DRUG INTERACTION
DRUG
INTERACTION INTRODUCTION
DEFINITION:
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“Drug interaction
refers to an adverse drug response produce by the administration of drug or
co-exposure of drug with another substance which modify the patient response to
the drug”.
OR
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The pharmacological
result, either desirable or undesirable, of drugs interacting with themselves
or with other endogenous chemical agents, with components of the diet, or with
chemicals used in or resulting from diagnostic tests”.
OR
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“The drug interaction
occurs when a patient’s response to a drug is modified by food, nutritional
supplements, formulation excipients, environmental factors, other drugs or
disease”.
These interactions
are difficult to detect, since they may be mistaken for therapeutic failure or
progression of the disease. Drug interactions may be harmful or beneficial.
Harmful drug interactions are important as they cause 10-20% of the adverse
drug reactions requiring hospitalization and they can be avoided. Elderly
patients are especially vulnerable with strong relationship between increasing
age, the number of drugs prescribed and the frequency of potential drug-drug
interactions.
The net effect of the combination may
manifest as an additive or enhanced effect of one or more drugs, antagonism of
the effect of one or more drugs, or any other alteration in the effect of one
or more drugs. Clinically significant interactions refer to a combination of
therapeutic agents which have direct consequences on the patient's condition.
Therapeutic benefit can be obtained from certain drug interactions, for
example, a combination of different antihypertensive drugs may be used to
improve blood pressure control or an opioid antagonist may be use to reverse
the effect of an overdose of morphine.
The increasing availability and non-prescription use of herbal and
complementary medicines has also led to greater awareness of their potential
for adverse interactions. St John's wort, a herbal extract used for treatment
of depression, can cause serious interactions as a result of its
enzyme-inducing effects. Drug interactions with food and drink are also known
to occur, exemplified by the well-known interaction between monoamine oxidase
inhibitor antidepressants (MAOIs) and tyramine-containing foodstuffs.
Grapefruit juice is a potent inhibitor of cytochrome P450 3A4 and causes
clinically relevant interactions with a number of drugs including simvastatin
and atorvastatin, thereby increasing the risk of statin-induced adverse
reactions such as myopathy and myositis.
TYPES
OF drugs involved in drug interaction:
A. Precipitant drug.
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“A precipitant drug
is a drug, chemical or food element causing the interaction”.
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For Example:
a. Non steroidal anti-inflammatory drugs interacts with ACE
inhibitors and decreases the anti-hypertensive effects of ACE inhibitor. In
this case NSAIDs are precipitant drug.
b. Cimetidine interacts with
lidocaine, phenytoin, propranolol, quinidine, theophylline and increases the
effects of these drugs due to inhibition of hepatic metabolism. In this case
cimetidine is precipitant drug.
c. Beta-blockers
interacts with insulin and masking the
symptoms of hypoglycemia. In this case beta blockers are precipitant drugs.
B. Object drug.
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“That is a drug
affected by precipitant drug”.
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For Example:
a. Erythromycin interact with quinidine, and increases the risk of toxicity due to inhibition of hepatic metabolism. In this case quinidine is object drug.
a. Erythromycin interact with quinidine, and increases the risk of toxicity due to inhibition of hepatic metabolism. In this case quinidine is object drug.
b. Ketoconazole
increases risk of toxicity due to inhibition of metabolism of omeprazole,
lovastatin. In this example omeprazole and lovastatin are object drugs.
c.
Furanocoumarins(grapefruit juice) increases the effect of alprazolam,
atorvastatin due to inhibition of hepatic metabolism. In this case alprazolam
and atorvastatin are object drugs.
Drug
interaction may be:
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1. Rapid (within 24
hours).
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2. Delay (after 24
hours).
OUTPUT
NATURE:
The nature of response
produced by severity of drug interaction may be:
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A. Major.
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B. Moderate.
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C. Minor.
Drug
interaction can result from pharmacokinetic alternation, pharmacodynamics
changes, or a combination of both.
TYPES
OF DRUG INTERACTIONS:
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1. DRUG-DRUG
INTERACTION.
