A• ADVERSE

D • DRUG

R• REACTIONS

ADVERSE DRUG REACTIONSWHO DEFINITION

Any noxious, unintended & undesired effect of a drugwhich occurs at a dose used in humansfor prophylactic, diagnostic or therapeutic

purposes

FDA Definition

an adverse event occurring in the course of the useof drug in professional practice

an adverse event from drug overdose whetheraccidental or intentional

an adverse event occurring from drug abuse

an adverse event from drug withdrawal

any significant failure of expected pharmacological action.

Classification

• Type A (predictable)

extension of pharmacologic effect

often predictable and dose dependent

responsible for at least two-thirds of ADRs

e.g. anticholinergics and dry mouth

• Type B (unpredictable)

idiosyncratic or immunologic reactions

rare and unpredictable

e.g., chloramphenicol and aplastic anemia

Penicillin induced anaphylactic shock

Predictable

Pharmacologic side effect Dry mouth from antihistaminics

Secondary pharmacologic side effect Thrush while taking antibiotics

Drug toxicity Hepatotoxicity from diclofenac

Drug-drug interactions Seizure from theophylline while taking

erythromycin (increased thephylline

level)

Drug overdose Seizure from excessive lidocaine

(Xylocaine)

Unpredictable

Pseudoallergic Anaphylactoid reaction after ASPIRIN

Idiosyncratic Hemolytic anemia in a patient with

G6PD deficiency after ciprofloxacin

therapy

Intolerance Tinnitus after a single, small dose of

aspirin

• Type C

associated with long-term use

involves dose accumulation

e.g., NSAID induced nephropathy

• Type D

delayed effects (dose independent)

Carcinogenicity

Teratogenicity

Type E: End-of-use

◦ Withdrawal

◦ Related to discontinuation which is too abrupt

◦ Examples:

Addisonian crisis after steroid withdrawal

Angina pectoris after stopping -blockers

CLASSIFICATION OF ADRs

~According to SEVERITY~ Mild

Does not affect patient’s day-to-day activity

ModerateAffects patient’s day-to-day activity to some extent

SevereAdversely affects patient’s health may lead to death

ADVERSE DRUG EFFECTS

1. Side Effects

Unwanted but unavoidable

pharmacodynamic effects

occuring at therapeutic doses.

Side effect may be based on same

action as therapeutic effect.

Eg. Atropine and dry mouth

Codeine and constipation

2. SECONDARY EFFECTS

Indirect consequences of a primary action

of the drug.

a.Super infection due to tetracyclines.

b.Latent tuberculosis activated by

corticosteroids.

3. Idiosyncratic reactions

Gentically determined abnormal reactivity to a

chemical.

Chloramphenicol – aplastic anemia

4. INTOLERANCE

Failure to tolerate even a single dose of the drug

Appearance of characteristic toxic effects of a drug

in an individual at therapeutic doses.

Aspirin - gastric bleeding

Poisons and Poisoning

chemical

substance that

endangers life by

affecting one or

more vital functions

of the body.

Accidental?

Suicidal Homicidal

Deliberate?

hypersenstivity:

Immunological

Type I reaction (IgE-mediated)

Anaphylaxis from

β-lactam antibiotic

Type II reaction (cytotoxic) Hemolytic anemia from

penicillin

Type III reaction (immune complex) SLE, RHEUMATOID

ARTHRITIS

Type IV reaction (delayed, cell-mediated) Contact dermatitis from

topical antihistamine

Immune reaction Mechanism Clinical

manifestation

Timing of

reactions

Type I (IgE-mediated) Drug-IgE complex

binding to mast cells

with release of

histamine,

inflammatory

mediators

Urticaria, angioedema,

bronchospasm,

pruritus, vomiting,

diarrhea, anaphylaxis

Minutes to hours after

drug exposure

Type II (cytotoxic) Specific IgG or IgM

antibodies directed at

drug-hapten coated

cells

Hemolytic anemia,

neutropenia,

thrombocytopenia

Variable

Type III (immune

complex)

Tissue deposition of

drug-antibody

complexes with

complement activation

and inflammation

Serum sickness,

fever, rash,

arthralgias,

lymphadenopathy,

urticaria,

glomerulonephritis,

vasculitis

1 to 3 weeks after

drug exposure

Type IV (delayed,

cell-mediated)

MHC presentation of

drug molecules to T

cells with cytokine and

inflammatory mediator

release

Allergic contact

dermatitis,

2 to 7 days after

cutaneous drug

exposure

Drug abuse

It is the use of a drug for a

nontherapeutic effect.

