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

Controlled human studies show no risk

Exemples :

Vitamins : B,C,D,E, Folic acid,

Tyroxine, Inj.mag.sulfate

A

No evidence of risk in humans

Exemples :

Metronidazole,Paracetamol,Piperazine,penicillin,erythr

omycine

B

Risk cannot be ruled out Most drugs C

Positive evidence of risk Antiepileptics D

Contraindicated in pregnancy Teratogenic drugs X

Drugs prescribing during pregnancy, Diseases/Condition drugs to be

used

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

pregnancy)

Nausea and

vomiting

Methyldopa Hypertension

Diphenhydramine, Codiene, Dextromethorphan Cough

Paracetamol, Codiene, Benzodiazepines Aspirin and other

NSAID s(1 st and 2 nd trimesters)

Headache

Heparin Anti coagulants

Milk of Magnesia, DocusateSodium, Glycerin, Mineral oil,

Bisacodyl

Constipation

Sucralfate, H2 blockers, Bismuth Salicylate, Non Systemic

Antacids

Peptic ulcer

Isoniazid & Ethambutol, Rifampin Tuberculosis

Metronidazole Anti-amoebic

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

Risks of NSAID used from 30 weeks of pregnancy onwards

premature closure of the ductus arteriosus Oligohydramnios

Deficiency of amniotic fluid

NSAIDS

Fetal hydantion syndrome Craniofacial abnormalities Hypoplasia of

distal phalanges Growth deficiency Mental deficiency Cleft palate

Phenytoin

↓ absorption of folic acid Neural tube defects Valproic acid

Craniofacial defects Spina bifida. Hypoplasia of distal phalanges Carbamazepine

(Tegretol)

Increased risks of clear cell Adenocarcinoma of the vagina and cervix

and of breast cancer have been found for daughters of women who

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.

DES

(diethylstilboes

trol

The effectes of some drugs in use during pregnancy

It is a rare heart defect in which parts of the tricuspid valve are abnormal. Lithium salts

fetal defects Vitamin A

Hyperbilirubinemia Jaundice Kernicterus Primaquine G6PD deficiency Sulphonamides

Fetal warfarin syndrome Nasal hypoplasia Hypoplasia of the extremities

Developmental retardation Other: Central nervous system defects

Spontaneous abortion Stillbirth Prematurity Hemorrhage Ocular defects.

Warfarin

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.

Social Drugs

Foetal alcohol syndrome:

Risk of miscarriage

Inadequate growth before or after birth Facial defects

A small head Mental retardation Nail dystrophy

Alcohol

↓ blood flow across placenta

↓ the absorption of iron

↑ risk of anemia

↑ risk of fetal death Advice

limit coffee to 3cups/day .

Caffeine

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

Neonatal hypothyroidism Amiodarone

Drowsiness Barbiturates

Lethargy Benzodiazepines

Hypothyroidism Carbimazole

Diminish milk supply, ↓ nitrogen and protein content Contraceptives

Reye’s syndrome Aspirin

Irritability Ephedrine

Tooth discoloration Tetracyclines

Gray baby syndrome Chloramphenicol

Drugs which suppress /inhibit lactation

Large doses of Alcohol and Caffeine

Estradiol Oral contraceptives

Theophylline

Bromocriptine

Levodopa

Drugs absolutely contraindicated in nursing mothers

Sulphonamides Phenylbutazone Anti cancer drugs

Mercurials Chloramphenicol Radiopharmaceuticals

Atropine Ergot and its derivatives

(methysergide)

Thiouracil Iodide Lithium

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 B Type A

Rare Yes Often predictable and dose

dependent

Non Yes Dose dependence

low high Incidence

low high Morbidity

high low Mortality

Stop using the

drug

Dose adjusment Therapy

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.