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2. DRUG-HERBAL
INTERACTION.
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3. DRUG-FOOD
INTERACTION.
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4. PHARMACOGENETIC
INTERACTION.
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5. CHEMICAL-DRUG
INTERACTION.
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6. DRUG-LAB
INTERACTION.
1. DRUG-DRUG
INTERACTION:
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“The change in the
pharmacological response of a drug by the action of another drug”.(change in
pharmacokinetic or pharmacodynamics or both)
FOR
EXAMPLE:
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a. Antacid decreases
gut absorption due to reaction with tetracycline.
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b. When diuretics are
given concurrently in the treatment of CHF. Diuretics can cause potassium
depletion that if uncorrected could become excessive and lead to an increased
action of digoxin and adverse events.
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c. Erythromycin
inhibit the metabolism of carbamazepine and increases the risk of toxicity.
2. DRUG-HERBAL
INTERACTION:
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“The interaction of
herbs and herbal products with drug, when administered both concomitantly, and
changes the pharmacological response of drug”.
FOR
EXAMPLE:
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a. St. john’s wort, a flowering plant, increases
the metabolism of cyclosporine and oral contraceptives and decreases efficacy.
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b. Kava causes
additive sedation when given concomitantly with sedative hypnotics.
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c. Garlic, gingko
interact with anti-coagulants and antiplatelet agents and increases risk of
bleeding.
3. DRUG-food INTERACTION:
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“The interaction of
food or certain dietary items influence the activity of a drug”.
FOR
EXAMPLE:
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a. Griseofulvin given
with fatty food to increase absorption.
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b. Grapefruit juice
interacts with increasing the amount of benzodiazepines, vincristine,
atorvastatin, clarithromycin in blood.
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c. Dietary fiber, especially
insoluble fiber such as wheat bran can slow down the absorption of digoxin and
lessen its effects.
4. PHARMACOGENETIC
INTERACTION:
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“Pharmacogenetic
interaction occurs when the pharmacokinetic effect of drug is effected by
genetic polymorphism in effecting processes”.
FOR
EXAMPLE:
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a. Isoniazid may
inhibit the metabolism of phenytoin, and adverse drug reaction occurs and this
isoniazid related toxicity with phenytoin according to study are seen in slow
acetylators.
b.
Plasma pseudo cholinesterase deficiency, about 1/1500 people, decreased
succinylcholine inactivation. With conventional succinylcholine doses,
prolonged paralysis of respiratory muscles and sometimes persistant apnea
requiring mechanical ventilation until the drug can eliminated by alternate
pathway.
c.
G6PD dehydrogenase 10% of black males higher prevalence in people of
Mediterranean descent, with use of oxidant drugs such as certain antimalarials
(e.g chloroquine, primaquine) and increases the risk of hemolytic anemia.
5. CHEMICAL-DRUG
INTERACTION:
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“The interaction of
drug with chemical substances, to change the activity of drug”.
FOR
EXAMPLE:
a.
When patient is on antihistamine (chlorpheniramine maleate), also consume
alcohol, leads to increase sedative effects.
b.
In combination with acute alcohol consumption, some antibiotics (furoxone,
metronidazole, griseofulvin) may cause nausea, vomiting, headache and possibly
convulsions.
c.
Acute alcohol consumption enhances the warfarin availability.
6. DRUG-LABORATORY
INTERACTION:
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“It is the
interaction of drug with the laboratory test and alter the laboratory tests
results”.
FOR
EXAMPLE:
a.
Cimetidine raises LFT. (ALT, AST)
b.
When prednisolone is given with theophylline, cortisol and digoxin there is a false
increase in levels of all these drugs.
c.
Prednisolone also shows the false –ive
skin allergy test.
CLASSIFICATION OF DRUG
INTERACTION:
Drug
interactions are divided into:
1. INVIVO DRUG INTERACTION.
2. INVITRO DRUG INTERACTION.
1.
INVIVO DRUG INTERACTION:
Divided into:
A). Pharmacokinetic Drug
interaction or Biopharmaceutical interaction.
B.)
Pharmacodynamic Drug interaction.
