ADVERSE DRUG REACTIONS:
Definition : Adverse Reaction:
“Any response
that is noxious and unintended that occur at the doses used for diagnosis, prevention
and treatment of disease.”
Drug toxicity may come in many forms:
- Acute versus chronic,
- Mild versus severe,
- Predictable versus unpredictable,
- Local versus systemic.
Administration of drug may result in:
•
Side effects.
•
Untoward effects.
•
Toxic effects.
Definition:
Pharmacological effects of drug produced at
therapeutic doses that depending upon the condition; may be desirable or
undesirable.
For example :
Atropine
produces dryness of mouth.
•
Dryness of mouth is side effect when atropine
is used for treatment of sinus bradycardia,
•
but it is desirable when atropine is
used as preanesthetic medication.
UNTOWARD EFFECTS:
Undesirable effects produced at therapeutic doses,
when severe enough, necessitate cessation of drug therapy.
For example: Hypokalemia produced by loop diuretics.
TOXIC EFFECTS:
•
produced when drug is repeatedly
administered or given in large doses.
For example :
Respiratory depression produced by morphine.
Important systemic adverse effects:
DRUG INTOLERANCE:
Inability to tolerate the drug.
Drug intolerance may be:
A. Quantitative.
B. Qualitative
a)
Idiosyncrasy.
b)
Hypersensitivity (Allergy).
QUANITATIVE INTOLERANCE:
•
Some persons show increased response to
therapeutic or even smaller doses of the drugs such people are called “HYPER
REACTORS.”
For example:
G.I
bleeding and vomiting with single dose of salicylates.
QUALITATIVE INTOLERANCE:
IDIOSYNCRASY:
•
Unusual individual response to certain drugs
due to deficiency or complete lack of certain enzymes in drug recipient.
OR
•
Genetically controlled abnormal reaction
to a drug..
For example:
Hemolysis
produced by Primaquine and Sulfonamides in patients with G.6.P.D deficiency.
HYPERSENSITIVITY
(ALLERGY):
•
Exaggerated sensitivity to certain
foreign substances which are harmless to great majority of population. It has
an immunological basis.
•
Allergy can be distinguished from other
forms of drug toxicity in some respects
First, prior exposure to drug or closely related compound.
Second, intensity of response is usually dose independent.
Third usually similar signs and symptoms produced
irrespective of the drug used .
Drugs commonly producing allergic reactions are:
•
Penicillins,
•
Sulfonamides,
•
Quinidine,
•
Insulin,
•
Dextran.
4 groups of allergic reactions:
TYPE-I:
• Immediate form of allergy
•
disturbances appear within minutes or
hours.
•
Immune reaction is initiated by
attachment of antigen to IgE antibodies to surface of mast cells and basophils.
• Rupture of these cells liberates histamine and
other mediators of inflammation.
•
Major signs and symptoms are erythema,
urticaria, itching, broncho-constriction, edema, abdominal cramps and diarrhea.
Anaphylaxis:
Severe form of type-I reaction.
•
Life threatening reactions are common
with parenteral drug injection than oral or topical drug application.
•
Epinephrine reverse the manifestation of
severe reactions;
•
Antihistamines and Corticosteroids are
also useful.
TYPE-II Reactions:
•
Mediated by circulating IgG.
•
usually delayed responses from several
hours to days after drug exposure.
Examples:
•
Drug induced hemolysis,
•
leukopenia and
•
thrombocytopenia.
TYPE-III:
•
immune complexes are formed between
antigen & antibody.
•
deposited in small blood vessels or
within interstitial spaces resulting in activation of complement cascade that
attract neutrophils.
•
lysosomal enzymes liberated by
neutrophils cause local tissue damage and promote thrombosis of affected blood
vessels.
TYPE-IV:
•
mediated by sensitized T lymphocytes.
•
usually delayed .
G.I.T DISTURBANCES:
•
Many drugs produce gastrointestinal
disturbances. Like;
•
Nausea and vomiting by digitalis,
morphine, anticancer drugs.
•
Constipation by opioids, verapamil and
antidiarrheal agents
Diarrhea by colchicine and purgatives.
