Dr. Badar Uddin Umar

Drugs have:Beneficial effectsHarmful effects

Facts Drugs save life & improve healthDrugs also threaten life

“Cur’d yesterday of my disease

I died last night of my physician”

- Mathew Prior: 17th Century

From, the remedy worse than the disease

So, the important question is ALWAYS:

“Do the potential benefits of the medication outweigh the potential risks for the individual?”

Definition

‘An adverse drug reaction is any undesirable effect of a drug beyond its anticipated therapeutic effects occurring during clinical use.’

The term (ADR) usually excludes-

nontherapeutic overdosage (e.g. toxicities due to accidental exposure or attempted suicide) and

lack of efficacy of drug

WHO definition:• “Any response to a drug that is noxious and unintended and that occurs at doses used in humans for prophylaxis, diagnosis, or therapy of disease, or for the modification of physiologic function.”

• It excludes therapeutic failures, overdose, drug abuse, noncompliance, and medication errors

Injury resulting from the medical use of a drug. Includes Medication Error & ADR Medication error: An injury resulting from an

error in preparing, procuring, prescribing, dispensing, administering, or monitoring.

Adverse drug reaction (ADR): An injury resulting from the medical use of a drug where no error is involved.

ADRs are a common clinical problem.

Causes adverse consequences to patients…

From mere inconvenience to death and

Have very high incidence in clinical practice

For marketed drugs in USA

Occur in 5% of all hospital admissions

10-20% of hospital inpatients

About 25% in general practice

Significant cause of death (0.5-0.9%)

In the UK Non Steroidal Anti-Inflammatory Drug (NSAID) use alone accounts for1 • 65,000 emergency admissions/year• 12,000 ulcer bleeding episodes/year• 2,000 deaths/year

1Blower et al. Emergency admissions for upper gastrointestinal disease and their relation to NSAID use. Aliment Pharmacol Ther 1997; 11: 283-291

Consequences of ADRs:

Adversely affects patients’ quality of life

Complicate drug therapy

Decrease compliance and delay cure

Increase cost of patient care

Cause patients to lose confidence in their doctors

May mimic disease, resulting in unnecessary investigations and delay in treatment

ADRs are usually classified depending on

− Onset

− Severity

− Type

Acute Within 60 minutes

Sub-acute 1 to 24 hours

Latent > 2 days

ADR: Onset of event:

Mild

Do not require an antidote, therapy, or prolongation of hospitalization

Commonly known as side-effects

Moderate

Require a change in, but not necessarily cessation of the drug and may prolong hospitalization or require special treatment

ADR: Severity of event:

SevereAre potentially life threatening, requiring

discontinuation of the drug and specific treatment of the adverse reaction

Lethal Directly or indirectly contributes to the patient's

death

• Result in death• Life-threatening• Require hospitalization• Prolong hospitalization• Cause disability• Cause congenital anomalies• Require intervention to prevent permanent

injury

FDA: Serious ADR

2 main types: Type A (Augmented) Type B (Bizarre)

3 other sub-types:Type C, D & E

Type A (known pharmacological adverse drug reactions)

Type A reactions represent an Augmentation of the pharmacological actions of a drug

Predictable & dose-dependent

Readily reversible on reducing the dose or withdrawing the drug.

Commonest type of ADRs (accounting for over 80% of all ADRs)

Not usually life threatening.

Type A adverse reactions:

Are of 2 types:

A) Extension of primary effectB) Secondary effect

Effects due to extension of the primary pharmacological actions of the drug

Augmentation of the drug's therapeutic actions

Example: Bradycardia with Propranolol(due to effect on desirable beta1 blocking effect)

Effects due to the secondary pharmacology of the drug

The action different from the drug's therapeutic actions

The action still rationalisable from the known pharmacology of the drug

Example: Bronchospasm with propranolol (due to effect on undesirable beta2 blocking effect)

Thus, for propranolol:Bradycardia is primary pharmacological adverse

effects

Bronchospasm is a secondary pharmacological adverse effect.

More emphasis is now placed on the secondary pharmacology of new drugs during preclinical evaluation to anticipate problems that might arise once the drug is given to humans.

Type B adverse reactions: (unknown pharmacological adverse drug reactions)

These are Bizarre

Not predictable i.e., cannot be predicted from the known pharmacology of the drug.

Not dose dependent

Can’t be readily reversed

Less common but often serious

Life threatening

Type B ADRs may be:

1) Idiosyncrasy2) Drug Allergy or Hypersensitivity

Idiosyncrasy: (Pharmacogenetics)

Inherent qualitative abnormal response to a drug

Due to genetic abnormality, mainly due to deficiency of enzymes in the body

Also may be due to abnormal receptor activity

Incidence:

Happens to very small population

Rare but serious

Idiosyncrasy due to enzyme abnormalityHemolysis with primaquine

if glucose 6-phosphate dehydrogenase (G6PD) enzyme deficiency in any person

⇓If primaquine given

⇓Hemolysis leading to hemolytic anemia

Idiosyncrasy due to receptor abnormality

Malignant hyperthermia with general anesthetics (Halothane)

Sudden huge rise in IC calcium concentration

Increase in muscle contraction

Increase in metabolic activities

Rise of body temperature

Drug allergy

Also known as hypersensitive reaction

Due to antigen-antibody interactions

1st dose acts as an antigen

Antibody is produced against the antigen in the body

Subsequent dose causes antigen-antibody reaction

e.g. Penicillin induced anaphylaxis

(Type 1 hypersensitivity reaction)

