Download ADVERSE DRUG REACTIONS Natasza Balcer Katarzyna

ADVERSE DRUG REACTIONS
Natasza Balcer
Katarzyna Korzeniowska
Adverse event (AE)
Any unfavorable and unintended reaction (sign, abnormal laboratory finding, symptom or
disease) associated with the use of a medical treatment or procedure, regardless of whether it is
considered related to the medical treatment or procedure.
Adverse drug reaction (ADR)
Any appreciably harmful and unintended reaction, resulting from an intervention related to the
use of a medicinal product, in dosages recommended in people for prophylactic, diagnostic and
therapeutic purposes, as well as for modification of physiological functions
Types of ADR
1. ADR type A – DRUG ACTIONS
2. ADR type B – PATIENT REACTIONS
3. ADR type C – CHRONIC USE
4. ADR type D – RETARDED ACTIONS
5. ADR type E – END OF USE
6. ADR type F – FAILURE OF THERAPY
Divisions of Adverse Drug Reactions
1. ADR type A – associated with DRUG ACTION
•Depend on pharmacological properties of drugs and administered dosage
•Most frequent (70-80% of all reported cases)
2. ADR type B - associated with PATIENT REACTIONS
•Independed on administered dosage
•no relationship between their appearance and action mechanism of a drug
•they constitute approximately 20-25% of adverse drug reaction
Division of ADR type B
Allergic reactions type I:
-anaphylactic shock
-angioedema
-allergic symptoms (urticaria , vomiting, abdominal pain)
allergic reactions type II:
-haemolytic anaemia
-granulocytopenia or agranulocytosisthrombocytopenia
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allergic reactions type III:
-serum sickness
-arthritis, glomerulitis, iritis , vasculitis, utricaria, etc
allergic reactions type IV:
-contact dermatitis
photoallergic reactions
autoimmune diseases (systemic lupus erythematosus)
drug-induced allergic damage of liver
drug-induced allergic nephropathy
drug-induced fever
non- allergic reaction
idiosyncrasy
intolerance reactions
3. ADR type C – associated with CHRONIC USE
• reactions connected with chronic application of a drug
4. ADR type D – associated with RETARDED ACTIONS
• appears after long application of a drugs
5. ADR type E – associated with END OF USE
• induced by coming off a medicine, or end of therapy
6. ADR type F - associated with FAILURE OF THERAPY
• induced by failure of the therapy
Factors determining ADR occurrence:
1.Features of the drug
–properties :
•physico- chemical
•farmacokinetic
•farmacodynamic
–form of a drug
–dosage
–frequency and way of administration
–interactions with other simultaneously used drugs
2. Individual patience`s features
a) age
b) sex
c) weight
d) pregnancy
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e) genetic conditions
3. Egzogenic factors
4. Pathological factors
5. Interactions
Methods of preventing and decreasing the number of ADRs:
1. Individualisation of pharmacotherapy
2. Assessment of drug safety profile
3. Pharmacovigilance
DRUG INTERACTIONS
Drug interaction - is a phenomenon based on interplay of simultaneous application of several
drugs, which results in change of drug action of some of them, what may have profitable or
unprofitable clinical implication. This is an influence of one drug on the final result of an action
of another one, simultaneously applied drug
Risk factors which increase the possibility of appearance of Adverse Drug Interactions
(ADI):
•polypharmacotherapy (polypragmasy) intensified with:
patient`s age and concomitant diseases
drug advertisement in mass media
general availability of drugs, especially from OTC group (over the counter drugs)
popularization of selfmedication of ill people
exertion of patient simultaneously other methods of treatment- e.g.homeopaty, herbal medicine
treatment of one patient by several doctors simultaneously (lack of communication between
doctors)
•taking contraceptives, which may cause interactions with simultaneously applied drugs
•seriousness of the condition, which coexists especially with diseases/insufficiency of organs
metabolizing and eliminating drugs (liver, kidneys)
•connected with age otherness in functioning of circulatory system, central nervous system,
liver and kidneys
•exertion of strong medicines (with narrow therapeutic index) and drugs described as
substances potentially creating the greatest danger of interaction appearance
•inborn or acquired enzymatic defects
•disbacteriosis of alimentary canal
•obesity
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Phases of drug interactions:
1. pharmaceutical
2. pharmacodynamic
3. pharmacokinetic
1) pharmaceutical phase
Pharmaceutical interactions – prescription discrepancies or drugs interactions in vitro
Taking into account drug action mechanism, interactions in this phase can be divided into:
•physical interactions
•chemical interactions
a) Physical interactions:
•exceeding of solubility – prescription does not give enough of solvent or improper solvent
•linkage of immiscible
•reduction or total loss of action force as a result of mixing the drug with absorbing agent
•hygroscopic mixture forming as a result of mixing some
b) Chemical interactions
it is based on chemical reaction between drugs and auxiliary substances, as a result of this
reaction inactivation or precipitation of one of component is achieved
2) pharmacodynamic phase
Interactions are based on change of time, force and action range of one drug under the influence
of pharmacological functioning of the other, simultaneously used drug.