HEMOPOETIC TOXICITY:
ANEMIA:
•
Chloramphenicol,
•
Primaquine,
•
Methyldopa,
•
Sulfonamides.
LEUKOPENIA:
•
Phenylbutazone,
•
Thiouracil,
•
Chlorpromazine,
•
Imipramine
•
Chloramphenicol.
•
THROMBOCYTOPENIA.
•
Quinidine,
•
Tolbutamide,
•
Digitalis
•
Rifampin.
BLEEDING:
•
Aspirin,
•
Corticosteroids,
•
Heparin
•
Warfarin.
HEPATOTOXICITY:
Direct:
•
Isoniazid,
•
Tetracycline and Halothane.
Immunological:
•
Isoniazid,
•
Rifampin,
•
Pyrazinamide,
•
Methyldopa,
•
Indomethacin and chlorpromazine.
NEPHROTOXICITY:
•
Aminoglycosides,
•
Amphotericin B,
•
Vancomycin,
•
Bacitracin,
•
Polymyxins,
•
Sulfonamides,
•
Hydralazine,
•
Pencillamine,
•
Phenacetin and Acetaminophen.
BEHAVORIAL TOXICITY:
Reserpine: Suicidal tendencies.
Amphetamine: Disorientation, Confusion
Glucocorticoids: Euphoria.
ELECTROLYTE DISTURBANCES:
•
Hypokalemia:
Diuretics.
•
Hypernatremia:
Carbenoxolone,
Corticosteroids.
ENDOCRINE DISTURBANCES:
Chlorpromazine: Menstrual irregularities.
Oral contraceptives: Suppression of lactation.
Corticosteroids: Hyperglycemia
Cimetidine: Gynecomastia.
Ketoconazole:
Gynecomastia.
Lithium carbonate: Goiter.
SKIN TOXICITY:
Skin
rashes (Urticaria) by
•
PENICILLINS,
•
CEPHALOSPORINS,
•
AMIODARONE
•
CLOFAZEMINE,
•
SULFONAMIDES AND TETRACYCLINES.
CARCINOGENESIS:
•
Estrogens produce breast and endometrial
cancer;
•
reserpine produces breast cancer,
•
metronidazole is mutagenic and produces
tumors.
TERATOGENICITY:
•
Some drugs produce developmental
abnormalities in fetus (teratogenic effect) like phocomalia by thalidomide,
cleft palate by phenytoin.when these drugs administered during pregnancy.
DRUG DEPENDENCE:
•
Certain drugs when used repeatedly may
make the individual psychologically and physiologically dependent upon the drug
i.e. discontinuation of drug may produce withdrawal syndrome.
•
Morphine alcohol and cocaine can produce
drug dependence.
UNMASKING OF DISEASE:
•
Thiazides and corticosteroids unmask
diabetes mellitus, and epilepsy is unmasked by isoniazid.
IATROGENIC EFFECT:
•
Disease produced physician through the
use of certain drugs is called iatrogenic effect.
For
example:
•
Parkinson’s disease produced by antipsychotic
drugs,
•
peptic ulcer by NSAIDs.
DEFINITION;
It is the
modification of the effect of one drug (the object drug ) by the prior
concomitant administration of another (precipitant drug).
OUTCOMES OF
DRUG INTERACTIONS
- Loss of therapeutic effect
- Toxicity
- Unexpected increase in pharmacological activity
- Beneficial effects e.g additive & potentiation (intended) or antagonism (unintended).
- Chemical or physical interaction e.g I.V incompatibility in fluid or syringes mixture
STORAGE CONDITIONS:
Pharmacokinitics
involve the
effect of a drug interaction from point of view that includes absorption
,distribution , metabolism and excretion.
Pharmacodynamics
are related
to the pharmacological activity of the interacting drugs e.g
synergism.antagonism, altered cellular transport, effect on the receptor
site.
Drug interactions: Pharmacodynamic and Pharmacokinetic
Pharmacodynamic Interaction
Drug A alters the effect of Drug B without a change in the concentration
of Drug B Pharmacokinetic
Interaction
Drug A alters the effect of Drug B by changing the plasma concentration
of Drug B
Pharmacokinetic
interactions
1) Altered
GIT absorption.
