Adverse Drug Reactions453453453445667.pptx

Adverse Drug Reactions

1. Adverse Drug Reactions Dr. Shakir, PhD (Pharmacology), Post doc (Neuroscience)

2. WHO definition ⯈ any undesirable effect of a drug beyond its anticipated therapeutic effects occurring during clinical use. Edwards and Aronson, Lancet, 2000; 356(9237):1255-9 ⯈ an app r e c iably harmfu l o r unpleasa n t r e a ction, r esulting from an intervention related to the use of a medicinal product, which predicts hazard from future administration and warrants prevention or specific treatment, or alteration of the dosage regimen, or withdrawal of the product Definitions

3. New EU Pharmacovigilance Legislation ( DIRECTIVE 2010/84/EU; 15 Dec 2010) ⯈ the definition of the term ‘adverse reaction’ should be amended to ensure that it covers noxious and unintended effects resulting not only from the authorised use of a medicinal product at normal doses, but also from medication errors and uses outside the terms of the marketing authorisation, including the misuse and abuse of the medicinal product .

4. Classifications of Adverse Drug Reactions

5. ABCDE classification T yp e A : Predictable, acute, related to mechanism of action T yp e B : Idiosyncratic, unpredictable, acute / sub-acute, not related to k n o w n m e c h a n ism T yp e C : Consequence of cumulative effect of long-term therapy T yp e D : Delayed, caused by teratogenic or carcinogenic mechanisms T yp e E : E n d o f d o s e (w i th d r a w a l ) r e a c ti o ns

6. Do se T iming S usceptibility DoTS Classification BMJ. 2003 Nov 22;327(7425):1222-5

7. The Burden of Adverse Drug Reactions Admission (6.5%) In patients (14.7%) Emergency Room (2.5%) Primary Care (25%)

8. Dose-Response Curve External dose Internal dose P a r e n t drug Metabolites

9. Adverse drug reaction Primary pharmacology Secondary pharmacology Augmentation of known actions Example  - blo c k er- in d uced bradycardia Often involves different organ system, but rationalisable from the known pharmacology Example  - blo c k er- in d uced bronchospasm

10. Type Example Toxicity Mechanism Pharmaceutical Phenytoin Phenytoin toxicity (ataxia, n y s t agmu s , e t c ) Increase in bioavailability as a result of a change in formulation Pharmacokinetic (can involve absorption, distribution, metabolism and excretion) Digoxin Digoxin toxicity (nausea, arrhythmias, etc) Decreased elimination if renal function is impaired Pharmacodynamic Indomethacin Left ventricular failure Water and sodium retention Genetic Nortriptyline Confusion Reduced hepatic elimination as a result of a deficiency of CYP2D6 Drug-drug interactions (can involve any of the above processes) Lithium- nonsteroidal anti- i n flamm a t ory drugs Lithium toxicity Inhibition of excretion of lithium Pharmacologically Predictable ADRs

11. Variability in Dose Requirements: Clinical Factors Comorbid diseases Compliance Concomi t a n t medications N u tritio n al status Gender BMI Age

12. Drug Metabolism and Adverse Drug Reactions

13. DRUG Cellular accum u l a tion Response Cell Damage Cell Death Carcinogenicity Hypersensitivity Toxic m e t aboli t es Stable m e t aboli t es Excretion Phase I/II/III Chem ic al Stress Modification of: Nucleic acid enzyme, transporter, signalling protein, receptor, random autologous protein bioactivation bioinactivation Physiolgical , Pharmacological and Toxicological aspects of metabolism of xenobiotics and endobiotics

14. Immune-Mediated Adverse Drug Reactions

15. Delayed Hypersensitivity Cutaneous Reactions Mac u lo p ap u lar exanthem Hy p e r s e nsitivity syndrome Stevens- Johnson S yn d r ome Toxic Epid e rm a l N e c r ol y sis S e v erity Mor t ali t y Rarity

16. Drug De n dritic cell T cell MHC II T CR Curtsinger et al., 1999, 2003 Stimulation of Naïve T-cells Co-stimulation CD40, CD80 / CD86 Signal 1 – MHC-restricted antigen Signal 2 – Co-stimulation

17. Drug De n dritic cell Innate response Il-1 / Il-12 T cell MHC II T CR Stimulation of Naïve T-cells Co-stimulation CD40, CD80 / CD86 Signal 1 – MHC-restricted antigen Signal 2 – Co-stimulation Signal 3 – Innate response Curtsinger et al., 1999, 2003

18. Type 1 Tissue damage in skin CD4 CD8 Type 2 Innate response Il-1 / Il-12 Drug De n dritic cell T cell MHC II T CR Signal 1 – MHC-restricted antigen Signal 2 – Co-stimulation Signal 3 – Innate response Stimulation of Naïve T-cells Co-stimulation CD40, CD80 / CD86 Curtsinger et al., 1999, 2003

19. MHC Region on Short Arm of Chromosome 6 3.6Mb on 6p21.3 150 genes, many of involved in autoimmune and inflammatory disorders >40% involved in immune system and T-lymphocyte signalling Many genes with unknown functions

20. International terminology for reporting of adverse drug reactions WHO’s Adverse Reaction Terminology (WHO-ART) broad “high-level” terms “preferred” terms “included” term more specific and disease-related or symptom-related frequently reported alternative and true synonyms Hierarchical terminology International Classification of Diseases (ICD) link these classifications, so that WHO-ART will become a subset of ICD medical terminology for drug regulatory authorities (MedDRA) MedDRA is currently being promoted commercially and is accepted by the European Union, the USA, and Japan International terminology for reporting of adverse drug reactions

21. Summary Adverse drug reactions common Many different mechanisms – most of these are complex and involve different parameters Interaction between drug, host and environment a factor in mechanism Interventions to overcome ADRs therefore likely to be complex