits the MAO (Mono Amino Oxidase) enzyme which results in
accumulation of large quantities of unmetabolized tyramine, which acts to release more nor-epinephrine
from adrenergic neurons as a result of MAO inhibition.
Foods containing the highest tyramine content are aged cheeses, certain alcoholic beverages (eg, Chianti
wine), pickled fish (eg. herring), concentrated yeast extracts, and broad-bean
pods (also known as fava beans or
Italian green beans).
GRAPE FRUIT JUICE:
Consumption of grapefruit juice increases the serum concentration and activity of a number of
medications such as certain calcium channel blockers (eg. amlodipine, felodipine,
nisoldipine), certain HMG-CoA reductase inhibitors (eg. lovastatin), and cyclosporine.
The bioavailability of most of these agents is generally low. Primarily as a result of
extensive first-pass metabolism.
Components of grapefruit juice reduce the activity of the cytochrome P-450enzymes
(primarily CYP3A4) in the gut wall that is involved in the metabolism of these
agents. As a result, a larger amount of unmetabolized
drug is absorbed, and serum
concentrations are increased.
6.ALTERATION
OF GASTROINTESTINAL FLORA
Antibiotics can cause changes in the microbial flora
of the GI tract & may alter the production or metabolism of
certain agents, which inturn affects the absorption and clinical response.
ANTICOAGULANTS-ANTIBIOTICS
A number of
anti-infective agents enhance the effect of concurrently administered anticoagulants as a result of inhibiting
the production of Vitamin K by the microorganisms in the GI
tract. Eg: Broad-spectrum antibiotics
such as the tetracyclines.
Other mechanisms: when sulfonamides and anticoagulants are given concurrently, anticoagulant effect is increased, due to
displacement of the anticoagulant from protein-binding sites and/or
inhibition of its hepatic metabolism by sulfonamides.
DIGOXIN-ANTIBIOTICS
In G.I tract,
significant portion of the digoxin compound is
converted to inactive metabolites by the bacterial flora of
the Intestine.
When
Erythromycin or Tetracycline is administered concurrently, serum concentrations
of digoxin are elevated due to inhibition of the bacterial flora.
ORAL
CONTRACEPTIVES-ANTIBIOTICS
The estrogen
component of the contraceptive formulation is conjugated to a large extent in
the liver and excreted in the bile. Bacteria in the intestine hydrolyses the
conjugated form of the estrogen, permitting the free drug to be reabsorbed, and
contribute to the serum concentration
of the estrogen.
Several
Antibiotics (eg: Ampicillin ), by reducing the bacterial flora, may interrupt
the enterohepatic circulation, with a resultant reduction in serum estrogen
concentrations.
MALABSORPTION STATES
Certain drugs, such as laxatives, colchicine,
cholestyramine, and colestipol, have been reported to cause malabsorption problems
that result in decreased absorption of vitamins and nutrients from the G.I
tract.
B. DISTRIBUTION
1. ALTERATION
OF DISTRIBUTION
Displacement
from Protein-Binding Sites
An interaction
of this type may occur when two drugs that are capable of binding to proteins are administered concurrently.
Although they may bind at different sites on the protein, the binding
characteristics of one of the drugs may be altered (noncompetitive
displacement).
Probably more
significant are the situations in which two drugs are capable of binding to
the same sites on the protein (competitive displacement). Since there are only
a limited number of protein-binding sites, competition will exist, and the drug
with the greater affinity for the
binding sites will displace the other from plasma or tissue proteins.
The
protein-bound fraction of a drug in the body is not pharmacologically active. However, equilibrium exists between bound
and unbound fractions, and as the unbound or free form of the drug is
metabolized and excreted, bound drug is released gradually to maintain the
equilibrium and pharmacological response.
The binding of
acidic drugs to serum albumin represents the type of drug-protein binding that
has been studied most extensively. The binding to albumin is readily
reversible, and the albumin-drug complex essentially serves as a reservoir
that releases more drug as the free drug is metabolized and/or excreted.
The importance
of the binding of basic drugs (eg, propranolol, lidocaine) to Alpha1(α1)-acid glycoprotein
(AAG) also has been recognized. Even small increases in the reactant protein
concentration, such as might be associated with infection and inflammation, can result in
significant changes in the concentration of free drug.
The risk of an
interaction occurring is greatest with drugs that are highly protein-bound
(more than 90%) and also have a small apparent volume of distribution. Since
only a small fraction of the drug ordinarily would be available in the free form, the displacement
of even a small percentage of the amount that is bound to proteins could
produce a considerable increase in
activity.
The risk of
interactions resulting from protein displacement appears to be greatest during
the first several days of concurrent therapy. It has been suggested that drugs
having the greatest capability of displacing a highly bound drug such as
warfarin can increase the anticoagulant response within 24 hr
and exhibit maximum potentiation in 3 to 5 days. After this period the effect levels off since
the drug, as a result of greater amounts being available in the unbound form,
also is being metabolized more rapidly and excreted. Therefore, the anticoagulant
usually has a shorter half-life when a displacing agent is given concurrently.
METHOTREXATE
Salicylates displace
the Methotrexate from protein binding sites of plasma proteins to which it is
highly bound.
salicylates also
increase the action of methotrexate by inhibiting its renal excretion.
PHENYTOIN-VALPROIC ACID
Valproic acid
displace phenytoin from plasma protein-binding sites, and also inhibit the
metabolism of phenytoin, which leads to increased free phenytoin concentrations
and the occurrence of adverse events.
REDUCED ALBUMIN CONCENTRATIONS
As many drugs
are bound extensively to plasma proteins, a decreased concentration or amount
of protein could change the availability of drugs and thus their activity. Incidence of adverse events with
certain drugs may be higher in patients with conditions associated with
hypoalbuminemia (eg, renal, hepatic, and GI diseases).