•
Altered pH, Altered bacterial flora,
formation of drug chelates or complexes, drug induced mucosal damage and
altered GIT motility.
•
Altered pH;
•
The non-ionized form of a drug is more
lipid
•
soluble and more readily absorbed from
GIT
•
than the ionized form does.
ENZYME INHIBITION:
It is the
decrease of the rate of metabolism of a drug by another one.This will lead to
the increase of the concentration of the target drug and leading to the
increase of its toxicity
Inhibition
of the enzyme may be due to the competition on its binding sites , so the onset
of action is short may be within 24h.
First-pass
metabolism
Oral
administration increases the chance for liver and GIT metabolism of drugs
leading to the loss of a part of the drug dose decreasing its action. This is more
clear when such drug is an enzyme inducer or inhibitor
RENAL EXCRETION
•
Active tubular secretion;
It occurs in
the proximal tubules (a portion of renal tubules). The drug combines with a
specific protein to pass through the proximal tubules.
PREVENTION OF DRUG INTERACTION
1)
Monitoring therapy and making adjustments
2)
Monitoring blood level of some drugs
with narrow
therapeutic index e.g., digoxin, anticancer
agents…etc
3)
Monitoring some parameters that may help to
characterize the the early
events of interaction
or toxicity e.g., with warffarin
administration, it
is recommended to monitor the
prothrombin time
to detect any change in the drug activity.
Main offenders :
Light (sodium nitroprusside)
water (aspirin)
Air (oxidation of drug)
drug Interactions: Outside Body
Mechanisms
of drug interactions
Things to
Remember
- Interactions are easily forgotten when prescribing
- Interactions are difficult to remember
- Pharmacodynamic interactions can often be predicted across drug classes
- Pharmacokinetic interactions can not be predicted – experiments needed
- Many interactions probably remain undescribed – so look out for them
- The chances of interaction are 60 times higher in a patient taking 5 drugs than in one taking 2.
USE
OF DRUGS IN PREGNANCY:
·
The FDA to indicate the Potential
of systemically absorbed drugs for causing birth defects; establishes
five pregnancy categories:
CATEGORY
A:
·
Controlled studies in the pregnant women
fail to demonstrate a risk to the fetus in first trimester with no evidence of
risk in later trimesters.
·
The possibility of fetal harm is remote
o
Examples:
o
INSULIN,
o
VITAMIN B,
o
VITAMIN D,
o
PARACETAMOL..
CATEGORY
B:
·
Either animal reproduction studies have
not demonstrated fetal risk but there are no controlled studies in pregnant
women OR animal reproduction.
·
Studies shown an adverse effect (Not
Teratogenic) that was not confirmed in controlled studies in women, in the
first trimester and there is no evidence of risk in later trimesters.
o
Example:
o
RABEPRAZOLE, AMOXICILLIN, METOPROLOL,
METHYLDOPA.
CATEGORY
C:
·
Either studies in animals have revealed
adverse effects on fetus (Teratogentic) and there are no controlled studies in
women, OR
o
Studies in women and animals are not
available.
·
Drug should be given only if the
potential benefits justify the potential risk to the fetus.
o
Examples:
o
ACETAZOLAMIDE,
o
OMEPRAZOLE,
o
ACYCLOVIR.
CATEGORY
D:
·
There is positive evidence of human
fetal risk, but the benefits from use in pregnant women may be acceptable
despite the risk e.g. if the drug is needed in the life-threatening situations
or for a serious disease for which safer drugs are ineffective.
·
Examples:
o
DIAZEPAM,
o
METHOTREXATE,
o
PHENYTOIN.
CATEGORY
X:
·
Studies in animals or human beings have
demonstrated fetal abnormalities or there is evidence of fetal risk based on
human experience, or both, and the risk of use of drug in pregnant women
clearly outweighs any possible benefit. The drug is strictly contraindicated in
women who are pregnant.
o
Examples:
o
DOXORUBICIN,
o
SIMVASTATIN,
o
TESTOSTERONE.
