Adverse Drug ReactionsAdverse Drug ReactionsADRsADRs

Drug Safety has always been a concern Drug Safety has always been a concern …. and should remain so…. and should remain so

‘First do no harm … it is a good remedy sometimes to use nothing.’

(Hippocrates, 5th Century BC)

‘All things are poisons and there is nothing that is harmless … the dose alone decides that something is a poison.’

(Paracelsus, 1500s)

‘Patients may recover in spite of drugs … or because of them.’

(Gaddum, 1959)

IntroductionIntroduction• Any drug can cause an ADR• Perioperatively, multiple agents are

administered• Occult antigens pose major problems • Fatal ADRs leading cause of death • ADR costs may lead to an additional

$1.56-$4 billion/yr in US

Incidence of ReactionsIncidence of Reactions

• 5% adults in US are allergic to • >1 drugs • 30% of medical inpatients develop an ADR• 3% of all hospital admissions are due to

ADRs• Risk of an allergic reaction is approximately

1-3% for most drugs

Causes considerable morbidity and mortality; treating this is very expensive

Data on incidence is poor considering the scope of the problem

Typical figures for the USA (where most studies have been done) suggests:

― precipitate 1-4% of acute medical admissions― 4-9% of inpatients suffer an ADR― 7,000 deaths per annum directly reflect an ADR

― some sources put the figure closer to 100,000

― Cost for the US health care system > $100b/year― UK estimate £400m??

Importance of ADRs - 1Importance of ADRs - 1

Majority are preventable

Strategies for prevention include:

― Ward pharmacists― Electronic prescribing and dispensing

― Already in Primary Care/GPs― Extension to Hospitals

― Better education

Importance of ADRs - 2Importance of ADRs - 2

WHO Definition of ADRsWHO Definition of ADRs

Any noxious, unintended, undesired effect of a drug which occurs at doses used for prophylaxis, diagnosis, or therapy, excluding therapeutic failures, intentional and accidental overdose and drug abuse, and does not include ADRs due to errors in drug administration.

Classification of Adverse Drug ReactionsClassification of Adverse Drug Reactions

Severity Description

Mild No antidote or treatment is required; hospitalization is not prolonged

Moderate A change in treatment (eg, modified dosage, addition of a drug), but not necessarily discontinuation of the drug, is required; hospitalization may be prolonged or specific treatment may be required

Severe An ADR is potentially life threatening and requires discontinuation of the drug and specific treatment of the ADR

Lethal An ADR directly or indirectly contributes to a patient's death

UNPREDICTABLE REACTIONSUNPREDICTABLE REACTIONS

• Dose-independent

• Not related to drug’s actions

• Related to immune response (allergy)

PREDICTABLE REACTIONSPREDICTABLE REACTIONS

• Dose dependent• Related to drug’s actions• Occur in normal patients• 80% of adverse effects

• Overdosage or toxicity• Side effects• Secondary/Indirect effects• Drug interactions

ADR detection methodsADR detection methods

• Premarketing clinical trials• Post approval spontaneous case reports• Aggregate population-based data sources• Computerized data collections• Postmarketing studies• Case reports

SUMMARYSUMMARY

• Any drug can produce some form of ADR• Significant untoward risks, costs, and increased

hospital stays associated with ADRs• Allergy, atopy, or asthma pts have been suggested

to be at an increased risk• Antibiotics, blood products, drug preservatives and

polypeptides may be associated with a higher incidence of reactions

• Drug avoidance whenever possible is still the best method to avoid an ADR

Why do Patients vary in their Why do Patients vary in their response to Drugs?response to Drugs?

Genetic, environmental, and developmental factors that can Genetic, environmental, and developmental factors that can interact, causing variations in drug response among patientsinteract, causing variations in drug response among patients

• Genetics (PHARMACOGENOMICS)• Disease• Age (weight)• Concomitant drugs• Gender• Non-compliance - underestimated• Route of Administration - bioavailability• Food - protein malnutrition• Pollutants - smoking/herbicide residues• Timing - chronopharmacology

The Origin of patient to patient VariabilityThe Origin of patient to patient Variability

Biotransformation of Drugs:1. Oxidation/Reduction by the P450 system1. Oxidation/Reduction by the P450 system

Relative contribution of the major P450

isoforms to human drug metabolism

•Haem-containing proteins within the smooth ER responsible for most PHASE I biotransformations

• Large superfamily of enzymes - 12 gene families expressed in humans.

•Diverse range of xenobiotics are substrates for the P450 system - but all show high lipid solubility.

• CYP3A4 is the major isoform in humans with substantial extrahepatic expression especially in the gut wall.

Oxidation/Reduction by the P450 systemOxidation/Reduction by the P450 system

CYP3A4 CYP2D6 CYP2C9 CYP1A2 CYP2C19

40,1%

20,8%

15,8%

8,3%8,2%

GI Absorption

– Gastric pH may be influential

– Enhances weak acid absorption hence antacids and PPI/H2 antagonists will interfere (some drugs are packaged with an antacid e.g. antiretroviral didanosine)

– Generally maximal in upper SB

– Enteric-coating or modified-release formulation may shift this into the colon (local pH may be crucial for release here e.g. 5’-ASA SR formulations)

– Gastric emptying often rate limiting hence ….• AUC may be increased by metoclopramide/erythromycin• AUC may be reduced by antimuscarinics/

phenothiazines/antihistamines (sedating)

Variability: Pharmacokinetic factorsVariability: Pharmacokinetic factors

Direct & Indirect effects of food

• Drugs with high first-pass– (verapamil, propranolol) effect with food intake

• Specific effects of certain foods– grapefruit juice - felodipine/terfenadine/simvastatin– milk/antacids – tetracyclines– Hypericum - CyA

– Effect of co-administered drugs

• Anion exchange resins– generally reduce absorption (warfarin, T4 & digoxin)

• Activated charcoal (used in overdose)

Variability: Pharmacokinetic factors Variability: Pharmacokinetic factors ((continued)continued)

– First-pass metabolism * (inactivation before entering the systemic circulation)

– Gut lumen insulin/benzylpenicillin– Gut wall metabolism** tyramine/salbutamol– Liver metabolism propranolol, verapamil, lignocaine

** Transporters (P-glycoprotein) CyA, taxols

* Avoided by alternate route e.g. sublingual or topical GTN, intranasal

insulin, pr ergotamine.

Variability: Pharmacokinetic factors Variability: Pharmacokinetic factors ((continuedcontinued))

Drug Elimination

• Liver disease (cirrhosis) affects first-pass by:

• direct impairment of hepatocellular function• shunting drug directly into the systemic circulation

– increased bioavailability may be huge (10-fold for chlormethiazole)– pro-drug activation may be severely impaired e.g. ACEIs– hypoalbuminaemia will also complicate the picture if free fraction

affects clearance– certain liver diseases have little PK impact e.g. acute viral

hepatitis

Variability: Pharmacokinetic factors Variability: Pharmacokinetic factors ((continued)continued)

Drug Elimination

– Renal impairment affects:

• renal clearance (direct)• protein binding & hepatic metabolism (indirect)

– only binding of acidic drugs (e.g. warfarin/phenytoin) are affected– HD does not restore reduced albumin binding but transplant does– reduced hepatic clearance (e.g. propranolol/nicardipine) depends on dialyzable factors in uraemic plasma– active metabolites may accumulate e.g. morphine-6-glucuronide

Variability: Pharmacokinetic factors Variability: Pharmacokinetic factors ((continued)continued)