Eg: A
relationship between prednisone dosage, frequency of adverse events, and serum
albumin concentrations.
When the serum
albumin concentration is less than 2.5 g/100 ml, the frequency of prednisone adverse events is almost doubled,
and this is attributed to an increased concentration of prednisolone, an active
metabolite of prednisone.
Eg: Incidence of adverse events to phenytoin is greater in hypoalbuminemic patients, due to increased circulating
concentrations of unbound phenytoin.
C. METABOLISM
1. STIMULATION OF METABOLISM
Drug metabolism occurs primarily in the liver and most commonly involves oxidation, reduction, hydrolysis, and conjugation (eg. with glucuronic acid)
reactions.
Quantitatively, the most important hepatic enzymes are the cytochrome P-450 enzymes, which have been divided into families and
subfamilies (eg. CYP3A4) on the
basis of the similarity of their amino acid sequences. These enzymes are
responsible for the oxidation,
hydroxylation.
Many drug interactions results from, the ability of one drug to stimulate the metabolism
of another, most often by increasing the activity of hepatic enzymes that are involved in the metabolism of numerous therapeutic agents. The
increased activity
probably is due to enhanced enzyme synthesis, resulting in increased amounts of
drug-metabolizing enzymes, an effect frequently referred to as Enzyme Induction.
Eg: Barbiturates,
phenytoin, carbamazepine, rifampin, & herbal product
In most situations, drugs are converted to less active, water-soluble metabolites, and enzyme
induction usually will result in an increased metabolism and excretion and a reduced pharmacological action of the agent being metabolized by
hepatic enzymes. Less frequently, a drug may be converted to a metabolite that is more active than
the parent compound, and there may be an enhanced response. However, the initially increased effect may subsequently diminish,
since the drug will be excreted more rapidly and have a shorter duration of
action.
The stimulation of hepatic enzyme activity is not only a factor in the development of drug interactions, but also may be responsible for a drug (eg.
carbamazepine) stimulating its own metabolism. With continued use, the half-life of the
drug will decrease
and possibly resulting in a need to increase the dosage.
WARFARIN-PHENOBARBITAL
Phenobarbital increases the rate of metabolism of warfarin by causing enzyme
induction which results in a decreased response of the anticoagulant. As warfarin is being more
rapidly metabolized and excreted, possibly leading
to an increased risk of thrombus formation.
ORAL CONTRACEPTIVES
Phenobarbital, rifampin, and other drugs are known to increase the metabolism
of steroid hormones, including
estrogens and progestins that are used in oral contraceptive formulations.
As Phenobarbital, rifampin, and other drugs are capable of causing enzyme induction indeed may reduce the
effectiveness of oral contraceptives, possibly resulting in an unplanned pregnancy.
HIV PROTEASE INHIBITORS
HIV protease inhibitors (eg, amprenavir, atazanavir, lopinavir, nelfinavir) are extensively metabolized via CYP3A/3A4 pathways, and the concurrent use of an enzyme
inducer could reduce their action and compromise the effectiveness
of the anti-retroviral regimen for HIV infection/AIDS.
Rifampin
is such a strong enzyme inducer, so concurrent use with HIV protease inhibitors
is contraindicated.
SMOKING
In individuals who are heavy smokers, the effects of certain drugs may be
decreased,
because of increased hepatic enzyme activity resulting from the action of polycyclic
hydrocarbons
that are present in cigarette smoke.
Drugs like diazepam, propoxyphene, theophylline, pentazocine, & olanzapine, whose metabolism is increased and therapeutic
activity likely to be reduced due to smoking.
When therapy is given with certain drugs , careful monitoring is done as the drugs
are metabolized by hepatic enzyme systems in patients who are
moderate or heavy smokers. And caution also must be exercised if a patient treated with
such a medication
discontinues smoking.
A significant
risk of toxicity exists when oral contraceptives are used by women who smoke, as smoking increases the
risk of serious cardiovascular effects (eg. myocardial infarction), especially in women over 35 years of age.
ALCOHOL
Alcohol may either stimulate or inhibit the activity of hepatic enzymes. Rate of metabolism of warfarin
and phenytoin is
increased in alcoholic patients. This was attributed to increased liver enzyme activity
caused by chronic administration of
alcohol.
In contrast, acute use of alcohol by nonalcoholic individuals may cause inhibition of hepatic
enzymes. This may decrease the rate of metabolism; thereby increasing the
effect of other agents administered concurrently, and may be responsible for the enhanced sedation experienced when alcoholic beverages and sedative
drugs are taken together by individuals who are not alcoholics.
LEVODOPA-PYRIDOXINE
Pyridoxine reduces the action of levodopa by accelerating its decarboxylation to dopamine in the peripheral tissues.
Consequently, less levodopa reaches and crosses the blood-brain barrier, with
the result that less dopamine is
formed in the brain and the therapeutic
effect is diminished.
Doses of pyridoxine of 10 to 25 mg rapidly reverse the effect of the anti-Parkinson drug. Sinemet contains both levodopa and carbidopa, the carbidopa acting as an
inhibitor of decarboxylase enzymes. When levodopa is administered with carbidopa, the dose of the levodopa is lowered, as decarboxylation
pathway of levodopa is inhibited by carbidopa. The decrease
in dosage often is accompanied by a decreased incidence of adverse effects. Since carbidopa does not cross the blood-brain
barrier, it will not hinder the conversion
of levodopa to dopamine in the brain.
Levodopa is metabolized also in the peripheral tissues in a pathway that is catalyzed by catechol-O-methyl transferase (COMT). When the decarboxylation
pathway is inhibited by carbidopa, the O-methylation
pathway becomes the primary pathway through which levodopa is metabolized in the
peripheral tissues. The COMT inhibitor entacapone was developed to inhibit this metabolic pathway and has
been used in conjunction with levodopa and carbidopa.
