Adverse Drug Reactions

After approval of a drug, the FDA assigns the drug to one of the
following categories: prescription, nonprescription, or controlled
substance.
1- Prescription drugs :
are drugs that the federal government has designated to be potentially
harmful unless their use is supervised by a licensed health care provider,
such as a nurse practitioner, physician, or dentist.
Although these drugs have been tested for safety and therapeutic effect,
prescription drugs may cause different reactions in some individuals.
2- Nonprescription Drugs :
Nonprescription drugs are drugs that are designated by the FDA to be
safe (if taken as directed) and obtained without a prescription.
These drugs are also referred to as over-the-counter (OTC) drugs and
may be purchased in a variety of settings, such as a pharmacy, drugstore,
or in the local supermarket.
OTC drugs include those given for symptoms of the common cold,
headaches, constipation, diarrhea, and upset stomach.
3- Controlled Substances :
Controlled substances are the most carefully monitored of all drugs.
 Drug use and pregnancy

The use of any medication prescription or nonprescription carries a risk

of causing birth defects in the developing fetus.
Drugs administered to pregnant women, particularly during the first
trimester (3 months), may cause teratogenic effects.
A teratogen is any substance that causes abnormal development of the
fetus leading to a severely deformed fetus. Drugs are one type of
teratogen.
In an effort to prevent teratogenic effects, the FDA has established five
categories suggesting the potential of a drug for causing birth defects .
In general, most drugs are contraindicated during pregnancy or lactation
unless the potential benefits of taking the drug outweigh the risks to the
fetus or the infant.
During pregnancy, no woman should consider taking any drug, legal or
illegal, prescription or nonprescription, unless the drug is prescribed or
recommended by the primary health care provider.
Smoking or drinking any type of alcoholic beverage also carries risks,
such as low birth weight, premature birth, and fetal alcohol syndrome.
Children born of mothers using addictive drugs, such as cocaine or
heroin, often are born with an addiction to the drug abused by the
mother.
FDA categorization of drugs in pregnancy Category
Description Examples

A Controlled human studies show no risk

Exemples :
Vitamins : B,C,D,E, Folic acid,
Tyroxine, Inj.mag.sulfate
B No evidence of risk in humans
Exemples :
Metronidazole,Paracetamol,Piperazine,penicillin,erythr
omycine
C Risk cannot be ruled out Most drugs

D Positive evidence of risk Antiepileptics

X Contraindicated in pregnancy Teratogenic drugs

Drugs prescribing during pregnancy, Diseases/Condition drugs to be
used

Nausea and Cyclizine, Meclizine, Metoclopromide(safe in 3 rd trimester of

vomiting pregnancy)
Hypertension Methyldopa
Cough Diphenhydramine, Codiene, Dextromethorphan
Headache Paracetamol, Codiene, Benzodiazepines Aspirin and other
NSAID s(1 st and 2 nd trimesters)
Anti coagulants Heparin
Constipation Milk of Magnesia, DocusateSodium, Glycerin, Mineral oil,
Bisacodyl
Peptic ulcer Sucralfate, H2 blockers, Bismuth Salicylate, Non Systemic
Antacids
Tuberculosis Isoniazid & Ethambutol, Rifampin
Anti-amoebic Metronidazole
drugs
 Teratogenesis
Terato "monster" Genesis producing A teratogen is any infectious agent
drug, chemical or radiation that alters fetal morphology or fetal function
if the fetus is exposed during a critical stage of development.
-Examples :
cleft lip/palate, clubfoot, neural tubal defects, missing or malformed
limbs/fingers.
Also- behavorial and/ or biochemical abnormalities.
- Teratogenesis maybe :
Direct- i.e ,-malformations of structures
Or indirect-such as interfering with oxygen or nutrients.
 The effectes of some drugs in use during pregnancy

