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Le reazioni avverse:
presentazione del corso
Achille P. Caputi
Università di Messina
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.
ADR can be classified:
1) according to Dose-relatedness, Timecourse, and
Susceptibility (DoTS).
2) on the basis that some reactions are common, doserelated, and explained by the known pharmacology of the
drug (Type A ‘Augmented pharmacological’), while others
were not (Type B ‘Bizarre’)
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
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
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
ADRs that occur at sub-therapeutic doses in susceptible
patients (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
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
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
Time-dependent ADR
(6 subtypes)
1.
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).
2.
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).
3.
Early reactions :occur early in the course of treatment and then abate (patients
develop tolerance, such as nitrate-induced headache).
4.
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)
5.
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).
5.
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
ADRs associated with long-term corticosteroid use
ADR and time
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.
Abnormal drug metabolism
Glucose-6-phosphate
dehydrogenase
deficiency.
Abnormal responses
to drugs
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.
ADR and genetic differences
(acute intermittent porphyria)
An autosomal dominant disorder characterized by recurrent attacks of
abdominal pain, neurological disturbance and excessive amounts of daminolaevulinic 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 .
No drug is 100% safe for all
people in all circumstances
(Organizzazione Mondiale della Sanità)
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
Il rapporto beneficio/rischio
Efficacia
clinica
Reazioni
avverse
Frequenza delle reazioni avverse
da farmaci (ADR)
 Circa il 10% dei pazienti trattati con farmaci
ha una reazione avversa
Ann Pharmacother. 2007 41(9):1411-26
 Il 3-6% dei ricoveri in ospedale è dovuto ad
una ADR
Arch Intern Med. 2008 22;168(17):1890-6
 Il 6-10% dei pazienti ricoverati in ospedale ha
una ADR
PLoS ONE. 2009;4(2):e4439
“Pharmaceutical Package”
Commissione Europea - 10 dicembre 2008
• Il 5% di tutti i ricoveri ospedalieri in 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 decessi
in ospedale
• 197.000 decessi/anno in EU dovuti ad ADRs
• I costi calcolati per ADRs sono stati pari a 79
miliardi/anno
Ann Intern Med.
2007; 147:755-65
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e
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