Stalevo® contains combination of Levodopa + carbidopa + entacapone.
2. INHIBITION OF METABOLISM
One drug inhibits the metabolism
of another, usually resulting in a prolonged and intensified activity of the latter drug.
ALCOHOL-DISULFIRAM
Disulfiram is used in the
treatment of alcoholism. Disulfiram inhibits the activity of aldehyde dehydrogenase, thus
inhibiting oxidation
of acetaldehyde, an oxidation product of alcohol. This results in accumulation of
excessive quantities of acetaldehyde and development of the unpleasant effects characteristic of
the disulfiram reaction.
Disulfiram is not a selective inhibitor of aldehyde dehydrogenase but exhibits several inhibitory actions that can result in
the development of drug interactions. It can enhance the activity of warfarin
and phenytoin by inhibiting their metabolism.
Another example is reaction
between metronidazole and alcohol.
MERCAPTOPURINE OR AZATHIOPRINE – ALLOPURINOL
Allopurinol is used in the treatment of gout. Allopurinal acts by
inhibiting the enzyme xanthine oxidase , reduces the production of uric acid .
Xanthine oxidase also has an important role in the metabolism of potentially toxic
drugs such as mercaptopurine and azathioprine, and when this enzyme is inhibited by allopurinol, the effect of the latter agents can be increased markedly.
When allopurinol is given in doses of 300 to 600 mg/day concurrently with
either of these drugs, it is advised that the dose of mercaptopurine or
azathioprine be reduced to about
1/3 to 1/4 the usual dose.
CIMETIDINE
Cimetidine inhibits hepatic oxidative enzyme systems. So the action of other agents that are metabolized
extensively via these pathways will be increased.
Cimetidine has interactions with carbamazepine, diazepam, phenytoin, theophylline, warfarin, and other agents. So it is
necessary to reduce the dosage of
these agents when cimetidine is
included in the therapeutic
regimen.
Ranitidine also binds to a limited extent to the cytochrome P-450 enzymes involved in
the metabolism of these agents, but it appears to have a lesser affinity for the enzymes
than does cimetidine.
Other Histamine H2-receptor antagonists (famotidine and nizatidine) are not likely to inhibit oxidative
metabolic pathways and to interact
with other drugs via this mechanism.
THEOPHYLLINE - MACROLIDE
ANTIBIOTICS
Erythromycin increases the serum concentrations of theophylline by
inhibiting its hepatic metabolism.
Patients receiving high doses of theophylline or who are otherwise predisposed to theophylline toxicity should be
monitored closely if erythromycin is administered concurrently. The clarithromycin and telithromycin also inhibit the
metabolism of theophylline, whereas azithromycin is unlikely to interact.
THEOPHYLLINE-FLUOROQUINOLONES
Ciprofloxacin increase the plasma concentrations and activity of
theophylline by inhibiting its hepatic metabolism, and concurrent use is best avoided.
Certain other fluoroquinolones, such as levofloxacin, are not likely to inhibit hepatic
enzyme systems and interact with
theophylline.
MAOIs
There have been many reports of drug interactions involving use of an MAOI with
another drug or with certain dietary items. It is likely that MAOIs enhance the
effect of drugs such as the barbiturates and opioid analgesics by inhibiting hepatic enzyme systems involved
in their metabolism. However, other mechanisms are involved in some of the more publicized problems with these
compounds and are considered elsewhere
in this chapter.
CALCIUM CHANNEL BLOCKING AGENTS
Calcium
channel blocking agents (eg. Diltiazem, nifedipine, verapamil) interact with a
number of drugs, although the mechanisms through which these interactions occur are not
completely defined.
It has been suggested that verapamil and diltiazem may inhibit the hepatic metabolism
of carbamazepine, thereby increasing the activity of
the latter agent. Because the calcium channel blocking agents are metabolized themselves in the liver, they may
interact with certain drugs because they are competing for the same metabolic
pathways.
D. EXCRETION
1. ALTERATION
OF EXCRETION
Although some therapeutic agents are eliminated via other mechanisms, most drugs and their
metabolites are excreted via kidneys.
The most important clinical implications of altering
renal excretion involve the use of drugs that are excreted in their unchanged form or in the
form of an active
metabolite. Thus, substances with pharmacological activity are being reabsorbed or excreted to a greater
extent when renal excretion is altered.
In contrast, when only inactive metabolites are being excreted, changes in therapeutic
activity are less likely to be associated
with the use of other drugs that can influence renal excretory pathways.
2. ALTERATION
OF URINARY pH
SALICYLATES-ACIDIFYING
AND ALKALINIZING AGENTS
A change in
urinary pH will influence the ionization of weak acids and weak bases and thus
affect the extent to which these agents are reabsorbed and excreted. When a
drug is in its non-ionized form it will
diffuse more readily from urine back into blood. Therefore, for an
acidic drug, there will be a larger proportion of drug in the non-ionized form
in acid urine than in alkaline urine
where it will exist primarily as an ionized salt. The result is that from acid
urine more of an acidic drug will diffuse back into the blood and produce a prolonged, and perhaps
intensified, activity.
Salicylate
dosage regimen that provided a serum concentration of 20 to 30 µg/mL in a
patient when the urinary pH was approximately 6.5 produced serum
concentrations that were approximately twice as high when the urinary pH was
decreased to 5.5. The risk of a significant interaction is greatest in patients
who are taking large doses of salicylates (eg, for arthritis).
AMPHETAMTNES-ALKALINIZING
AGENTS
The excretion of
a dose of basic drug like dextroamphetamine at urinary pH values of
approximately 5 & 8. when the urinary pH was maintained at approximately
5, 54.5% of the dose of
dextroamphetamine was excreted within 16
hr, compared with a 2.9% excretion in the same period when
the urinary pH was maintained at approximately 8.