NSAIDS Risks of NSAID used from 30 weeks of pregnancy onwards

premature closure of the ductus arteriosus Oligohydramnios
Deficiency of amniotic fluid
Phenytoin Fetal hydantion syndrome Craniofacial abnormalities Hypoplasia of
distal phalanges Growth deficiency Mental deficiency Cleft palate

Valproic acid ↓ absorption of folic acid Neural tube defects

Carbamazepine Craniofacial defects Spina bifida. Hypoplasia of distal phalanges

(Tegretol)

DES Increased risks of clear cell Adenocarcinoma of the vagina and cervix
(diethylstilboes and of breast cancer have been found for daughters of women who
trol took DES during pregnancy.
Fertility problems are also more common among these daughters.
Women who took DES during pregnancy have an increased risk of
breast cancer.
 The effectes of some drugs in use during pregnancy
Lithium salts It is a rare heart defect in which parts of the tricuspid valve are abnormal.
Vitamin A fetal defects
Sulphonamides Hyperbilirubinemia Jaundice Kernicterus Primaquine G6PD deficiency
Warfarin Fetal warfarin syndrome Nasal hypoplasia Hypoplasia of the extremities
Developmental retardation Other: Central nervous system defects
Spontaneous abortion Stillbirth Prematurity Hemorrhage Ocular defects.
Social Drugs Cigarette smoking A reduction in birth weight Birth defects of heart,
brain & face Risk of sudden infant death syndrome(SIDS) Mis-located
placenta Preterm labor Miscarriages Uterine infections spontaneous
abortions.
Alcohol Foetal alcohol syndrome:
Risk of miscarriage
Inadequate growth before or after birth Facial defects
A small head Mental retardation Nail dystrophy
Caffeine ↓ blood flow across placenta
↓ the absorption of iron
↑ risk of anemia
↑ risk of fetal death Advice
limit coffee to 3cups/day .
 Drug Passage into Breast Milk Diffusion
The movement of the drug from a high concentration area (blood) to a
low concentration area (breast milk).
Active transport : the movement of the drug from blood with a low
concentration to breast milk with a high concentration.
This mechanism concentrates the drug in the breast milk.
After diffusion or active transport, drugs pass through spaces between
alveolar cells into the milk .
Drug transfer into breast milk Ionization of the drug
Drugs that are not protein bound and nonionized are more likely to be
transferred into breast milk.
Lower molecular weight drugs are more likely to be transferred to the
breast milk than higher molecular weight drugs.
Lipid soluble drugs pass more freely into breast milk than water soluble
drugs.
Weakly alkaline drugs have higher breast milk levels than weak acids.
 Drugs to be avoided in during lactation

Amiodarone Neonatal hypothyroidism

Barbiturates Drowsiness

Benzodiazepines Lethargy

Carbimazole Hypothyroidism

Contraceptives Diminish milk supply, ↓ nitrogen and protein content

Aspirin Reye’s syndrome

Ephedrine Irritability

Tetracyclines Tooth discoloration

Chloramphenicol Gray baby syndrome

 Drugs which suppress /inhibit lactation

Large doses of Alcohol and Caffeine

Estradiol Oral contraceptives

Theophylline
Bromocriptine

Levodopa
 Drugs absolutely contraindicated in nursing mothers

Anti cancer drugs Phenylbutazone Sulphonamides

Radiopharmaceuticals Chloramphenicol Mercurials

Ergot and its derivatives Atropine

(methysergide)

