Adverse Drug Reactions

(ADRs)

Pathama Leewanich
Department of Pharmacology Faculty of Medicine Srinakharinwirot University

Objectives/ Contents
Define adverse drug reactions Classification of ADRs Drug allergy Prevention

Therapeutic Effect Desired Effect

Adverse Reactions Undesired Effect

 Adverse Drug Reactions

Noxious, unintended and undesired effects that occur at normal drug doses
Exclude overdose drug abuse noncompliance therapeutic failures

Classification
Criteria Onset of event Severity of reaction Type of reaction

Classification - Onset
Acute : within 60 minutes
:- ampicillin

Sub-acute : 1 to 24 hours Latent (chronic) : > 2 days

:- chloramphenicol--> aplastic anemia

Classification - Severity
Mild
bothersome but requires no change in therapy

Moderate
requires change in therapy, additional treatment, hospitalization

Severe
disabling or life-threatening

Classification - Type
Type A
extension of pharmacologic effect often predictable and dose dependent responsible for at least two-thirds of ADRs
:- propranolol and heart block, anticholinergics and dry mouth

Classification - Type
Type B
idiosyncratic (genetic predisposition) or immunologic reactions rare and unpredictable
:- chloramphenicol and aplastic anemia

Classification - Type
Type C
associated with long-term use involves dose accumulation
:- phenacetin and interstitial nephritis or antimalarials and ocular toxicity

Classification - Type
Type D
Delayed effects, dose independent Carcinogenicity
:- immunosuppressants

Teratogenicity (birth defect)

:- fetal hydantoin syndrome

Drug allergy
or

Drug hypersensitivity
(Immunologic Drug Reactions)

Urticaria/Hives (left) and delayed reaction to penicillin (right)

Who is more likely to suffer drug allergy ?

 Drug allergies are no more likely to occur in people with other allergies (such as hay fever, asthma or eczema) than anyone else. While there are reports of some families who have many people with drug allergies, most drug allergies are not inherited.

Comparison of Different Types of hypersensitivity

Type-I Characteristics
Antibody Antigen IgE exogenous

Type-II
(cytotoxic) IgG, IgM cell surface minutes-hours lysis and necrosis antibody and complement antibody

Type-III
(immune complex) IgG, IgM soluble 3-8 hours erythema and edema, necrosis complement and neutrophils antibody

Type-IV
(delayed type) None tissues & organs 48-72 hours erythema and induration monocytes and lymphocytes T-cells tuberculin test, poison ivy, granuloma

(anaphylactic)

Response time 15-30 minutes Appearance Histology Transferred with Examples weal & flare basophils and eosinophil antibody

erythroblastosis SLE, farmer's allergic asthma, fetalis, lung disease hay fever Goodpasture's nephritis

Specific Drug Hypersensitivity Caused by Non-IgE Immune Mechanisms

Causative drug
Hydralazine (anti HT) Procainamide (antiarrhythmia) Carbamazepine (Anticonvulsant) Phenytoin (Anticonvulsant) Sulfonamides Anticonvulsants

Syndrome
Lupus-like syndrome

Anticonvulsant hypersensitivity syndrome

Stevens-Johnson syndrome

Common Causes of ADRs

Antibiotics
Antineoplastics* Anticoagulants Cardiovascular drugs* Hypoglycemics Antihypertensives NSAIDs / analgesics Diagnostic agents CNS drugs*

*high incidence of fatal ADRs

ADRs Risk Factors

Age (children and elderly) Multiple medications Multiple co-morbid conditions Inappropriate medication prescribing, use, or monitoring End-organ dysfunction: liver, kidney Altered physiology Prior history of ADRs Extent (dose) and duration of exposure Genetic predisposition

ADRs Detection
Subjective report
Patient complaint History of the symptoms

Objective report:
Direct observation of event Abnormal findings
physical exam laboratory test diagnostic procedure

Ways to minimize ADRs

Avoid harmful drugs

Monitor for signs & symptoms

Educate Clinical testing

 ADRs 1. ADRs ? 2. ADRs onset ? 3. ADRs ? 4. ADRs ? 5. ADRs 6. ? 7. ? 8. ? 9. ADRs ? 10. ADRs ? 11. ADRs ?

