Introduction to Adverse Drug Reactions

Adverse Drug Reactionsdsdht.wikispaces.com

What is ADRWHO definition : Any undesirable effect of a drug beyond its anticipated therapeutic effects occurring during clinical use

An adverse drug reaction (ADR) is an expression that describes harm associated with the use of given medications at a normal dosage during normal use. -

ADRs may occur following a single dose or prolonged administration of a drug or result from the combination of two or more drugs

The meaning of this expression differs from the meaning of "side effect", as it might also imply that the effects can be beneficial.

Why ADR is Important to know

• Over 2 Million serious ADRs yearly.• 100,000 deaths yearly.• ADRs 4th leading cause of death ahead of

pulmonary disease, diabetes, AIDS, pneumonia, accidents and automobile deaths.

• Ambulatory patients ADR rate—unknown• Nursing home patients ADR rate— 350,000

yearly.

Institute of Medicine, National Academy Press, 2000 Lazarou J et al. JAMA 1998;279(15):1200–1205 Gurwitz JH et al. Am J Med 2000;109(2):87–94

Classification of adverse drug reaction

ABCDE ClassificationRawlins and Thompson devised a classification scheme in 1991, which continues to be the most frequently used.

• Type A: Predictable, acute, related to mechanism of action• Type B: Idiosyncratic, unpredictable, acute / sub-acute, not

related to known mechanism • Type C: Chronic effects (continuous) • Type D: Delayed effects • Type E: End-of-treatment effects

Type A • Dose Related• 80% of ADR, usually a consequence of the

drug’s primary pharmacological effect (e.g. bleeding from warfarin, Headache with glyceryltrinitrate (GTN))

• a low therapeutic index (e.g. nausea from digoxin)

Classification of adverse drug reaction

Classification of adverse drug reaction

Type B• Bizarre effects (or idiosyncratic) • dose independent and • Unpredictable (not an extension pharmacological

action of the drug) • For example: hepatotoxicity due to paracetamol

tinnitus induced by aspirin ototoxicity with aminoglycosides of main

Classification of adverse drug reaction

• Type A less likely to have fatal consequences than type B reactions

Type Type A Type B

Dose Relationship Yes No

Frequency Common Rarer

Mortality Low Higher

Morbidity High Lower

Treatment Stop drug or reduce dose

Stop drug

Classification of adverse drug reaction

Type C• Results from Chronic or continuous use • For example, Analgesic nephropathy • osteoporosis during continued high-dose

glucocorticoid therapy • tardive dyskinesia during continuous use of

antipsychotic drugs

Classification of adverse drug reaction

Type DThese reactions refer to carcinogenic and teratogenic effects. These reactions are delayed in onset and are very rare since extensive mutagenicity and carcinogenicity studies are done before drug is licensed.

• Teratogenic Thalidomide - amelia or micromelia or phocomelia • phenytoin -fetal hydantoin syndrome • tetracyclines -teeth malformation and discoloration • aspirin -early closure of ductus arteriosus • carbamazepine -cleft lip and palate, microcephaly • wafarin - saddle nose • sodium valproate - spina bifida • DES - vaginal clear cell adenocarcinoma

Classification of adverse drug reaction

Type E

• Rebound adrenal insufficiency • Withdrawal syndrome (tachycardia on abrupt

discontinuation of β-adrenoceptor blockade)• Second malignancies following successful

chemotherapy.

Physiological, Pharmacological and Toxicological aspects of metabolism of Drugs

Drug- Drug Interactions

Pharmacokinetic and pharmacodynamic properties of one drug affect either the pharmacokinetics or pharmacodynamics of another drug

Pharmacokinetics:“What the body does to the drug”

Pharmacodynamics:“What the drug does to the body”

Types of Drug Drug Interactions

• Potentiation: Drugs with similar actions cause an additive effect

• Coumadin and aspirin taken together cause excessive bleeding

• Sedatives and alcohol cause excessive sedation

Types of Drug Drug Interactions• Interference: One drug accelerates or slows the

metabolism or excretion of another drug

Erythromycin taken with

– Digoxin = elevated blood levels of digoxin

– Coumadin = enhanced action of Coumadin

Potential for serious adverse effects!