For basic drug like quinidine, quinidine
toxicity is observed when urine becomes alkaline, since excretion of quinidine
is decreased considerably as urinary pH was raised.
For
pseudoephedrine, when the urinary pH was increased to about 8 with sodium bicarbonate, the plasma half-life of
pseudoephedrine was approximately double that in normal subjects. When urinary
pH in the same subjects was decreased to 5.2. using ammonium chloride, the plasma half-life
decreased markedly from control values.
3. ALTERATION
OF ACTIVE TRANSPORT
PENICILLINS-PROBENECID
A number of
organic acids undergo active transport from the blood into the tubular urine
and vice versa. In some situations these agents interfere with the
excretion of each other.
Probenecid
increase serum concentrations and prolong activity of penicillin derivatives
by blocking their tubular secretion.
Probenecid
also decreases renal excretion of
other agents, including methotrexate.
METHOTREXATE - NONSTEROIDAL ANTI-INFLAMMATORY DRUGS
Nonsteroidal
anti-intlammatorydrugs(NSAIDs) increase the activity and toxicity of methotrexate. Methotrexate toxicity is seen in patients
receiving ketoprofen, as it inhibits the active renal tubular secretion of
methotrexate.
LITHIUM - NONSTEROIDAL ANTIINFLAMMATORY DRUGS
The serum
concentrations and incidence of adverse effects of lithium salts are increased by the
concurrent administration of anti-inflammatory agents such as ibuprofen,
indomethacin and piroxicam.
It is suggested
that the renal clearance of lithium is reduced as a result of the action of
these anti-inflammatory agents to inhibit renal prostaglandin synthesis.
4. ALTERATION
OF DRUG TRANSPORT
P-glycoprotein
has more importance in the absorption, distribution, metabolism, and excretion of certain drugs. P-glycoprotein
functions as a transport system that may act as a barrier for certain agents
and as a pump that facilitates the transport of certain agents across
membranes.
For example, it
limits cellular uptake of certain drugs from the blood into the brain and from
the intestinal lumen into epithelial cells.
The role of
P-glycoprotein in the overall absorption of a drug that is administered orally
in high milligram doses is not clinically important because this transport
system is quickly saturated by the
high concentrations of drug in the intestinal lumen. However, its role may be
important in the absorption of drugs that are administered orally in very small
doses (eg, digoxin).
There are
numerous substrates for P-glycoprotein including drugs such as cyclosporine, digoxin,
diltiazem, verapamil, atorvastatin, lovastatin, simvastatin, doxorubicin,
pacfitaxel, HIV protease
inhibitors, and loperamide.
There is
overlapping substrate specificity between P-glycoprotein and CYP3A4, and many
of the drugs that inhibit or induce CYP3A4 also inhibit or induce
P-glycoprotein. Therefore, drug interactions that result from inhibition or
induction of CYP3A4 often also
involve inhibition or induction of P-glycoprotein.
Inhibitors of
P-glycoprotein are clarithromycin, erythromycin, itraconazole, ketoconazole, quinidine, and
verapamil. Inducers include such agents as rifampin and
DIGOXIN-QUINIDINE
OR VERAPAMIL
Concurrent use
of quinidine or verapamil with digoxin results in greater serum digoxin
concentrations.
Both quinidine
and verapamil are inhibitors of P-glycoprotein which results in increased
absorption, decreased elimination, and higher concentrations of digoxin.
Inducers of
P-glycoprotein such as rifampin and
LOPERAMIDE-P-GLYCOPROTEIN
Antidiarrheal
agent loperamide, cause central nervous system adverse events because P-glycoprotein prevents it from crossing the
blood-brain barrier and gaining access to the central nervous system.
If a patient
using loperamide is also treated with a P-glycoprotein inhibitor, CNS effects
that are characteristic of the opioids may be experienced.
PHARMACODYNAMIC INTERACTIONS
DRUGS HAVING OPPOSING PHARMACOLOGICAL
EFFECTS
Interactions resulting from
the use of two drugs with opposing effects should be among the easiest to
detect. However, these sometimes are due to the secondary effects of certain
drugs and this and other factors may preclude early identification of such
situations.
DIURETICS
The thiazides and certain other diuretics
elevate blood glucose concentrations.
When the diuretic is prescribed for a diabetic patient being treated with
insulin or one of the oral antidiabetic agents, this action may partially
counteract the glucose-lowering action of the antidiabetic drug, necessitating
an adjustment in dosage.
Similarly, many
diuretics produce hyperuricemic effect. Therapy in patients with gout should
be monitored closely, as the hyperuricemic action of a diuretic may
necessitate an adjustment in dosage of the agent being used in the treatment of
gout.
DRUGS
HAVING SIMILAR PHARMACOLOGICAL EFFECTS
An excessive response attributable to the concurrent use of drugs having similar actions is the type of interaction that
occurs most often, and these potential problems warrant particular attention.
CNS DEPRESSANTS
Concurrent use
of two or more drugs exhibiting a depressant action results in an excessive CNS depressant effect. Patients experience effects such as sedation
and dizziness are at increased risk
of falls and injuries, such as hip fractures.
In considering
multiple drug regimens, agents (eg, sedative-hypnotics, antipsychotics,
tricyclic antidepressants, opioid analgesics, and most antihistamines) that can
exhibit a depressant effect that will be at least additive to the effect contributed
by other drugs.
ALCOHOI - OTHER CNS
DEPRESSANTS
In patients who
take alcoholic beverages, CNS depressant effect of the drug prescribed is
increased.
DRUGS HAVING ANTICHOLINERGIC ACTIVITY
Drugs that
differ considerably in their primary pharmacological actions may exhibit the
same secondary effects.
Some patients
being treated with antipsychotic agents such as chlorpromazine are given an
antiparkinson agent such as trihexyphenidyl to control the extrapyramidal
effects of the chlorpromazine. In addition, a number of these patients
experience symptoms of depression,
and a tricyclic antidepressant such as amitriptyline
might be added to the therapy.