C.) Pharmacogenetic Drug
interaction.
A. Pharmacokinetic Drug
Interaction:
“The
drug interaction occurs when absorption, distribution, metabolism, excretion,
of a drug is effected by other drug, chemical or food items”.
Absorption:
Some drugs can alter the
absorption of another drug into your bloodstream. For example, calcium can bind
with some medications and block absorption. The HIV treatment dolutegravir (Tivicay) should not be taken at the same time as calcium carbonate (Tums, Maalox, others), because it can lower the amount
of dolutegravir absorbed into the bloodstream and reduce its effectiveness in
treating HIV infection. Dolutegravir should be taken 2 hours before or 6 hours
after medications that contain calcium or other minerals to help prevent this
interaction. In the same manner, many drugs cannot be taken with milk or dairy
products because they will bind with the calcium. Drugs that affect stomach or
intestine motility, pH, or natural flora can also lead to drug interactions.
Distribution:
Protein-binding interactions can occur when
two or more highly protein-bound drugs compete for a limited number of binding
sites on plasma proteins. One example of an interaction is between fenofibric
acid (Trilipix), used to lower cholesterol and triglycerides in the blood, and
warfarin, a common blood thinner to help prevent clots. Fenofibric acid can increase the effects of
warfarin and cause you to bleed more easily.
Metabolism:
Drugs are usually
eliminated from the body as either the unchanged (parent) drug or as a
metabolite that has been changed in some way. Enzymes in the liver, usually the
CYP450 enzymes, are often responsible for breaking down drugs for elimination
from the body. However, enzyme levels may go up or down and affect how drugs
are broken down. For example, using diltiazem (a blood pressure
medication) with simvastatin (a medicine to lower cholesterol) may elevate the
blood levels and side effects of simvastatin. Diltiazem can inhibit
(block) the CYP450 3A4 enzymes needed for the breakdown (metabolism) of
simvastatin. High blood levels of simvastatin can lead to serious liver and
muscle side effects.
Excretion:
Some nonsteroidal
antiinflammatory drugs (NSAIDs),
like indomethacin, may lower kidney function and affect the excretion of lithium, a drug used for bipolar
disorder. You may need a dose adjustment or more frequent monitoring by your
doctor to safely use both medications together..
FOR EXAMPLE:
1.
Ciprofloxacin, penicillin form complex with antacids, food and mineral
supplements containing Al, Mg, Fe, Zn and Ca ions and poorly soluble and un
absorbed complex.
2. Aspirin interact
with metoclopramide and causes rapid gastric emptying, increased rate of
absorption.
3.
Antibiotics interact with digoxin, increases bioavailability of digoxin due to
destruction of bacterial flora that inactivates digoxin in lower intestine.
b. Pharmacodynamic Drug
Interaction:
“The
drug interaction occurs when the pharmacodynamics of a drug is altered by
another drug, chemical, or food items to produce synergies, antagonize or
nullify the effects of drugs”.
1.
Antagonism:
A drug with an agonist
action at a particular receptor type will interact with
antagonists at that receptor. For example, the bronchodilator action of a
selective β2-adrenoreceptor agonist such as
salbutamol will be antagonized by β-adrenoreceptor antagonists. Acetyl choline and nor adrenaline have
opposing effects on heart rate.
2.
Additive/synergistic:
If two
drugs with similar pharmacological effects are given
together, the effects can be additive CNS
depressants like sedative and hypnotics enhances the analgesics activity of
aspirin.
3: Drug–food
interactions
Food can cause clinically important changes in drug absorption through effects on gastro-intestinal absorption or motility, hence the advice that certain drugs should not be taken with food, for example, iron tablets and antibiotics.
Grape juice:
Grapefruit juice can also cause the body to metabolize drugs abnormally,
resulting in lower or higher than normal blood levels of the drug. Many
medications are affected in this way, including antihistamines, blood pressure
drugs, thyroid replacement drugs, birth control, stomach acid-blocking drugs,
and the cough suppressant dextromethorphan. It's best to avoid or significantly
reduce intake of grapefruit juice when taking these medications.
