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Author: Netherlands Pharmacovigilance Centre Lareb Version date: 14 Nov 2017

Author: Netherlands Pharmacovigilance Centre Lareb Version date: 14 Nov 2017

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Author: Netherlands Pharmacovigilance Centre Lareb Version date: 14 Nov 2017

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  1. Author: Netherlands Pharmacovigilance Centre Lareb Version date: 14 Nov 2017 Content: This lecture describes Clinical Pharmacological aspects of ADRS, by R. van Eekeren, PharmD, The Netherlands. This lecture can be used for teaching key aspect 2,3,4: preventing, recognizing, managing ADRs.

  2. Clinical pharmacology of adverse drug reactions Course Pharmacovigilance 2017 Drs R (Rike) van Eekeren Pharmacist

  3. Learning objectives • In this lecture, you learn to- apply the pathophysiologic principles that underlie to the occurrence of side effects • Characterize adverse drug reactions based different formats:- type A/B classification- DoTS classification • Discuss which patients have an increased risk of developing side effects

  4. Dosis sola facit venenum “All substances are poisons; there is none which is not a poison. The right dose differentiates a poison and a remedy” Paracelsus (1493-1541)

  5. Classification system 1 Exemple:Beta-blocking agents  1◦ dizziness, hypotension  2◦ Raynaud phenomena, dyspnoea in astma

  6. Pharmacologic ADRs

  7. Classification system 2: Type A/B B “Bizarre” • Idiosyncratic • Rare • Serious • Not detected in clinical trials A “Augmented” • Pharmacological effect • Dose dependent • Occurs frequently • Often detected in clinical trials Talbot J, Waller P. Stephen’sdetection of new adverse drug reactions. 5e editie, 2004. John Wiley &Sons Ltd. Chichester. P.92

  8. Type A drug related Dose dependent Reversible Disappears after dose reduction or cessation of therapy Rechallenge often positive

  9. Type B patient related Not dose dependent Sensibilization may be needed Reduction of dose often no effect on ADR Treatment is often needed Dechallenge positive

  10. Type B patientrelated • Allergic / immunological reactionsExamples: Blood: seriousblood disordersLiver: hepatitisKidney: nephritisLung: pneumonia, alveolitis Skin: urticaria, angioedema, anaphylaxis • Otherpatient-related factors- Idiosyncrasy (undefinedsusceptibility)- Genetic factors (enzymedeficiencies, HLA-types)

  11. AB types: No sharp distinction? When we do not know the exact mechanism:- Nausea in antibiotics  type A, but unknown pharmacology? When the immune systems is triggered by toxicity mechanism- Toxic hepatitis  Often, auto-immune component after initial hepatocellular damage In pseudo-allergy: allergic-like symptoms due to pharmacological effect- ACE-inhibitor induced angio-edema Time relationship?  ADR’s after chronic use…Patient susceptibility?  Why some patients develop ADR

  12. AB classification to G

  13. Classification ADRs • Text • Text • Text • Text Mydriasis by amitriptyline Type? A(ugmented)

  14. Classification ADRs Suppression of Hypothalamus-Pituitary- Adrenal cortex- axis (HPA) due to corticosetroids Type?C(hronic)

  15. Classification system 3: DoTS • Do Doserelatedness • T Time relatedness • S Susceptibility

  16. Dose relatedness • Effects of medicines are based on interactions between chemical substances, to which law of mass action is applicable • Even for immunological disorders like- Hay Fever!- Desensitisation- Allergic skin reactions

  17. Dose relatedness Alternativeclassificationrelatestoreactionsthatoccur in • Supra-therapeutic doses (toxicdose) • Standard therapeutic doses (collateraleffects) • Subtherapeutic doses (allergicreactions)

  18. Time relatedness Time-independent reactionscanoccur at any time; independent of theduration of the treatment  treatthecauseifpossible • Change in concentration at site of action- Dose- Renalfunction- Drug interaction (kinetic)- … • Whenpharmacological response altersduetoothercauses- Comorbidity- Ageing- Drug interaction- …

  19. Timing • Time dependentreactions • Rapidreactionsonlywhen a drug is administeredrapidly- Red man syndrome on vancomycin-  administerslowly • First dosereaction. In particular, at first dose, notnecessarilytherafter- Hypotension ACE inhibitors, alfa-1-blockers  precautionsfor 1st dose- Type I allergicreactions  avoid re-exposure

  20. Timing • Early reactions- early in treatment but then disappears through adaptation (tolerance)- Example: nitrate-dependent headache predictable, monitor, reassurance of patient • Intermediate reaction. Risk increases at first (days to month) and than diminishes- Hypersensitivity reactions II-IV- Venous thrombo embolism – antipsychotic drugs  monitoring not needed after risk period  withdraw drug if reaction develops  susceptible population