Each of these three agents possesses anticholinergic activity, and the additive
effect could result in side effects such as dryness of the mouth, blurred vision, urinary
retention, constipation, and
elevation of intraocular pressure.
The patient experiencing persistent
dryness of the mouth as a side effect and when nitroglycerin tablets were administered sublingually for the
management of exertional angina, the relief of the symptoms is delayed because of the slower dissolution of the sublingual tablets.
An excessive anticholinergic effect can cause an atropine like delirium, particularly in geriatric
patients. This effect could be
misinterpreted as an increase in psychiatric symptoms, which might be treated
by increasing the
dosage of the therapeutic agents that are actually responsible for causing the problem. This example points out
the difficulty
that often can exist in distinguishing between the symptoms of the
condition(s) being treated and the effects of the drug(s) being employed as therapy.
The blurring of vision, which also may be associated with the use of
drugs having anticholinergic activity, may be especially distressing for older patients,
particularly those whose physical activities may be limited and for whom reading is a
favorite activity.
Patients taking
phenothiazine-antiparkinson combinations & exposed to high environmental temperature and humidity severe hyperpyrexia is observed. As combinations interfere with
the thermoregulatory
system of the body, So for physicians it is recommended that patients treated in hot
and humid climates should minimize outdoor exposure of patients receiving high doses of these agents.
DRUGS EXHIBITING HYPOTENSIVE
EFFECTS
Certain antihypertensive drugs as well as some other classes of medications (eg. tricyclic
antidepressants) can cause orthostatic hypotension, resulting in symptoms such as
dizziness, lightheadedness,
and in more severe cases syncope.
Older patients are more susceptible to this type of response and the associated risks such as falls and
injuries, and appropriate precautions should be exercised whether these agents are given alone or in combination.
The use of sildenafil, tadalafil, and vardenafil in the treatment of erectile dysfunction is contraindicated in patients treated with nitrates because
these agents may potentiate the hypotensive
effect of the nitrates.
NSAIDs
Some patient unknowingly may take several
different products that contain the same NSAID. An arthritic patient whose condition who take ibuprofen obtained through
prescription may purchase an ibuprofen product available
without a prescription for pain/discomfort not associated with the arthritis,
without recognizing that the two products
contain the same drug and that there is an increased risk of adverse effects.
3.ALTERATION
OF ELECTROLYTE CONCENTRATIONS
Several important drug
interactions occur as a result of the ability of certain therapeutic agents to
alter the concentration of electrolytes such as potassium and sodium.
DIGOXIN – DIURETICS:
Diuretics (eg, the thiazide derivatives) cause
an excessive loss of potassium.
Particular caution is necessary in patients being treated with digoxin, many of
whom would be candidates for diuretic therapy. If
potassium depletion remains uncorrected, the heart may become more sensitive to the effects of the cardiac glycoside and arrhythmia
may result.
When both digoxin & diuretic therapy is given, alternately potassium
supplementation are given but sometimes it may leads to risk of
hyperkalemia , such risk is more in patients with diminished renal function.
In addition to
the diuretics, other agents also cause potassium
depletion. Prolonged therapy with cathartics and corticosteroids may cause potassium depletion, not
likely to occur as quickly or to the same extent as with diuretics.
Diuretic therapy may lead to development of magnesium depletion, and as observed when potassium is depleted, the activity of
digoxin may be increased and possibly result in toxicity.
In some patients with digoxin toxicity, low serum-magnesium concentrations may coexist with
normal potassium values.
ANGIOTENSIN CONVERTING ENZYME INHIBITORS -
POTASSIUM SPARING DIURETICS
ACE inhibitors (eg, enalapril, lisinopril, ramipril) may cause an elevation of serum
potassium concentrations.
Potassium-sparing
diuretics (amiloride, spironolactone, and
triamterene) or potassium supplements should
be used concurrently with caution, because of the risk of hyperkalemia and associated complications. Salt
substitutes containing potassium
also should be used with caution.
LITHIUM-DIURETICS
Sodium depletion is known to increase lithium toxicity.
So it has been recommended that lithium salts should not be used in patients on diuretic therapy or on a sodium-restricted diet. Even
protracted sweating or diarrhea can cause sufficient depletion of sodium to result in decreased
tolerance to lithium.
The sodium depletion caused by diuretics reduces the renal clearance and increases the activity
of lithium.
4.
INTERACTIONS AT RECEPTOR SITES
MAO INHIBITORS - SYMPATHOMIMETIC AGENTS
MAO metabolizes the catecholamines such as nor-epinephrine. When the enzyme is inhibited, the concentrations of nor-epinephrine within adrenergic
neurons increase, and a drug that can stimulate its release can bring about an
exaggerated response.
Exaggerated response is due to interactions between MAO Inhibitors and indirectly acting sympathomimetic
amines (eg. amphetamine) is
seen. The effects due to these
interactions are severe headache,
hypertension (possibly a
hypertensive crisis), and cardiac arrhythmias.
Although most sympathomimetic amines, such as amphetamine, are available only by prescription, others such as phenylephrine, which also interact similarly with MAOIs, are found in
many nonprescription cold and allergy preparations. It is important that patients being treated with
MAOIs avoid using products containing these agents.
MAO INHIBITORS - TRICYCLIC
ANTIDEPRESSANTS
Concurrent use of MAO Inhibitors
with a tricyclic antidepressant (eg, amitriptyline, imipramine) results in severe
atropine-like reactions, tremors, convulsions, hyperthermia, and vascular collapse.