Some of the most commonly abused drugs

are alcohol; nicotine; marijuana;

amphetamines; barbiturates;

cocaine;opium alkaloids; synthetic opioids;

benzodiazepines, phencyclidine; ketamine;

and anabolic steroids.

Drug abuse may lead to organ damage,

addiction, and disturbed patterns of

behavior.

Use of these drugs often incurs criminal

penalty in addition to the potential for

physical, social, and psychologic harm

Drug dependence Drug dependence is the body's

physical need, or addiction, to a

specific agent.

It is a state in which use of

drugs for personal satisfaction

often in the face of known risk

to health.

Types:

Psychological dependence

Physical dependence.

Psychological dependencedevelops when the individualsbelieve that optimal state ofwell being is achieved throughthe action of the drug.

It results in compulsive druguse in some individuals.

Intensity of dependence varyfrom desire to craving.

Physical dependence

it is manifested by a withdrawal

(abstinence) syndrome, in which

untoward physical effects occur when the

drug is stopped or when its effect is

counteracted by a specific antagonist.

Drugs that cause strong physical

dependence include heroin, alcohol,

benzodiazepines, and cocaine.

Reinforcement :

Ability of the drug to produce effects that make the

user wish to take it again.

Ex., opiods,cocaine,LSD,benzodiazepines.

Drug addiction Drug habituation

Drug addiction is a state of periodic

or chronic intoxication produced by

the repeated consumption of a drug

(natural or synthetic).

Its characteristics include:

1) An overpowering desire or need

(compulsion) to continue taking the

drug and to obtain it by any means;

2) A tendency to increase the dose;

3) A psychic (psychological) and

generally a physical dependence

on the effects of the drug;

Drug habituation (habit) is acondition resulting from therepeated consumption of adrug.

Its characteristics include:

1) A desire (but not acompulsion)to continue takingthe drug for the sense

of improved wellbeing which itengenders:

2) Little or no tendency to increasethe dose;

3) Some degree of psychicdependence on the effect of thedrug,but absence of physicaldependence and hence of anabstinence syndrome;

Addiction habituation

Teratogenicity

Definition :

Ability of a drug to

cause fetal

abnormalities when

administered to a

pregnant women.

PHOTOSENSITIVITY Cutaneous reaction resulting from drug induced

sensitisation of the skin to UV radiation

Phototoxic

◦ Photochemical

◦ Erythema, edema, hyperpigmentation, desquamation

◦ Fluroquinolones, sulfonamides, tetracyclines,

ibuprofen, naproxen

Photoallergic

◦ Cell mediated immune reaction

◦ Papule or contact dermatitis

◦ Sulfonamides, ketoprofen, and celecoxib, grasofulvin

Sun burn

HyperpigmentationDesquamation

Contact Dermatitis

Iatrogenic disease

Any adverse condition in apatient occurring as the resultof treatment by a physician,surgeon, or other healthprofessional, especiallyinfections acquired by the patientduring the course of treatment.

drug induced / physician induced disease.

Ex.,hepatitis by isoniazid

Peptic ulcer by salicylates and corticosteroid.

Carcinogenicity &

mutagenicity.

"The term carcinogen denotes a chemical

substance or a mixture of chemical substances

which induce cancer or increase its incidence“

Mutagen is An agent, such as a chemical,

ultraviolet light, or a radioactive element, that can

induce or increase the frequency of mutation in

an organism.

Effects of Medication on Oral

Tissues Most but not all drugs have effect on the

health of oral .

One of the most common and the earliestknown adverse/side effect involved the use oftetracycline.

The administration of tetracycline to pregnantwomen resulted in tooth staining/discolorationin their children. It resulted in yellow brownstains on the teeth of these children.

Most common oral effects of medicationsinclude dry mouth, a common condition thatmay lead to decay of teeth, opportunisticinfections like candidiasis and/or difficulty inspeaking and swallowing. .

Contact stomatitis

It is a localized reaction of the oralmucosa usually after repeated contactwith the causative agent.

It may result in erythema or ulcerativelesions with or without burning sensation.

The reaction may occur as early as oneday after the drug usage

Antibiotics, iodine, mouthwashes,toothpastes, certain cosmetics, etchave the potential to cause contactsomatitis.

aphthous ulcers

aphthous ulcers or more commonly

known as the canker sores. These are

tiny, painful lesions which occur either

singly or in groups on the labial or buccal

mucosa.

These usually heal without scar

formation within 14 days.

Various drugs including NSAIDs,

captopril, losarton and penicillamine

can cause aphthous ulcers.

Dry mouth Certain drugs such as sedatives,

anticholinergics, omeprazole, anticancer drugs, antidepressants etccause dry mouth as these affect thefunction of the saliva glands reducing thesaliva.