Lithium Thiouracil Iodide

 Conclusion
Completely avoid alcoholic beverages in pregnancy & lactation.
Cut down or eliminate food and drinks which contain caffeine such
as coffee, tea, colas and other soft drinks, cocoa and chocolate.
Stop smoking or cut down your smoking when pregnant.
Avoid smokers and smoking areas whenever possible.
Check with your physician for his/her recommendations before
using drugs.
The responsibility of all clinicians including pharmacists to counsel
the patients with complete and current information on the risks
& benefits of using drugs during pregnancy and lactation.
 Adverse Drug Reactions
Patients may experience one or more adverse reactions (side effects)
when they are given a drug.
Adverse reactions are undesirable drug effects.
Adverse reactions may be common or may occur infrequently.
They may be mild, severe, or life threatening.
They may occur after the first dose, after several doses, or even after
many doses.
An adverse reaction often is unpredictable, although some drugs are
known to cause certain adverse reactions in many patients.
For example,
drugs used in the treatment of cancer are very toxic and are known to
produce adverse reactions in many patients receiving them.
Other drugs produce adverse reactions in fewer patients.
Some adverse reaction is predictable, but many adverse drug reactions
occur without warning.
Some texts use both terms side effect and adverse reactions.
These texts distinguish between the two terms by using side effects to
explain mild, common, and nontoxic reactions; adverse reaction is
used to describe more severe and life-threatening reactions.
For the purposes of this text only the term adverse reaction is used, with
the understanding that these reactions may be mild, severe, or life
threatening.
 Classification of adverse durg reactions
• Type A
• extension of pharmacologic effect
• often predictable and dose dependent
• responsible for at least two-thirds of ADRs
• e.g., propranolol and heart block, anticholinergics
and dry mouth
• Type B
• idiosyncratic or immunologic reactions
• rare and unpredictable
• e.g., chloramphenicol and aplastic anemia
• Rash caused by beta lactam antibiotics
 Comparison between type A and type B in the Adverse drug
reactions
Type A Type B
Often predictable and dose Yes Rare
dependent
Dose dependence Yes Non

Incidence high low

Morbidity high low

Mortality low high

Therapy Dose adjusment Stop using the

drug
 Allergic Drug Reactions
An allergic reaction also is called a hypersensitivity reaction.
Allergy to a drug usually begins to occur after more than one dose of the
drug is given.
A drug allergy occurs because the individual’s immune system views the
drug as a foreign substance or antigen.
Even a mild allergic reaction produces serious effects if it goes
unnoticed and the drug is given again.
Some allergic reactions occur within minutes (even seconds) after the
drug is given; others may be delayed for hours or days.
Allergic reactions are manifested by a variety of signs and symptoms
include itching, various types of skin rashes, and hives (urticaria).
Other symptoms include difficulty breathing, wheezing, cyanosis, a
sudden loss of consciousness, and swelling of the eyes, lips, or
tongue.
 Anaphylactic shock
is an extremely serious allergic drug reaction that usually
occurs shortly after the administration of a drug to which
the individual is sensitive.
This type of allergic reaction requires immediate medical
attention.
All or only some of these symptoms may be present.
Anaphylactic shock can be fatal if the symptoms are not
identified and treated immediately.
- Treatment :
is to raise the blood pressure, improve breathing, restore
cardiac function, and treat other symptoms as they occur.
• Epinephrine (adrenalin) 0.1 to 0.5 mg may be given by
subcutaneous or intramuscular injection.
• Hypotension and shock may be treated with fluids and
vasopressors.
• Bronchodilators are given to relax the smooth muscles of
the bronchial tubes.
• Antihistamines may be given to block the effects of
histamine.
 Common Causes of ADRs :
- • Antibiotics
• Antineoplastics
• Anticoagulants
• Cardiovascular drugs
• Hypoglycemics
• Antihypertensives
• NSAID/Analgesics
 ADR Risk Factors
• Age (children and elderly)
•Multiple medications
• Inappropriate medication prescribing, use, or
monitoring
• Altered physiology
• Prior history of ADRs
• Extent (dose) and duration of exposure
• Genetic predisposition
 Management Options

