Transcript Adverse Drug Reactions

Somayyeh Nasiripour Pharm.D
assistant professor at IUMS
WHO definition:
Any response to a drug which is
Noxious and Unintended, and
which occurs at doses used in men
of prophylaxis, diagnosis or
treatment.
Adverse Event
Diseases
Genetics
Diet
Adverse Drug Reaction
(event attributed to drug)
Other
factors
All Spontaneous
reports
Other Drugs
Compliance
Events not attributed to drug
Environment
Preventable
Medication Errors
Not
NotPreventable
Preventable
Inherent
Drug
InherentRisk
Risk of Drug
Adverse Drug Reactions
Adverse Drug Events
Potential Adverse
Drug Events
Trivial Medication
Errors
Adapted From: http://www.annals.org/cgi/content/full/142/1/77
4
The science and activities relating
to the detection, assessment,
understanding and prevention of
adverse effects or any other
drug-related problem.
Vigilare = to watch
alert watchfulness
forbearance of sleep; wakefulness
watchfulness in respect of danger; care;
caution; circumspection
the process of paying close and
continuous attention
6
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Adverse Drug Reactions are the 4th to 6th
largest cause of mortality in the USA
(Lazarou J. et al., 1998)
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The percentage of hospital admissions due to
drug related events in some countries is about
or more than 10%.
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UK Study : 10.1 % (Bhalla et al, 2003)
French study : 10.3 % prevalence of ADRs
(Imbs et al, 1999)
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Up to 40% patients in the community experience
ADRs
In the UK Non Steroidal Anti-Inflammatory Drug
(NSAID) use alone accounts for1
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65,000 emergency admissions/year
12,000 ulcer bleeding episodes/year
2,000 deaths/year
1Blower
et al. Emergency admissions for upper gastrointestinal disease and
their relation to NSAID use. Aliment Pharmacol Ther 1997; 11: 283-291
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In 1922, there was an enquiry into the JAUNDICE
associated with the use of SALVARSAN, an organic
arsenical used in the treatment of Syphillis.
In 1961, it was reported in West Germany that there
was an outbreak of PHOCOMELIA (hypoplastic and
aplastic limb deformities) in the new born babies.
It was shown subsequently that thalidomide, a non
barbiturate hypnotic, was to blame.
The crucial period of pregnancy during which
thalidomide is TERATOGENIC is the first three
months.
History of drug safety after
thalidomide disaster
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1961 :
Dr William McBride (Australia)( thalidomide 4000 cases)
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1964 :
UK started “yellow cards” system
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1968 :
start of WHO Programme for International Drug Monitoring
Drug
Year
Adverse Reaction
Sulfanilamide
1937
Liver damage due
Solvent changed;
to diethylene glycol FDA established
Thalidomide
1961
Congenital
Malformations
Withdrawn
Chloramphenicol
1966
Blood Dyscrasias
Uses restricted
Benoxaprofan
1982
Liver damage
Withdrawn
Aspirin
1986
Reye’s syndrome
Uses restricted
Flecainide
1989
Cardiac
Arrhythmias
Uses restricted
Noscapine
1991
Gene toxicity
Withdrawn
Triazolam
1991
Psychiatric
disorders
Withdrawn
Sunday, March 26, 2017
Outcome
12
drug
year
Adverse reaction
Outcome
Temafloxacin
1992
Various serious
adverse effects
Withdrawn
Co-trimoxazole
1995
Serious allergic
reactions
Uses restricted
Terfenadine
1997
Interactions
(e.g. with
grapefruit juice)
Withdrawn from
OTC sale
Sotalol
1997
Cardiac
arrhythmias
Uses restricted
Astemizole
1998
Interactions
Withdrawn
Cisapride
2000
Cardiac
arrhythmias
Withdrawn
Cerivastatin
2001
Rhabdomylosis
Withdrawn
Sunday, March 26, 2017
ASHUTOSH MISHRA
13
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Dose related adverse reactions have led to the
concept of the THERAPEUTIC INDEX, or the
TOXIC:THERAPEUTIC RATIO.
This indicate the margin between the therapeutic
dose and the toxic dose.
The bigger the ratio, the better.