Types of Drug Drug Interactions

• Displacement: Two drugs compete for protein binding sites

– One drug “wins” (is bound to protein)

– Displaced drug is active in greater quantities

– Same effect as taking a higher dose of the displaced drug!

A major cause of drug-drug interactions!

Types of Drug Drug Interactions

• Antagonism: One drug decreases the effectiveness of another drug because of divergent actions – Oral ketoconazole (Nizoral) is absorbed in an

acidic environment

– H2-receptor antagonists or proton pump inhibitors decrease acidity in the stomach

– Differing action decreases Nizoral effectiveness

Types of Drug Drug Interactions• CYP450 enzymes and drug-drug interactions

– CYP450 Inhibitors: Drug A inhibits CYP450 enzymes in the liver; slows metabolism of drug B, toxic levels of drug B accumulate

– CYP450 Inducers: Drug A stimulates production of CYP450 enzymes; increases rate of metabolism of drug B, clears drug B out of the system faster

A major source of drug-drug interactions!

Drug Food Interactions• Food can alter the absorption or metabolism

of medications • Diets can alter the bacterial flora of the

intestine and may affect the metabolism of certain drugs

• Iron taken with acidic foods can cause increased iron absorption

• Acetaminophen or Aspirin taken with or after alcohol have a high chance for severe liver damage.

Types and Examples of Adverse Reactions

Drug Induced liver Injury

• The liver is the main site of metabolism for drugs and other exogenous compounds.

• vulnerable organ, exposed to parent drug and metabolite.

• despite this vulnerability, the liver is not the major target for adverse drug reactions, only about 9.5% of these involve the liver .

• Overdose of Acetaminophen is a common cause of hepatic injury, accounting for ~40 % of cases of acute liver failure in the USA

Types of Drug Induced Hepatoxcity

http://ispub.com/IJPHARM/7/1/3723#

Case Study on Troglitazone (Rezulin)

• Troglitazone(Thiazolidinediones class)

• Class of Oral Antidiabetics for (peroxisome proliferator-activated receptor gamma)

• Mechanism:Troglitazone lowers blood glucose levels through increased glucose uptake by skeletal muscle, decreased hepatic glucose production. Approved by FDA 1997

Adverse Reaction Study

At Clinical trials , elevations of serum alanine aminotransferase (ALT) more than three times the upper limit of normal were observed in 48 out of 2,510 patients (1.9%) treated with troglitazone as compared to 0.6% in patients who received placebo. Troglitazone reported to get associated idiosyncratic hepatotoxicity with some patients showing severe or fatal liver damage.

Withdrawn from the market in the US and Japan in March 2000.

Troglitazone Metabolites

Metabolite 1:Troglitazone sulphate Metabolite 2: Troglitazone glucuronideMetabolite 3:Troglitazone quinone Metabolite 4: Hydroxylated Metabolite 1

phenol sulfotransferase, ST1A3 Glucuronosyltransferase

CYP3A4,CYP2C8

Oxidation of troglitazone to a quinone-type metabolite catalyzed by cytochrome P-450 2C8 and P-450 3A4 in human liver microsomes. Drug Metab Dispos. 1999 Nov;27(11):1260-6.

Websites for Side Effects and Adverse Drug Reactions

• FDA : FAERS Systeme Data From 2004-2012• Sider : The SIDER Side Effect Resource represents

an effort to aggregate dispersed public information on side effects(http://sideeffects.embl.de/)

• MedEffect Canada: The Canada Vigilance Adverse Reaction Online Database contains information about suspected adverse reactions

References• http://ispub.com/IJPHARM/7/1/3723#• https://www.med.upenn.edu/gastro/documents/NEJMdrughepatotoxicity

II.pdf• http://www.fda.gov/downloads/Drugs/ResourcesForYou/Consumers/Buyi

ngUsingMedicineSafely/EnsuringSafeUseofMedicine/GeneralUseofMedicine/UCM229033.pdf

• http://www.bmj.com/content/316/7140/1295• http://www.sciencemag.org/content/321/5886/263• http://stm.sciencemag.org/content/4/125/125ra31.long