  21. Timing • Late reaction. The risk of the onset of the side effect increases with time- Osteoporosis in use of corticosteroids- Tardive dyskinesia at dopamine antagonists asses base-line function, monitor during treatment- Withdrawal reactions (like myocardial infarction after discontinuation of ß-blockers)  withdraw slowly • Delayed reaction- Especially after prolonged use or repeated exposure- Increased risk of breast carcinoma after the use of estrogens in menopause  avoud drug of screen; counseling patient

  22. Individualsusceptibility Risks of an adverse reaction depends on various factors such as • Age • Seks • Genetic factors • Renal function • Hepatic function • Exogenous factors

  23. From: Aronson 2003

  24. Children

  25. Drug therapy in young children Tan et al. MJA 2003

  26. Adverse drug reactions in children • Different patterns compared to adults • Sometimes higher frequency- Liver failure and valproate- Stevens Johnson Syndrome and lamotrigine • Alterations in pharmacokinetics and pharmacodynamics

  27. Pharmacokinetics in children DevelopmentalPharmacology – Drug Disposition, Action, andTherapy in InfantsandChildren Keams GL, Abdel-Rahman SM, Alander SW, Blowley DL, Leeder JS, Kauffman RE, NEMJ 2003

  28. Pediatrics: absorption

  29. Pediatrics: distribution

  30. Pediatrics: metabolism

  31. Pediatrics: excretion

  32. Pharmacodynamics • Increased or decreased sensitivity • Antihistamines: central stimulating effects • Benzodiazepines: paradoxical effects • Ketotifen: aggressive/hyperactive behaviour • Cyclosporin: High immunosuppressive response • Effects of growth and development

  33. Elderly

  34. Drug therapy in theelderly • Aging process differs among individuals • Aging of various tissues may differ (within individuals) • Multiple morbidity • Polypharmacy (interactions) • Long term use of drugs • Compliance • Practical problems

  35. ADRs in elderly 5-6% of all hospital admissions are preventable

  36. ADRs in elderly JAMA. 2003;289:1107-1116.

  37. Changes in function elderly Body composition Homeostasis e.g.- Temperature control- Orthostasis- Control of thirst Changes in tissues and organs (more vulnerable)

  38. Pharmacokinetics: absorption Reduced motility of the oesophagus Local irritation of tablets (bisphosphonates) pH increase Slower gastric emptying Longer transit time intestine

  39. Pharmacokinetics: distribution • Decrease in musclemass decrease in lean body mass • Lipophilicsubstances have greaterdistribution volume  plasma concentrationinitally low • Hydrophilicsubstances have smaller distribution volume  highertoxicityand more side effects • Albuminconcentrationhardly changes (decreasedbyunderlying disorders)

  40. Elimination by liver Volume decreases, reduction of phase I reactions - Enzyme levels decreased - Especially CYP 1A2 and 3A4 Reduction of blood flow hepaticarteryand portal vein - Clearance of drugs with high first pass effect reduced - e.g. Propranolol 45% andmorphine 35%

  41. Elimination by kidney In about 1/3 of theelderly no deterioration of renalfunction In 2/3 changes occurdueto i.e.- Cortical area - Numberanddensity of glomeruli - Lengthand volume of proximaltubuli - Vascular changes

  42. Kidney function and age Stevens et al. NEJM. 2006;354 (23): 2473

  43. Pharmacodynamics • Changes may occur in:- Receptor density- Receptor structure- Propagation of signals • Sensitivity for various drugs- Increased (): psychiatric drugs, opioids, dopamine, agonists, parasympaticolytics- Decreased (): ß-blockers and insulin

  44. ADRs in elderly: risk of falling • Balance is complex mechanism controlled by- Vestibular system, Vision, Proprioception (orientation and movement), Muscle responses • Falling may occur due to- Cardiovascular effects: Orthostatic effects - Inadequate response due to vasodilatation - Reduction in function of baroreceptors - Insufficient fluid intake - α- or ß blocking agents, duiretics, ACE inhibitors, … • Psycho active drugs- Sedation, dizziness, confusion- Effect on extrapyramidal system- Muscle relaxants (benzodiazepines)

  45. Psychoactive agents and falls Neth J Med2005;36:91-96

  46. ADRs in elderly: thermoregulation • Problems in thermoregulation- Homeostasis for maintaining core temperature is changed- Ability to increase temperature (shivering) - Risk for hypothermia/poikilothermia • Antipsychotics may increase risk!

  47. ADRs in elderly: cerebral function • Loss of neurons and receptors for cholinergic transmission • Additional neurologic disorders (i.e. stroke) • Anticholinergic drugs may influence cerebral function to large extent

  48. Summary: DoTSand basic aspects • Dose- Pharmacological mechanism- Drug properties • Time • Susceptibility- Patient properties- Pharmacodynamics- Pharmacokinetics

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