Types of allergic reactionsType I - immediate, anaphylactic (IgE)

e.g., anaphylaxis with penicillins

Type II - cytotoxic antibody (IgG, IgM)

e.g., methyldopa and hemolytic anemia

Type III - serum sickness (IgG, IgM) antigen-antibody complex

e.g., procainamide-induced lupus

Type IV - delayed hypersensitivity (T cell)

e.g., contact dermatitis

Type C or Continuous type:

Happens due to long term chronic use of a drug

Involves dose accumulation

e.g. Analgesic nephropathy with Paracetamol / NSAIDs

Type DDelayed effectADRs are found long term after use of drug

TeratogenesisCarcinogenesis

Teratogenesis: birth defect that is evident after birth but the drug taken during 1st trimester of pregnancy

Carcinigenesis: carcinoma detected long after use of a drug

Teratogenesis

Teratogenesis is the abnormal congenital malformation of fetus due to use of some drugs in 1st trimester of pregnancy

(4-10 weeks: period of organogenesis)

Teratogenic drugs:

1st detected teratogenic drug is ‘thalidomide’

It causes ‘phocomelia’--flipper-like limb defect (like penguin)

Thalidomide disaster in early ‘60s

Other teratogenic drugs:

Cytotoxic (anticancer) drugs Vitamin A (retinoid)Antithyroid drugsSteroid preparationsOAHs oral anticoagulants etc.

In general, all drugs should be avoided in 1st trimester of pregnancy to avoid teratogenic risk

Type E

Ending of drug use

ADRs are manifested after withdrawal of a drug which was used for a long period

When glucocorticoid is abruptly withdrawn/discontinued after prolonged use

Adrenocortical insufficiency

Suddenly body suffers from glucocorticoid crisis

Who might get an ADR?

Anyone who takes a medicine Differential diagnosis should include the

possibility of an ADR if the patient is taking any form of medication

Who is most at risk from ADRs?

Patients who;

are young, or old or female

are taking multiple therapies

50% of patients on 5 drugs or more

have more than one medical problem

have a history of allergy or a previous reaction to drugs

What should raise suspicion of an ADR?

A symptom that….

appears soon after a new drug is started

appears after a dosage increase

disappears when the drug is stopped

reappears when a drug is restarted

ADEs: Most Commonly Involved Drugs:

Antibiotics

Antineoplastics

Cardiovascular drugs

Hypoglycemics

NSAID/Analgesics

CNS drugs

Most Common ADEs:

Gastrointestinal tract events 22.1%

Electrolyte/renal 16.7%

Hemorrhagic 12.7%

Metabolic/endocrine 9.5%

Dermatologic (skin) /allergic 7.9%

Common Symptoms From ADEs:

Confusion

Nausea

Decreased balance

Change in bowel pattern

Sedation

Orthostatic hypotension

What conditions are often drug related?

Anaphylaxis

antibiotics, iron dextran injection

Stevens Johnson Syndrome

associated with carbamazepine, antibiotics

Blood dyscrasias

neutropenia with methotrexate and gold salts

thrombocytopenia with heparin

What questions should be asked if suspect an ADR?

Does the patient have a history of other drug-induced problems?

ask the patient

Does the patient take more than one drug ?

could an interaction be causing the ADR?

long term medication is unlikely to cause new problems

What else ...? When did the reaction or symptoms begin?

timings are useful

Have any of the clinical measurements or lab results recently become abnormal?

Does the patient have any medical problems?that could be causing the symptoms?some diseases predispose patients to ADRs

Causes of ADRs

ADRs may be due to:Drug causePatient causePrescriber’s error---

Type C D & E

Polypharmacy

Factors predisposing to ADRsA) Dose factor:Due to administration more than therapeutic dose

excessive insulin⇓

hypoglycaemia

B) Pharmaceutical factor:Due to wrong pharmaceutical preparation

Slow release NSAID⇓

Release in high concentration due to faulty preparation

⇓GIT bleeding

C) Pharmacokinetic factor:Due to decrease kinetic activities

Sulfonylurea⇓

Decreased elimination in renal insufficiency⇓

Hypoglycaemia

D) Pharmacodynamic factor:Due to drug’s mechanism of action

NSAID⇓

LVF due to salt & water retention

E) Polypharmacy: Drug-drug interaction factor:Erythromycin + terfenadine= Arrhythmia

Other factors:

age

gender

multiple disease

allergy

Prevention of ADRs

Whenever a drug is given a risk is taken

Risks may be avoidable or unavoidable

30-50% ADRs are preventableDrug interaction

Inappropriate medication

Unnecessary medication

Reduction of ADRs can be achieved by:

Better knowledge of diseases

Better knowledge of drugs

Site-specific delivery

Informed, careful and responsible prescribing

Management of ADRs:

Mild ADRs can often be recognized before they

become serious.

If an ADR occurs, the type and precipitating factors

must be determined immediately if possible.

Discontinue the offending agent if:it can be safely stoppedthe event is life-threatening or intolerablethere is a reasonable alternative

Continue the medication (modified as needed) if:it is medically necessarythere is no reasonable alternativethe problem is mild and will resolve with time

Discontinue non-essential medications

Administer appropriate treatmente.g., atropine, antihistamines, epinephrine,

corticosteroids, glucagon etc

Provide supportive or palliative caree.g., hydration, glucocorticoids, warm / cold

compresses, analgesics etc

Consider desensitization

Generally,

For dose-related ADRs:

Modify the dose or reduce precipitating factors

For ADRs unrelated to dose:

The drug usually should be withdrawn and re-exposure should be avoided.

Thank you very much