Examples of drugs with a low
TOXIC:THERPEUTIC RATIO:
Anticoagulants (warfarin, heparin)
Hypoglycemic drugs (insulin, sulfonylurea)
Antiarrythmic drugs (lidocaine, amiodarone)
ASHUTOSH
Sunday, March 26, 2017
MISHRA
14
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Most common adverse reactions are detected in
premarketing clinical trials (reported in prescribing
information)
However, most clinical trials are of short duration, and
patient numbers in trials are low compared to population
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Latent ADRs often missed
3000 patients at risk needed to detect with an incidence rate of
1/1000 with 95% certainty
Most trials also exclude the very young and old, pregnant
women, patients with multiple diseases, and any potentially
interacting medications
Additional ADRs are discovered once a drug enters the
marketplace
References: Ahmad S.R., J Gen Intern Med, 2003; 18:57-60
www.cc.nih.gov/researchers/training/ppt/calis_slides_2002-2003.ppt
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Nonimmunologic
Predictable
Pharmacologic side effect
Dry mouth from antihistamines
Secondary pharmacologic side
effect
Drug toxicity
Thrush while taking antibiotics
Hepatotoxicity from methotrexate
Drug-drug interactions
Seizure from theophylline while taking erythromycin
Drug overdose
Seizure from excessive lidocaine (Xylocaine)
Unpredictable
Pseudoallergic
Anaphylactoid reaction after radiocontrast media
Idiosyncratic
Hemolytic anemia in a patient with G6PD deficiency after primaquine
therapy
Tinnitus after a single, small dose of aspirin
Intolerance
G6PD = glucose-6-phosphate dehydrogenase.
Adapted From: http://www.aafp.org/afp/20031101/1781.html
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Type I reaction (IgE-mediated)
Anaphylaxis from b-lactam antibiotic
Type II reaction (cytotoxic)
Hemolytic anemia from penicillin
Type III reaction (immune complex)
Serum sickness from anti-thymocyte globulin
Type IV reaction (delayed, cell-mediated)
Contact dermatitis from topical antihistamine
Specific T-cell activation
Morbilliform rash from sulfonamides
Fas/Fas ligand-induced apoptosis
Stevens-Johnson syndrome
Toxic epidermal necrolysis
Other
Drug-induced, lupus-like syndrome
Anticonvulsant hypersensitivity syndrome
Adapted From: http://www.aafp.org/afp/20031101/1781.html
17
Adapted From: http://www.vh.org/adult/provider/pharmacyservices/PTNews/2003/may.html
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Central Nervous System
Hematologic
Cardiovascular
Renal/Genitourinary
Sensory
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Dermatologic
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Neuropathy
Auditory
especially visible lesions or eruptions
Gastrointestinal
Metabolic
19
Used with permission from Carl Allen, DDS and eMedicine.com, Inc., 2005
20
Used with permission from Michelle Ehrlich, MD and eMedicine.com, Inc., 2005
21
The total cost of drug-related morbidity
and mortality exceeds the cost of the
medications themselves.
Ref: Ernst Frank R, Grizzle Amy J. J Am Pharm Assoc. 2001; 41: 192-9
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‫ثبت عوارض جدید‪:‬‬
‫‪Unepected ADR‬‬
‫تداخالت‬
‫وابستگی‬
‫‪Long term efficacy‬‬
‫‪Risk factor‬‬
‫کیفیت فراورده‬
‫تشخیص سریع تر واکنش های ناخواسته‬
‫‪Increase frequency‬‬
‫رده بارداری و شیردهی‬
“yellow cards”
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‫جمعیت بزرگی را در بر می گیرد‬
‫مشاهده ای و هزینه ای ندارد‬
‫عوارض ناخواسته ثبت میشود‬
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Only 2-4% of all ADRs are reported
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Only 10% of serious ADRs are reported
Never assume that someone else will report!