MAO INHIBITORS - SELECTIVE SEROTININ REUPTAKE
INHIBITORS
Serious consequences may result from the combined use of an MAO Inhibitors and selective serotonin reuptake
inhibitors (SSRI) (citalopram,
escitalopram, fluoxetine, fluvoxamine,
paroxetine, sertaline). So concurrent use or use within 14 days before or after most of
these agents is contraindicated.
Because of the long half-lives of fluoxetine and its active metabolite, it is
recommended that at least 5 weeks should elapse between discontinuation of fluoxetine and initiation of therapy with an MAOI.
It should be noted that the antineoplastic procarbazine and the anti-infective furazolidone
and linezolid, also can inhibit MAO enzymes, and warnings applying to the use of other
MAOIs should be heeded for these
drugs also.
GUANETHIDINE-TRICYCLIC ANTIDEPRESSANTS
Guanethidine is transported to its site of action within adrenergic neurons by a transport
system that also is responsible for uptake of nor-epinephrine, as well as several indirectly
acting sympathomimetic amines such as
ephedrine and the amphetamines. Concentration of guanethidine in these neurons is
necessary for its antihypertensive action.
Tricyclic antidepressants inhibit the uptake of guanethidine into the neuron terminal, thereby preventing its
concentration at these sites and reducing its activity.
Antipsychotic agents such as chlorpromazine and haloperidol can act similarly to the tricyclic antidepressants in
reducing the antihypertensive effect of
guanethidine.
DRUG - FOOD INTERACTIONS
Ø
It is known that
food can influence the absorption of a number of drugs. In some situations, absorption may be delayed
but not reduced, whereas in other circumstances the total amount of drug
absorbed may be reduced.
Ø
The effect of
food in influencing drug absorption sometimes is due to its action in slowing gastric emptying. However, food also
may affect absorption by binding with drugs, decreasing the access of drugs to
sites of absorption, altering the dissolution rate of drugs, or altering the pH
of the GI contents.
ANTI INFECTIVE AGENTS - FOOD:
Ø
The presence of
food in the GI tract will reduce the absorption of many anti-infective agents.
Although there are some exceptions (eg. peni-cillin V, amoxicillin, doxycycline,
minocycline), it generally is rec-ommended that the penicillin and tetracycline
derivatives as well as certain
other anti-infective agents be given at least 1 hr before meals or 2 hr after
meals, to achieve optimum absorption.
Ø
Erythromycin
stearate formulations should be administered at least 1 hr before meals or 2 hr
after a meal, whereas formulations of erythromycin ethyl succinate may be
given without regard to meals.
CAPTOPRIL – FOOD :
Ø The presence of food in the GI
tract has been reported to reduce the absorption of captopril by 30 to
40%. Food does not appear to alter the absorption of most
of the other angiotensin-converting enzyme inhibitors
(eg, enalapril, lisinopril).
Ø ALENDRONATE AND RISEDRONATE-FOOD:
Food and even orange juice, coffee,
and mineral water reduce the bioavailability of alendronate and risedronate and it is recommended that these
drugs be administered soon after arising at least 1/2 hr before any food, beverage, or
medication, with plain water only.
ARBOSE & MIGLITOL - FOOD:
The
maximum effectiveness of acarbose (an antidiabetic drug) is attained when the
drug is taken immediately at the start of each meal (not ½ hr befor or after),
because it delays the carbohydrate absorption (from the meal) and reduce the elevation of blood glucose concentrations
by inhibiting the enzyme α- glucosidase.
Ø
SOME OTHER INTERACTIONS ARE :
- Several tyramine food
containing foods (eg: matured cheese, red wines, riped bananas, yoghurt, shrimp paste, salami)
are capable of producing hypertensive crisis in patients taking MAO
Inhibitors.
- Food can pharmacodynamically
antagonise the effect of many drugs. For example, spinach & brocoli
provide dietary source of vitamin K which antagonises the effect of warfarin
.
- Tetracyclines complex with
calcium found in milk products.
- Food increases the
bioavailability of griseofulvin, metoprolol , propronolol, phenytoin , dextropropoxyphene , & dicumarol.
- Food delays or reduces the bioavailability
of NSAIDS, tetracycline, ethanol & didanosine (antiviral drug).
- Grape fruit and oranges
inhibit CYP 3 A 4 isoenzyme system, increases the bioavailability of indinavir , saquinavir , midazolam ,
nimodipine , nifedipine , lovastatin ,
carbamazepine &
verapamil.
- Rich protein diet results in
acidic urine (pH 5.9), which Promotes excretion of basic drugs (like amphetamines)
while low protein diet provides alkaline urine (pH 7.5) which promotes
excretion of acidic drugs (eg: aspirin).
- The rate of metabolism of theophylline
is increased in individuals consuming large amounts of charcoal broiled
beef because of enzyme inducing effects of polycyclic hydrocarbons
(introduced in this cooking process).
BAL INTERACTIONS DRUG - HER
Ø The
nature of herb-drug interactions is not a chemical interaction between a drug
and an herb component to produce something toxic. Instead, the interaction may
involve having an herb component cause either an increase or decrease in the
amount of drug in the blood stream.
Ø A
decrease in the amount of drug could occur by herb components binding up the
drug and preventing it from getting into the blood stream from the
gastrointestinal tract, or by stimulating
the production and activity of enzymes that degrade the drug and prepare
it for elimination from the body.
Ø An
increase in the drug dosage could occur when an herb component aids absorption
of the drug, or inhibits the enzymes that breakdown the drug and prepare it for
elimination. A decrease in drug dosage
by virtue of an interaction could make the drug ineffective.
Ø An
increase in the drug dosage could make it reach levels that produce side
effects.
Ø Alternatively,
an herb might produce an effect that is contrary to the effect desired for the
drug, thereby reducing the drug effect; or , an herb might produce the same
kind of effect as the drug and give an increase in the drug effect(without
increasing the amount of the drug).
v DUE TO THE HERB-DRUG
INTERACTIONS, THE HERB MAY
·
Increase or decrease
the effect of a blood thinner such as warfarin and lead to either a bleeding episode or formation of
dangerous clot.