Drug Interactions
(DIs)

Pathama Leewanich
Department of Pharmacology Faculty of Medicine Srinakharinwirot University

Objectives/ Contents
Define drug interactions Classification of drug interactions Prevention

Drug Interactions
Taking other drugs, herbs or even food can cause large changes in the amount of a medication in your bloodstream.
It is serious because too much of the drug in your bloodstream can cause serious side effects, and too little can mean that the drug will not work.

Drug Interactions
Drug-drug interaction

Drug-food interaction
Drug-herb interaction

Drug-Drug Interaction
a phenomenon which occurs when the effects of one drug are modified by the prior or concurrent administration of another drug(s)
increase with the number of drugs used and are associated with an increased risk of adverse drug events

Consequences of DDI
1) Intensification of effects

Increased therapeutic effects Increased adverse effects Reduced therapeutic effects Reduced adverse effects
:- alcohol + disulfiram unpleasant, dangerous response

2) Reduction of effects

3) Creation of unique response

Mechanisms
1. Chemical / physical interaction 2. Pharmacokinetic interaction 3. Pharmacodynamic interaction

Chemical / physical interaction

Inactivation
:- penicillin G + dextrose nitroplusside + light

Precipitation
:- kanamycin + methicillin

Pharmacokinetic interaction
Altered Absorption
By elevating gastric pH :- antacids Accelerate drugs passage through intestine
:- laxatives

Depress peristalsis :- morphine, atropine Induce vomitting Adsorb other drugs :- cholestyramine,
adsorbent drugs

Reduce regional blood flow :- epinephrine

Altered Distribution
Competition for protein binding increase free drug increase effects Alteration of extracellular pH ionization

Altered Metabolismliver

Consequences of Drug Metabolism

Inactive products Active metabolites Similar to parent drug More active than parent New action Toxic metabolites

Cytochrome P450 Isoforms

Relative Importance of P450s in Drug Metabolism
CYP2E1 CYP1A2

CYP2C

CYP3A

CYP2D6

Altered Metabolismliver
Induction of drug-metabolizing enzymes Enzyme Inducer :- phenobarbital increase drug metabolism decrease free drug Inhibition of drug-metabolizing enzymes Enzyme Inhibitor :- cimetidine decrease drug metabolism increase free drug

CYP3A Inhibitors Ketoconazole Itraconazole Fluconazole Cimetidine Clarithromycin Erythromycin Troleandomycin Grapefruit juice

CYP3A Inducers Carbamazepine Rifampin Rifabutin Ritonavir St. Johns wort

Enzyme Inducer
Enzyme A

A
Drug

A
inactive

Enzyme Inducer
Enzyme A

A
Drug

A
inactive

B
Drug

Enzyme B

B
inactive

Enzyme Inducer
Enzyme A

+
B Enzyme B B

Enzyme Inducer
Enzyme A

+
B Enzyme B B

Drug B is an enzyme inducer.

Enzyme .
Enzyme A

+
B Enzyme B B

Enzyme Inhibitor
Enzyme A

+
B Enzyme B B

Altered Renal Excretion

Reduced cardiac output
renal blood flow glomerular filtration rate ionization passive tubular

Altered urinary pH

reabsorption

Competed tubular secretion

Pharmacodynamic interaction
At receptor Actions at the same site:

agonist-antagonist interactions :- morphine + naloxone

inhibition

Actions at separate sites: physiologic interactions potentiation inhibition

:- morphine + diazepam

Drug-Drug Interactions

Risk Factors

Drug-Food Interaction
Consequences
Alter absorption : onset/ intensity of effect
:- calcium-containing foods + tetracycline

Affect drug metabolism

:- grapefruit juice inhibit cyt P-450

Inpact on drug toxicity

:- tyramine-rich foods + MAO inhibitors hypertension

Herb-Drug Interaction
St. Johns wort and digoxin, indinavir, cyclosporin, others Garlic can reduce blood levels of anti-HIV drugs.

 DIs 1. DIs ? 2. DIs ? 3. DIs ? 4. DIs ? 5. enzyme inducer enzyme inhibitor ? 6. DIs ? 7. DIs ?