‫‪ -1‬عدم اطالع از مكانیزم موجود براي ارسال گزارش‬
‫‪ -2‬عدم دسترسي به فرم مربوطه‬
‫‪ -3‬عدم اهميت عارضه از نظر گزارشگر‬
‫‪ -4‬نداشتن وقت در رابطه با فرم مربوطه‬
‫‪ -5‬اجتناب از درگيري در كارهاي اداري‬
‫‪ -6‬ترس از شكايات حقوقي‪ ,‬كيفري توسط دارو‪ADR‬‬
‫‪ -7‬عدم اطمينان از بوجود آمدن‬
NO
The Yellow Card Scheme
collects SUSPICIONS
A reaction that:
 is fatal
 is life threatening
 is disabling
 results in hospitalisation
 prolongs hospitalisation
 Is teratogen
Four critical pieces of information are
needed:
. Patient details
2 . Suspect drug
3 . Suspect reaction
4 . Reporter details
1
“All health-care professionals have a
responsibility to inform colleagues
about clinically important adverse drug
reactions that they detect, even if a wellrecognised or causal link is uncertain.”
Edwards IR and Aronson JK. Adverse drug reactions: definitions, diagnosis, and
management. Lancet 2000; 356: 1255-59
If you suspect an ADR..
Patients who:
 are young, or old or female
 are taking multiple therapies
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50% of patients on 5 drugs or more
have more than one medical problem
have a history of allergy or a previous
reaction to drugs
A symptom that
 appears soon after a new drug is
started
 appears after a dosage increase
 disappears when the drug is stopped
 reappears when a drug is restarted
Listen to the
patient!
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Does the patient have a history of other
drug-induced problems?
 ask the patient
Does the patient take more than one
drug ?
 could an interaction be causing the
ADR?
 long term medication is unlikely to
30-50% are preventable
 Obvious interactions
– many drugs interact with warfarin
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Use of contra-indicated drugs
– use of a non-selective beta-blocker in an asthmatic 
bronchospasm
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Drug use in an inappropriate clinical indication
or medically unnecessary
– antibiotics for a viral infection
antibiotics for viral infections
Iranian ADR Monitoring Center
‫مركز ثبت و بررسي عوارض ناخواسته داروها‬
‫معاونت غذا و دارو‬
‫وزارت بهداشت‪ ،‬درمان و آموزش پزشكي‬
‫تاریخ تدوین‪ :‬فروردین ‪1384‬‬
Diclofenac Na
( VOLTAREN )
176 cases of Foot drop and
walking difficulty (1377-1381)
2 New cases (1385)
4 Cases of Para-plegia following IT injection
2 of them led to Death
1380-‫درود‬
5 cases of death
1382 ‫آبان ماه‬
Stevens Johnson Syndrome
5 years old child
1382 ‫ آذر ماه‬-‫تهران‬
2 cases of Cardiac Arrest
1382 ‫ بهمن ماه‬-‫تهران‬
One case of Cardiac
Arrest
1383 -‫تهران‬
Anaphylactoid reactions
1383 ‫دی ماه‬
‫‪ 250‬مورد پریتونیت شیمیایی‬
‫اردیبهشت ‪1385‬‬
Many cases of Flushing and Red
Neck Syndrome following rapid
infusion of Vancomycin
‫شناسايی و ارسال گزارش موارد افزايش فراوانی در عوارض و‪/‬يا عدم اثربخشی‬
‫جهت بررسی فرآورده در موارد زير‪:‬‬
‫‪ -‬فنوباربيتال‬
‫‪ -‬وانکومايسين‬
‫‪ -‬فنی توئين‬
‫ واکسن ‪MMR‬‬‫‪ -‬هپارين‬
‫ هيدروکورتيزون کاسپين تامين و داروپخش‬‫ اکسی توسين‬‫ سيناوکس‬‫‪ -‬سيکلوسپورين‬
‫ محلول پوويدون آيداين‬‫ شيرخشک يارا نه ای‬‫ کنتراسپتيوهای خوراکی‬‫‪ -‬سفترياکسون‬
‫تهران‬
‫‪1522‬‬
‫زنجان‬
‫‪15‬‬
‫لرستان‬
‫‪10‬‬
.