·
Decreasing the effect
of a blood pressure medication, leading to high blood pressure and a stroke.
·
Decreasing the effect
of an anti-infection agent, letting the infection get out of control; or
·
Increasing the effect
of an anti-diabetes drug and plunge blood sugar to dangerously low levels.
v EXAMPLE OF CERTAIN
HERBS AND ITS EFFECT ON CERTAIN DRUG
·
Aloe Vera’s latex has
laxative properties & lowers blood sugar. Hence, concurrent
use of laxatives and hypoglycaemic agents should be avoided. It may also decrease
the intestinal absorption of vitamin k
and thus may potentiate anticoagulant
effects of warfarin.
·
Asian / Chinese ginseng
potentiates the effects of anticoagulants, antiplatelet drugs, sympathomimetics,
caffeine, MAO Inhibitors & CNS stimulants (“ginseng abuse syndrome” with diarrhoea,
hypertension & tremors). It decreases
the effects of antihypertensive
drugs, cardiac glycosides & hormone replacement therapy.
·
Ginkgo biloba increases
the bleeding tendency with concurrent use of antiplatelet and anticoagulant drugs.
·
Kava – Kava has
summative effects with benzodiazepines & other CNS depressants drugs. Use of antipsychotics
is levodopa may potentiate dystonias.
·
St.John’s wort leads to
phototoxicity when used with
tetracyclines, sulfonamides & proton pump
inhibitors & summation effects with CNS depressants; decreases plasma
concentration of digoxin , cyclosporin , warfarin , & protease
inhibitors.
·
Administration of
garlic with anticoagulant & antiplatelet drugs should be avoided because of
the risk of bleeding. Garlic decreases the effectiveness of gastrokinetic drugs
such as cisapride , metoclopramide & domperidone.
·
Ginger also, increases
the risk of bleeding when used concomitantly with antiplatelet / anticoagulant
drugs.
Ø In
China it is common for herbs to be combined with drugs. Their combination is
sometimes incidental, but is often intentional and based on a prevalent
favourable theory about using herbs and drugs.
Ø The
openion of Chinese doctors is that herbs reduce the side effects of drugs and
help them to perform their function better, inturn drugs with an herb formula
work more strongly and quickly. Together, herbs and drugs may produce a more
desirable result than either taken alone. But little attention has been paid to
adverse herb-drug interaction.
Ø In
the West, the drugs were more reliable than herbs. The reintroduction of herbs
bring with it suspicions and concerns about their unreliablity and the lack of
adequate knowledge about them.
Ø The
“ xanthines”, such that the caffeine containing herbs(eg: coffee and tea) could
counteract the action of sedatives or excessive stimulation with stimulant
drugs.
Ø The
“coumarine containing” which makes reference to the fact that sum herbs contain
coumarins which might act along with warfarin, a coumarine(binary coumarine,
much more potent than coumarins) or along with other blood thinners.
CHINESE HERBS
Ø The
possible interaction of minor bupleurum combination(Xiao Chaihu Tang; in Japan; Sho
Saiko To) with interferon in treatment of hepatitis to cause an immune response leading to lung damage.
Ø The
possible interaction of saliva (Danshen)
and warfarin, leading to excessive thinning.
Ø Th
e possible interaction of aristolochic acid and diuretic drugs(or others) to
cause renal failure.
HERBALS AND DRUG
INTERACTION
|
Name of Herb
|
Some common uses
|
Possible side effects
or drug interactions
|
|
Cayenne
|
Extenal:
used for muscle spasam and sourness
Internal:
GI tract disorders
|
External:potential
for skin ulceration and
blistering with greaterthan two days
of use.
Internal:
overuse may cause severe hypothermia.
|
|
Echinacea
|
Echinacea
boosts the immune system helps fight
colds and flu. Aids wound healing.
|
Echinacea
may cause inflamation of the liver if used with certain other medications,
such as anabolic steroids, methotrexate or others.
|
|
Ephedra
|
Ephedra
is also called Ma-huang. It is used in many over-the-counter diet aids as an
appetite suppressant. It is
also used for asthama or bronchitis.
|
Ephedra
may interact with certain antidepressant medications or certain high blood pressure medications to cause dangerous elevation
in blood pressure or heart rate. It could cause death in certain individuals.
|
|
Feverfew
|
Feverfew
is used to ward off migrane
headache and for arthritis, rheumatic disease and allergies.
|
Feverfew
may increase bleeding, especially in patients already taking certain
anti-clotting medications.
|
|
Garlic
|
Garlic
is used for lowering blood cholesterol, triglyceride levels and blood pressure.
|
Garlic
may increase bleeding, especially
in patients already taking certain anti-clotting medications.
|
|
Ginger
|
Ginger
is used for nausea, vomiting and
vertigo.
|
Ginger
may increase bleeding, especially in
patients already taking certain anti-clotting medications.
|
|
Ginkgo
|
Ginkgo,
also called Ginkgo billoba, it is
used for increasing blood circulation and oxigenation and for improving
memory and mental alertness.
|
Ginkgo
may increase bleeding especially in
patients already taking certain anti-clotting medications.
|
|
Ginseng
|
Ginseng
increases physical stamina and mental
concentration.
|
Ginseng may cause decreased
effectiveness of certain anti-clotting medications.Persons using Ginseng see
increased heart rate or high blood pressure. It may cause bleeding in women
after menopause.
|
|
Goldenseal
|
Goldenseal
is used as a mild laxative and also
reduces inflamation.
|
Goldenseal
may worsen swelling and or high blood pressure.
|
|
Kava-Kava
|
Kava-Kava
is used for nervousness,
anxiety or restlessness, it is also a muscle relaxant.
|
Kava-Kava
may increase the effects of certain anti-seizure medications and or prolong
the effects of certain anesthetics. It can enhance the effects of alcohol. It may increase risk
of suicide for people with certain
types of depression.
|
|
Licorice
|
Licorice
is used for treating
Stomach
ulcers.
|
Certain
licorice compounds may cause high blood pressure, swelling or electrolyte
imbalance.
|
|
Saw Palmetto
|
Saw
Palmetto is used for enlarged prostate and urinary inflamations.
|
People
using Saw Palmetto may see effects with other hormone therapies.
|
|
St. John’s Wort
|
St.