Natural Black Licorice (Glycyrrhiza):According to Plogsted, glycyrrhiza — a
natural ingredient used to make black licorice — can deplete the body of
potassium while causing an increased retention of sodium. When the body is
depleted of potassium, the activity of digoxin, a medication used to treat
heart failure, can be greatly enhanced, resulting in the heart not beating
properly.
Glycyrrhiza can also decrease the
effectiveness of high blood pressure medicines. And people taking Coumadin®
(warfarin) should beware that glycyrrhiza can break down the drug, resulting in
an increase in the body's clotting mechanism.
C.
Pharmacogenetic Drug Interaction:
“Pharmacogenetic
drug interaction when the pharmacokinetic effect of drug is effected by genetic
polymorphism in effecting processes”.
FOR
EXAMPLES:
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1. CYP2C9 genetic
polymorphisms, 30% in one study, more common among east Asians, reduced
enzymatic activation of clopidogrel, resulting in decreased antiplatelet effect
and increase risk of thrombosis in high risk patients.
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2. Genetic
polymorphisms of CYP2C9 and vitamin K epoxide reductase complex subunit
1(VKORC1), increased action of warfarin increasing risk of bleeding events.
2. INVITRO DRUG INTERACTION:
“These interaction are caused by physical or
chemical incompatibility when two or more drugs are mixed with each other in IV
infusions causing precipitation or inactivation of active drug”.
FOR
EXAMPLE:
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Phenytoin sodium that
will precipitate from a solution that has an acidic pH. e.g. Dextrose 5%. So,
it will be given with normal saline.
FACTORS
CONTRIBUTING TO THE OCCURRENCE OF DRUG INTERACTION:
A number of factors
contributing to the occurrence of drug interaction:
1. Multiple
Pharmacological Effects.
2. Multiple Prescribers.
3. Use of
non-prescription products.
4. Patient
non-compliance.
5. Drug abuse.
1. MULTIPLE
PHARMACOLOGICAL EFFECTS:
Most
drugs used in current therapy have the capacity to influence many physiological
systems. Therefore, two drugs concomitantly administered will often affect some
of the same systems.
When
considering the potential for interactions between drugs there often is a
tendency only to be concerned with the primary effects of the drugs involved
and to overlook the secondary activities they posses.
FOR
EXAMPLE:
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Combined therapy with
a phenothiazine antipsychotic (e.g, chlorpromazine), a tricyclic antidepressant
(e.g, amitriptyline), and an antiparkinson agent(e.g, trihexyphenidyl) is
employed in some patients. All three possess anticholinergic activity. Even
though the anticholinergic effect of any one of the drugs may be slight, the
additive effects of three agents may be significant.
2. MULTIPLE
PRESCRIBER:
It
is necessary for some individuals to see more than one physician, and it is
very common for a patient to be seeing one or more specialists in addition to a
family physician. Some individuals also are seeing other health professionals (e.g.
dentists, pedriatrists) who may prescribe medication.
FOR
EXAMPLES:
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One physician may
prescribe a medication capable of causing tiredness /sleepiness (e.g. certain
antihistamine, opioid analgesics) for a patient for whom another physician has
prescribed an antianxiety agent, with the possible consequences of an excessive
depressant effect.
3. USE OF
NON-PRESCRIPTION PRODUCTS:
Many
reports of drug interactions have involved the concurrent use of a prescription
drug with a non-prescription drug (e.g. aspirin, antacids, decongestants) or
herbal (St. John’s wort) or other natural product. When a physician questions
patients about medications that they are taking, the patients often will
neglect to mention the non-prescription products that they have purchased.
Many
patients have been taking preparations such as antacids, analgesics, laxatives,
dietary supplements, and herbal products for such long periods and in such a
routine manner that they do not consider them to be drugs or to be imported
with respect to the effectiveness and safety of medications.
Diphenhydramine
is included in many products for its anti-histamine action but also included
for its sedative effect in many non-prescription sleep aid formulations.
Therefore, an increased risk of drug interaction if the physician prescribed
any drug containing sedative effects then it leads to synergistic effect.