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Pharmacokinetic
Pharmacodynamic
Both
Chemical
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Absorption(ciprofloxacin/antacids)
Distribution(sulfa drugs/warfarin)
Metabolism(erythromycin/terfenadine)
Excretion(smx-tmp,NSAIDs/MTX)
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Anticholinergic,opioids,food (Cmax/AUC)
Prokinetic agents
C
OCPs
Divalent-trivalent cations
PH
t
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1A2
2C9,2C19
2D6
3A4
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TCA(tert.amines)
Clozapine
Theophylline
Propranolol
Tacrin
Caffeine
Halopridol
Phenothiazines
…
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2C19:
TCA(tert.amines)
Citalopram
Barbiturates
Propranolol
Omeprazol
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2C9:
bupropion
Phenytoin
Tolbutamide
(S)-Warfarin
NSAIDs
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TCA(second. amines)
Fluoxetine
Paroxetine
Venlafaxine
Nefazodone(mcpp
met.)
amphetamines
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Risperidone
Codeine
Hydrocodone
Dextrometorphan
Chlorpheniramine
Propranolol
metoprolol
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TCA(tert.amines)
Fluoxetine
Sertraline
Venlafaxine
Nefazodone
Carbamazepine
Quetiapine,pimozide
Triazolobenzodiazepine
Zolpidem
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Protease inhibitors
Astemizole,Terfenadine
Cisapride
Macrolides
Calcium channel blockers
Sex hormones(estrogen)
Corticosteroids
Lovastatin
Cyclosporine,Tacrolimus
Sildenafil,tadalafil,vardenafil
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MTX/Sulfonamides,Trimethoprim,NSAIDs
Probenecid
Potassium/trimethoprim
Li/Diuretics
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Inhibitor of 3A4
Digoxin ?
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TCA(tert.amines)
Fluoxetine
Sertraline
Venlafaxine
Nefazodone
Carbamazepine
Quetiapine,pimozide
Buspirone
Triazolobenzodiazepine
Zolpidem
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Protease inhibitors
Astemizole,Terfenadine
Cisapride
Macrolides
Calcium channel blockers
Sex hormones(estrogen)
Corticosteroids
Lovastatin
Cyclosporine,Tacrolimus
Sildenafil,tadalafil,vardenafil
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MAOI effect (reversible)
MAO
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Cations(…90%)
NSAIDS(fenbufen,naproxen…)
Azlocillin/cipro
Cyclosporine,cimetidine
Seizure threshold(/foscarnet)
Cipro,enoxacin,norfloxacin…inhibitor of 1A2
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TCA(tert.amines)
Clozapine
Theophylline
Propranolol
Tacrin
Caffeine
Halopridol
Phenothiazines
…
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Warfarin(2C9 inhibition?)
MTX
Cyclosporine
Azathiprione (leukopenia)
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Cimetidine transient reversible deafness.
Ergot
amputation
Inhibition of 1A2, 3A4
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TCA(tert.amines)
Clozapine
Theophylline
Propranolol
Tacrin
Caffeine
Halopridol
Phenothiazines
…
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TCA(tert.amines)
Fluoxetine
Sertraline
Venlafaxine
Nefazodone
Carbamazepine
Quetiapine,pimozide
Buspirone
Triazolobenzodiazepine
Zolpidem
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Protease inhibitors
Astemizole,Terfenadine
Cisapride
Macrolides
Calcium channel
blockers
Sex hormones(estrogen)
Corticosteroids
Lovastatin
Cyclosporine,Tacrolimu
s
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Clarithromycin,fluconazol,itraconazol, protease
inhibitor/rifampin
Inducer of 1A2,2C ,3A4
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Alcohol(disulfiram-like effect)
5FU
warfarin
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Alcohol(disulfiram…)
MAOI(weak)
Amitriptyline(psychosis)
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PH
Ket.,Food / Itra.,Food
Rifampin(ket.,itra.),phenytoin,
Carbamazepine
Fluconazol inhibition of 2C9
Ket.,Itra. Inhibition of 3A4
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Antihypertensives
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Warfarin…. effectiveness
Digoxin …. level up to 75%
Phenelzine,Haloperidol…. side effects
Morphine….block analgesic effects
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Digoxin….Toxicity
Warfarin…..effects
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Digoxin…. level up to 25%
SSRIs…. Side effects
Theophylline…. level up to 50%
Inhibitor of 3A4
Thanks for your
attention
Hand book of Drug Informations
(Apha), 2009