Some of the common problemsassociated with it are burning sensation,constant sore throat, speech problems,difficulty in swallowing and hoarseness.

Drugs that cause xerostomia mostcommonly are benzodiazepines,morphine, calcium channel blockers,etc

Teeth discoloration Tooth discoloration may be intrinsic or

extrinsic. Intrinsic stains are usually caused by

drugs which are taken during and affectthe tooth development, more so duringthe stages of enamel and dentinformation. Such drugs, for example,tetracycline gets accumulated in thedentin and enamel of the developingtooth and appears as yellow or brownstains on the tooth.

Extrinsic stains are the ones which aretaken up by the tooth after development.These include tea and coffee stains andstains caused by some drugs such aschlorhexidine, tobacco

Oral pigmentation

Pigmentation may occur either due to

systemic absorption or local use of drugs

in the oral cavity.

Pigmentation has been reported in cases

taking mercury, arsenic, gold, cupper,

zinc etc, especially around the gingival

margins around the teeth.

These are more prominent in the

presence of plaque and inflammation.

These may be temporary or permanent

but usually most of the pigmentation

disappears with the discontinuation of

the drug.

Burning mouth syndrome

This syndrome may occur due to hormonalwithdrawal, iron or vitamin deficiencies,psychogenic factors or hypersensitivityreactions to various dental materials ordrugs.

Glossitis

Glossitis or inflammation of the tongue ischaracterized by intense pain and swellingthat may be referred to the ear. It usuallyresults in difficulty in speaking, swallowingalong with systemic signs such fever andenlarged lymph nodes. Glossitis though not acommon side effect is usually associated withpenicillin, bleomycin, lansoprazole, etc.

Oral Ulceration More commonly referred to as burns of

the oral mucosa. Aspirin, cocaine,hydrogen peroxide, phenytoin,penicillin, etc can cause either localirritation or ulceration in the oral cavity.

Ptyalism Some drugs alter the function of salivary

glands by increasing the rate offormation of saliva, commonly known asptyalism. The saliva is thin and waterywithout its usual buffering propertiesleading to decay of hard and soft tissuesof the oral cavity. Example: pilocarpine

Drug induced Gingival hyperplasia

It is the painless overgrowth of the gingivaltissues, usually the interdentally papilla ismore affected, later extending to other areasof the gingival.

The common drugs causing the drug inducedgingival enlargement are cyclosporine,phenytoin, calcium channel blockers likenidefine and oral contraceptives.

Reducing the dose of the offending drugalong with the maintenance of good oralhygiene usually suffices the treatment forgingival hyperplasia. In severe casescomplete stoppage and/or changing to analternative drug is required to treat the case.

Taste disturbance

this may include alteration in taste by reducingthe sensitivity in taste perception, or a total lossof taste or a disturbance in correct identificationof taste.

Drugs that are capable of affecting/altering thetaste sensation are aspirin, cetrizine, variousantibiotics like penicillamine, ofloxacin,metronidazole, etc.

Halitosis

Halitosis or bad breadth can result from poor oralhygiene, ingestion of certain drugs, use oftobacco products, oral or dental infections, andsome systemic disorders. Sublingual nitrateand disulfiram have the potential to causehalitosis.

Oral candidiasis

At times the systemic drug therapy alters theoral micro flora predisposing the mouth tovarious bacterial and fungal infections. Alsothe drugs that reduce/suppress the immunityof the individual make the individualsusceptible to opportunistic infections suchas candidiasis. Such drugs includecorticosteroids, antimicrobials,immunosuppressive agents, anticancerdrugs,

Abnormal bleeding

Abnormal bleeding is caused by drugs suchas aspirin, NSAIDs, anticoagulants andsteroids which thin the blood, used inconditions of stroke, myocardial infarctionsand arrhythmias

Alveolar osteitis or, a dry socket, is a

complication of wound healing following extraction

of a tooth. It is known as "dry socket" as after the

clot is lost, the socket has dry appearance

because of exposed bone. The blood clot helps in

stopping the bleeding and lays framework for new

tissues to develop there but in case of dry socket,

the clot is dislodged and the bone is exposed. This

bare bone is exposed to bacteria in the saliva and

the food which the patient consumes and the bone

becomes infected and painful. The uses of oral

contraceptives have also been associated with

significant increase in the frequency

of dry socket.

Aphthous ulcer treatment

Treatment is symptomatic andincludes oral pain relievers, mouthrinses, topical creams with or withoutsteroids, diphenhydramine, andtetracycline suspension mixed withnystatin and diphenhydramine.

Aphthasol is a new topical drug which decreases the duration of healing and ulcer pain.