Although
many individuals will have their prescriptions dispensed in their local
pharmacy, they often purchase non-prescription drugs elsewhere, thus making
identification of potential problems extremely difficult for the pharmacist as
well as physician. For this reason, patient should be encourage to take the
prescription and non-prescription medications at a pharmacy.
4. PATIENT
NON-COMPLIANCE:
For
a variety of reason many patients do not take medication in the manner intended
by the prescriber. Some have not received adequate instruction from the
prescriber and pharmacist as to how and when to take their medication. In
elderly patients, they may be on multiple therapy regimen and have to take
different medications at different time can become confused or forget to take
medication.
FOR
EXAMPLE:
Some
patients if they realize they have forgotten a dose of medication, double the
next dose to make up for it. Some other patients
may act on an assumption that if the one tablet-dose that has been prescribed
provides partial, but not complete relief of symptoms, a two tablets
dose will be even more effective.
5. DRUG ABUSE:
The tendencies of some
individuals to abuse or deliberately misuse drugs also may lead to an increased
incidence of drug interactions. The antianxiety agents, opioid analgesics, and amphetamines
are among the agents most often abused, and the inappropriate use of these
drugs can result in a number of problems, including an increased potential of
drug interaction. For Example: increased metabolism of the other drugs due to
these drugs are enzyme inducers.
REASONS
OF UN-DETECTION OR UN-IDENTIFICTION OF DRUG INTERACTION:
Many
interactions that occurs are undetected or unreported. Koch-Weser (Drug
inform J,1972) observed that detection
of drug interactions by clinicians is inefficient and cited six reasons for
existence of this situation:
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1. In most cases the
clinical situation is too complex to allow recognition of an expected event in
a patient’s course as related to his or her drug therapy.
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2. With few
exceptions, the intensity of action of drugs in the therapeutic setting cannot
be quantitated accurately.
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3. Even when a
deficient, excessive, or abnormal response to one or both drugs is clearly
during concomitant administration, it is attributed usually to factors other
than drug interaction.
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4. Practicing
physicians tend to doubt their observations concerning drug interactions unless
the same interaction has been reported previously.
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5. Physicians frequently
fail to report drug interaction even when they unequivocally recognized them.
REDUCING
RISKS OF DRUG INTERACTIONS:
1 .Identify
the patients risks factors.
2.
Take thorough drug history.
3.
Be knowledge about the actions of the drugs being used.
4.
Consider therapeutic alternatives.
5.
Avoid complex therapeutic regimens when possible.
6.
Educate the patient.
7.
Monitor therapy.
Many of the variables that
may influence the activity of a drug and its ability to interact with other agents
contribute to the existing uncertainty.
PATIENT VARIBLES:
There
are many factors that influence the response to a drug in man.
1. AGE:
The
risk of drug-related problems increases with age, age is an important factor.
Studies indicate that there is an increased incidence of adverse drug events in
both young and geriatric patients, and it is reasonable to expect that the
occurrence of drug interaction also is highest in these patient groups.
Examples:
Elder patients;
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1. In heart failure
patients treated with diltiazem, verapamil, NSAIDs may promote fluid retention
and exacerbate heart failure.
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2. Delirium, treated
with (all TCAs, benzodiapines, drugs that have anticholinergic effects,
chlorpromazines, corticostreiods, worsened delirium in older adults with or at
high risk of delirium.
. Children:
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(i)Newborns cannot metabolize and eliminate
the antibiotic chloramphenicol.(gray baby syndrome)
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(ii)If tetracycline, is given to infants and
young children during the period when their teeth are being formed (up to 8
years), it may permanently discolor tooth enamel.
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(iii)Children under
18 years are at the risk of Reye syndrome if they are given aspirin while they
have influenza and/ chickenpox.
2. GENETIC FACTORS:
These
may be responsible for the development of an unexpected drug response in a
particular patients.
For Example:
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1. HLA-B 1502, in i-6/10,000
in countries with mainly white populations, in some Asian countries, about 10
times higher, increased risk of serious dermatologic reactions. (
steven-Johnson syndrome)
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2. Aldehyde
dehydrogenase-2 deficiency, about 50% of Japanese, Chinese and other Asian
populations, with alcohol ingestion, marked elevations of blood acetaldehyde,
causing facial flushing.