•Sensibilization test :
•Lewise Tripple Response
 Therapeutic Drug Monitoring
• Drug response differs between individuals.
• This variability results from two main sources:
• 1. variation in absorption, distribution, metabolism or
elimination (pharmacokinetic);
• 2. variation at or beyond tissue receptors or other macro-
molecular drug targets (pharmacodynamic).
• There must be a continuous variable that is readily
measured and is closely linked to the desired clinical
outcome.
 Example
• Antihypertensive drugs are monitored by their effect on
blood pressure,
• Statins by their effect on serum cholesterol.
• Oral anticoagulants by their effect on the international
normalized ratio (INR).
• Measuring drug concentrations in plasma or serum
identifies only pharmacokinetic variability, but can
sometimes usefully guide dose adjustment .
For example in treating an epileptic patient with an anti-
convulsant drug.
• Measuring drug concentrations for use in this way is often
referred to as ‘therapeutic drug monitoring’.
 ROLE OF DRUG MONITORING IN THERAPEUTICS
Measurement of drug concentrations is sometimes a useful complement
to clinical monitoring to assist in selecting the best drug regimen for
an individual patient.
Measurements of drug concentrations in plasma are most useful when:
1. There is a direct relationship between plasma concentration and
pharmacological or toxic effect
2. Effect cannot readily be assessed quantitatively by clinical
observation.
3. Inter-individual variability in plasma drug concentrations from the
same dose is large (e.g. phenytoin).
4. There is a low therapeutic index (e.g. if the ratio of toxic
concentration/effective concentration is 2).
5. Several drugs are being given concurrently and serious interactions are
anticipated.
• oral anticoagulants by their effect on the international
normalized ratio (INR).
• Measuring drug concentrations in plasma or serum
identifies only pharmacokinetic variability, but can
sometimes usefully guide dose adjustment .
• For example in treating an epileptic patient with an
anticonvulsant drug.
• Measuring drug concentrations for use in this way is often
referred to as ‘therapeutic drug monitoring’.
 Drug-induced immune haemolytic anaemias
Drugs may cause immlme haemolytic anaemias via three mechanisms :
1- Antibody directed against a drug-red cell membrane complex (e.g.
penicillin, ampicillin);
2- Deposition of complement via a drug-protein (antigen)-antibody
complex onto the red cell surface (e.g. quinidine, rifampicin); or
3- A true autoimmune haemolytic anaemia in which the role of the drug
is lmclear (e.g. methyldopa).
In each case, the haemolytic anaemia gradually disappears when the drug
is discontinued but with methyldopa the autoantibody may persist for
several months.
The penicillin-induced immune haemolytic anaemias only occur with
massive doses of the antibiotic.
Three different mechanisms of drug-induced immune haemolytic anaemia.
In each case the coated (opsonized) cells are destroyed in the reticulo endothelial
system
 Drug - Drug Interactions :
occurs when one drug interacts with or interferes with the action of
another drug.
For example, taking an antacid with oral tetracycline causes a decrease in
the effectiveness of the tetracycline.
The antacid chemically interacts with the tetracycline and impairs its
absorption into the bloodstream, thus reducing the effectiveness of the
tetracycline.
Drugs known to cause interactions include oral anticoagulants, oral
hypoglycemics, anti-infectives, antiarrhythmics, cardiac glycosides,
and alcohol.
Drug–drug interactions can produce effects that are additive, synergistic,
or antagonistic.
A- Synergism (Additive):
1- Penicillin + Gentamycin :
2- Aminophyllin + Ephedrine :
3- Ampicillin + Clavulinic Acid (Augmentin) :
B-Synergism (Enhancing):
1- Ergotamine + Caffeine (Cafergot) :
2- Fe SO4 + VitC :
3- Adrenaline + Procaine :
 Antagonisitic drug reaction
An antagonistic drug reaction occurs when one drug interferes with the
action of another, causing neutralization or a decrease in the effect of
one drug.
For example, protamine sulfate is a heparin antagonist.
This means that the administration of protamine sulfate completely
neutralizes the effects of heparin in the body.
The nonsteroidal anti-inflammatory drugs and salicylates are examples of
drugs that are given with food to decrease epigastric distress.
Still other drugs combine with a drug forming an insoluble food–drug
mixture.
For example, when tetracycline is administered with dairy products, a
drug food mixture is formed that is unabsorbable by the body.
When a drug is unabsorbable by the body, no pharmacologic effect
occurs.