Le reazioni avverse: presentazione del corso

1. Le reazioni avverse:presentazione del corso Achille P. Caputi Università di Messina

2. Definizioni • An adverse event is harm that occurs while a patient is taking a given drug, whether caused by it or not. • A side-effect is any effect caused by a drug other than the intended therapeutic effect, whether beneficial, neutral or harmful. • The term is sometimes taken to be synonymous with adverse drug reaction, and is sometimes used to describe ‘minor’ and predictable ADRs (e.g. constipation with opiates). • An adverse drug reaction (ADR) is ‘a response to a drug that is noxious and unintended and which occurs in doses normally used for the treatment, prophylaxis, or diagnosis of disease, or the modification of physiological function’ (World Health Organization). • The definition of ADR has now been extended in the European Union to include abuse, medication error, and overdose.

3. ADR can be classified: 1) according to Dose-relatedness, Timecourse, and Susceptibility (DoTS). 2) on the basis that some reactions are common, dose-related, and explained by the known pharmacology of the drug (Type A ‘Augmented pharmacological’), while others were not (Type B ‘Bizarre’)

4. 1. Adverse drug reactions divided according to the dose response curve for benefit and harm Occurring at doses: above the maximum dose required for a therapeutic effect (toxic effects); within the therapeutic range (collateral effects); below the therapeutic range in susceptible patients (hypersusceptibility reactions). ADR and dose

5. Adverse drug reactions as a toxic effetc They can occur if the dose is too high, or drug excretion is reduced by impaired renal or hepatic function or by interaction with other drugs. The reduced excretion of a drug due to a variety of factors, including dehydration, deterioration of renal function, and interaction with other drugs, can also result in toxicity. Examples • Nephrotoxicity with high doses of aminoglycosides, • Dysarthria and ataxia in lithium toxicity, • Cerebellar signs and symptoms with excessive dosage of phenytoin. ADR and dose

6. Collateral ADRs at standard therapeutic doses Examples: • beta-adrenoceptor antagonists given after myocardial infarction act on the heart to reduce heart rate and the risk of arrhythmia, but also act on beta-adrenoceptors in the lungs and as a consequence can cause bronchoconstriction and worsen asthma. ‘ • many broad-spectrum antibacterial agents can alter the bowel flora and increase the risk of overgrowth by toxigenic Clostridium difficile; as a result, the patient may develop pseudomembranous colitis. ADR and dose

7. ADRs that occur at sub-therapeutic doses in susceptiblepatients (hypersusceptibility reactions). Include reactions • on immunological basis, such as anaphylaxis caused by penicillin. • as a result of a genetic variant, as is the case in patients who suffer prolonged apnoea after standard doses of succinylcholine (phenotypic pseudocholinesterase –butyrylcholinesterase- deficiency. • caused by inflammatory mediators released in response to pharmacological rather than immunological stimuli (Aanaphylactoid reactions). They can appear similar to anaphylactic reactions (iodinated contrast media, acetylcysteine infusions and modified gelatin plasma expanders) ADR and dose

8. Adverse drug reactions and time-relatedness Many ADRs depend both on the concentration of the drug at the site of action and on the duration and frequency of its presence there. Examples. ADR of methotrexate is greater when a lower dose is administered frequently than when the same amount is given as a single dose. ADRs of corticosteroids are predominantly associated with treatment over weeks and months or with very high doses Two patterns of time-course can be distinguished for ADRs: time-dependent and time-independent. ADR and time

9. Time-independent ADR Can occur at any time during treatment and are independent of the duration of the course. They typically occur either when the concentration of drug at the site of action changes despite administering the same dose Examples, increased prothrombin time and bleeding risk with warfarin when co-administred with erythromycin (enzyme inhibitor ) digoxin toxicity associated with hypokalaemia (the pharmacological response is altered without a change in concentration). ADR and time

10. Time-dependent ADR(6 subtypes) Rapid reactions: occur only when a drug is administered too rapidly (the ‘red man syndrome’ due to histamine release caused by the rapid administration of vancomycin). First-dose reactions: occur after the first dose of a drug, and may not re-occur with subsequent doses ( ‘first dose hypotension’ with ACE-I, Type I hypersensitivity reactions, such as anaphylaxis to penicillin. The severity of Type I hypersensitivity reactions can increase with subsequent exposure). Early reactions :occur early in the course of treatment and then abate (patients develop tolerance, such as nitrate-induced headache). Intermediate reactions: occur after a delay, but if they have not occurred after a certain time, then it is unlikely that they will occur later (delayed-type immunological reactions such as StevenseJohnson syndrome with carbamazepine) Late reactions: the risk increases with continued or repeated exposure to a drug. (many of the adverse effects of corticosteroids ; withdrawal reactions, such as agitation and seizures on withdrawal of long-term benzodiazepine treatment). Delayed reactions: occur some time after exposure, even after the drug has been withdrawn. (exposure of the fetus to thalidomide in the first trimester, causing phocomelia, a limb-reduction deformity). ADR and time

11. ADRs associated with long-term corticosteroid use ADR and time

12. Susceptibility(The risk of an ADR may differ from one individual to another in an exposed population) genetic differences, age, sex, physiological variation, certain disease states, co-ingestion of other drugs. All of these factors can affect both the PK and PD of a drug.

13. Abnormaldrugmetabolism

14. Glucose-6-phosphate dehydrogenasedeficiency.Abnormalresponsestodrugs

15. ADR and genetic differences(rhabdomyolysis with statins) Much more frequent in those with a single nucleotide polymorphism in a region coding for a liver-specific organic anion transporter protein, designated SoLute Carrier Organic anion transporter 1B1 (SLCO1B1). The risk is about 4 times greater in those with a single defective allele, and 16 times greater in those with two defective alleles. It is likely that the failure of hepatic uptake results in a higher serum statin concentration and consequently greater muscle uptake, with resulting muscle damage.

16. ADR and genetic differences(acute intermittent porphyria) An autosomal dominant disorder characterized by recurrent attacks of abdominal pain, neurological disturbance and excessive amounts of d-aminolaevulinic acid and porphobilinogen in the urine. It is often provoked by drug therapy. An extensive list of drugs can precipitate the painful and life-threatening crises .

17. No drug is 100% safe for all people in all circumstances (Organizzazione Mondiale della Sanità)

18. Farmaci ritirati dal commercio per motivi di sicurezza in USA dal 1993 al 2006 N = 20 principi attivi media di ritiri per anno: 1,5 farmaci Current Drug Safety, 2007,2, 177-185

19. Il rapporto beneficio/rischio Reazioniavverse Efficacia clinica

20. Frequenza delle reazioni avverse da farmaci (ADR) • Circa il 10% dei pazienti trattati con farmaci ha una reazione avversaAnn Pharmacother. 2007 41(9):1411-26 • Il 3-6% dei ricoveri in ospedale è dovuto ad una ADRArch Intern Med. 2008 22;168(17):1890-6 • Il 6-10% dei pazienti ricoverati in ospedale ha una ADRPLoS ONE. 2009;4(2):e4439

21. “Pharmaceutical Package” Commissione Europea - 10 dicembre 2008 • Il 5% di tutti i ricoveri ospedalieriin EU sono dovuti ad ADRs • Il 5% di tutti i pazienti già ricoverati va incontro ad ADRs • Le ADRs sono la 5a causa più comune di decessiin ospedale • 197.000 decessi/anno in EU dovuti ad ADRs • I costi calcolati per ADRs sono stati pari a 79 miliardi/anno

22. Ann Intern Med. 2007; 147:755-65

23. Grazie per l’attenzione e buon lavoro