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3. Rapid acetylators
can metabolize isoniazid rapidly, so increase amount of isoniazid is require to
achieve pharmacological response.
3. DISEASE STATES:
A
number of disease states, other than the one for which a particular drug is
being used for which a particular drug
is being used, may influence patient response to a drug-impaired renal and
hepatic function are the most important conditions that may alter drug
activity( hypoalbuminemia ).
For Example:
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a. Conditions like cirrhosis, burns,
nephritic syndrome,pregnancy. There is decrease in albumin levels in blood so,
acidic drugs like valporic acid, aspirin , warfarin, piroxicam, more free fractions
of drug are available ,and toxic effects are produced.
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b. Basic drugs bind
to alpha-glycoprotein .like lidocaine, methadone binds 50-95% with it.
4. RENAL FUNCTION:
Renal
function is one of the most important determination of drug activity. Particularly
when drugs that are excreted primarily in an active form by the kidney .
For Example:
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The narrow therapeutic index drugs such as
aminoglycosides, digoxin, lithium, vancomycin, their dose must be titrated when
there is renal impairment.
5. HEPATIC FUNCTION:
Many
drugs are metabolized in the liver by a number mechanisms. Therefore, when
there is hepatic damage, these drugs may be metabolized at a slower rate and
exhibit a prolong effect.With aging hepatic function is reduced to 30%.
For Example:
a. In hepatitis patients when paracetamol
is given, as paracetamol is hepatotoxic then the interaction of both drug and disease
worsen the condition.
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b. Barbiturates
enhance the metabolism of other drugs when given with it, because barbiturates
activates the liver metabolic enzymes.
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c. Rifampicin is also
inducer of liver metabolic enzymes, and increases the metabolism of other
drugs.
6. ALCOHOL CONSUMPTION:
Several studies have
shown that the chronic alcohol consumption may increases the rate of metabolism
of drugs such as warfarin and phenytoin, probably by increasing the activity of
hepatic enzyme. However, in contrast, acute use of alcohol by non-alcoholic
individuals may causa an inhibition of hepatic enzymes.
For Example:
a. Alcohol
enhances acetaminophen metabolism into a toxic product, potentially causing
liver damage.
b. Chronic alcohol consumption induces phenytoin breakdown.
c. Antibiotic like erythromycin when given to a patient
who consumes alcohol with it, erythromycin increases the gastric emptying
leading to faster alcohol absorption in the small intestine.
7. SMOKING:
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A number of
investigations have suggested that smoking increases the activity of drug
metabolizing enzymes in the liver, with the result certain therapeutic agents (e.g.
diazepam, propoxyphene, theophylline, olanzapine) are metabolized more rapidly
and their effect is decreased.
For Example:
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Increase metabolism
of :
a. diazepam.
b. theophylline.
c. olanazapine.
8. DIET:
Food often may affect the
rate and extend of absorption of drugs from the gastrointestinal (GI) tract.
FOR EXAMPLE:
a. Many antibiotics should
be given at least 1 hour before meal or 2 hour after the meal to achieve
optimal absorption.
b. The type of food may be important with
regard to the absorption of concurrently administered drugs. The dietary items
such as milk and other dairy products that contain calcium, may decrease the
absorption of tetracycline, floroquinolones derivatives by forming a complex
with them in the GI tract that is not absorbed properly.
9. INDIVIDUAL VARIATIONS:
Even after the preceding factors
have been considered, wide variations in the response of patients to drugs will
be seen that are often difficult to explain.
Plasma concentrations of
certain drugs may vary widely among individuals using the same dosage regimen
over the same time period.
References
·
Clinical Pharmacy and Therapecutics by Roger Walker, 5th
Edition.
·
Stockley’s Drug Interaction by Karen Baxter, 8th
Edition.
·
http://www.eatright.org/resource/health/wellness/preventing-illness/common-food-drug-interactions
·
https://www.studyblue.com/notes/note/n/drug-interactions/deck/5164338
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