John’s Wort is used for mild to moderate depression or anxiety and sleep disorders.
|
St.
John’s Wort may prolong the effect of anesthetic agents.
|
|
Valerian
|
Valerian
is used as mild sedative or sleep aid. It is also a muscle relaxant.
|
Valerian
may increase the effects of certain anti-seizure medications or prolong the
effects of certain anesthetic
agents.
|
DRUG INTERACTIONS WITH
HERBAL PRODUCTS:
|
Herbal Product
|
Interacting Drugs
|
|
Ginkgo
biloba
|
Asprin,warfarin(Coumadin),ticpidine(Ticid),clopidogrel(Plavix),dipyridamole(Persantine)
|
|
St.
John’s wort
|
Antidepressants
|
|
Ephedra
|
Caffeine,decongestants,stimulants
|
|
Ginseng
|
Warfarin
|
|
Kava
|
Sedatives,
sleeping pills, anitpsychotics, alcohol
|
Ø Some
herbs, including garlic, ginkgo, ginseng and St. John’s Wort, have a
significant influence on concurrently administered drugs.
Ø Herbal
medicines may mimic, decrease, or increase the action of prescribed drugs. This
can be especially important for durgs with narrow therapeutic windows and in sensitive
patient populations such as older adults, the chronically ill, and those with
compromise immune system.
|
Activity
|
Commonly Used Herbs*
|
|
Anti-coagulant
|
Chamomile,dong
quai(tang-kuei),horse chestnut
|
|
Anti-platelet
|
Bilberry,
bromelain, cayenne, feverfew, flaxseed oil, garlic, ginger, ginkgo, ginseng,
green tea, meadowsweet,motherwort, and turmeric
|
|
Pro-coagulant
|
Goldenseal,Oregon
grape root,shepherd’s purse
|
|
*To
expand the list of anticoagulant and antiplatelet herbs, the following are mentioned in Pharmacology and
Applications of Traditioinal Chinese Medicine(#):
White
atracytlodes,cnidium(chuanxiong), salvia, garlic, zedoaria, pueraria,
carthamus, lysimachia, cinnamon bark, tien-chi(sanqi), and capillaris(also
listed:tang-kuei and turmeric).
|
|
DRUG
LABORATORY TESTS INTERACTIONS
Sometimes misinterpretation of laboratory test results
& consequently wrong diagnosis may result due to drug interference in test
values. Some examples are cited below:
- Occurrence of a false positive
test for urinary glucose after cephalosporin administration.
- Cephalosporin also produce spurious
serum creatinine levels due to interference with common laboratory test procedures.
- Diuretics can affect
electrolyte (Na+, K+) test results.
- Alcohol increases γ-glutamyl
transpeptidase values.
- Iodohydroxy quinoline &
radiocontrast media, being iodinated compounds, cause an increase in the
real values of I131 uptake and protein bound iodine.
- Salicylates, nalidixic acid
& vitamin C provide a false positive test of urine sugar if performed
by Benedict’s solution or Clintest reagents.
- Spironolactone causes
decreases in the renal values of digoxin plasma levels if performed by radioimmunoassay.
- Use of estrogens (in contraceptive
pills) causes an increase in serum thyroxine values due to hyperproteinaemia
(resulting from estrogens).
- Use of MAO Inhibitors causes
the decreases in the levels of urinary VMA due to reduced metabolism of nor-epinephrine.
REDUCING
THE RISK OF DRUG INTERACTION
The guidelines to reduce and manage drug interactions
are:
Identify the Patient Risk Factors Factors such as age, the nature of the patient's medical problems (eg. impaired renal function),
dietary habits, smoking, and problems
like alcoholism will influence the effect of certain drugs.
Take a Thorough Drug History of a Patient.
Be Knowledgeable about the Actions of the Drugs being used.
Consider
Therapeutic Alternatives.
Avoid Complex
Therapeutic Regimens.
Educate the
Patient about benefits and problems that could result from drug therapy.
Monitor Therapy
:
The risk of drug-related
problems warrants close monitoring, not only for the possible occurrence of drug interactions but also for
adverse events occurring with individual agents and noncompliance.
Individualize Therapy
§ As wide variations in the response of patients to the
same dose of certain individual drugs, priority should be assigned to the needs
and clinical response of the individual patient, rather than to the usual
dosage recommendations and standard treatment and monitoring guidelines.
§ The pharmacist will be involved actively in the
observance of the guidelines and to maintain complete and current patient
medication records, and also to supervise and monitor drug therapy more closely.
SUMMARY
v It
is impossible to remember all drug interactions, so medical pracitioners should
be alerted to take appropriate steps to minimize their occurrence.
v If
the combination of potentially interacting drugs is unavoidable, the dose of
any drug likely to have increased effects as a result of the interaction should
be reduced and the patient is monitored
for toxic effects using clinical variables or plasma drug levels for at least 2
weeks or until these are stable.
v Drugs
that are likely to have reduced effects as a result of the interaction, the
patient similarly should be monitored for therapeutic failure for at least 2
weeks or until stable, and the dose is
increased if necessary.
v Treatment
is given with the drug which does not interact.
v Patients
should be advised to seek guidance about their medication if they plan to stop
smoking or start a herbal remedy, as they may need close monitoring during the transition.\