Division of pharmacodynamic interactions:
•receptor interactions
•enzymatic interactions
•physiological/functional interactions
3) pharmacokinetic phase
Interactions based on influence of one drug on functioning of the other drug in the phase of:
•absorption
•binding with proteins in the blood plasma
•transporting through biological membranes
•distribution
•biotransformation
•excretion
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Interactions during absorption can lead to:
•decreasing or increasing the amount of drug
•deceleration or acceleration of absorption
Interactions concerning absorption from gastrointestinal tract
One drug can change the absorption of the other one by various mechanisms:
1. Creating insoluble complexes
2. Adsorption of one drug by other drug of a big surface
3. Changing of pH in intestinal contents
4. Substances changing surface tension
5. Drugs decreasing blood flow through intestines
6. Changing of intestinal motility:
Interactions concerning parenteral drug absorption:
•Drugs absorption from tissue is increased /decreased by vasoactive agents and by agents
influencing blood flow
Interactions concerning distribution
They concerning binding of drugs with plasma proteins or with tissue proteins.
Drugs binding with proteins depending on pH of the environment.
After simultaneous administration of several drugs to the patient these ones which result in a
higher concentration in blood or have higher affinity to proteins, supplant these drugs which have
lower affinity to proteins and drugs present in the blood in lower concentration
Interactions concerning metabolism
- Increasing of metabolism (induction)
- Decreasing of mtabolism (inhibition)
Enzymatic induction
is caused by the drugs which when used for a longer time increase the activity of enzymes
metabolising other drugs taken at the same time
Such drugs called: enzymatic inductors
As a result of enzymatic induction of the drug, its concentration and pharmacological activity is
lowered
Enzymatic inhibition
is caused by the drugs which when used for a longer time decrease the activity of enzyms
metabolising other drugs taken at the same time
Such drugs called enzymatic inhibitors
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As a result of the induction of cytochrome P450 group enzymes (CYP1A1, CYP1A2, CYP2A1,
CYP2A2, CYP2E1) increase concentration and pharmacological activity of drugs
Interactions concerning excretion
Excretion modyfing interactions are mostly related to drugs eliminated with urine also with
faeces and bile
Drugs excretion is increased /decreased by changing pH of urine
Possible consequences of drug interactions
Two of the most common consequences of drug interactions:
a)Inhibiting pharmacological activity and connected with it loss of therapeutic effect
b) Increasing pharmacological activity and/or adverse effects and toxicity of drugs
Decreasing of pharmacological effect of a drug may be caused by:
•pharmacodynamic antagonism
•inhibiting of absorption
•acceleration of biotransformation processes
•increasing of excretion
Increasing of pharmacological effect of a drug may be caused by:
•pharmacodynamic synergism
•drug displacement from its binding with plasma/tissue proteins
•deceleration of biotransformation processes
•decreasing of excretion
Drugs with the greatest danger of ADI’s occurence:
•anaesthetic drugs
•drugs have an influence on blood coagulation system
•oral antidiabetic drugs
•NSAIDs
•cardiovascular drugs
•hypolipemic drugs
•theophilline
•psychotropic drugs
•antiepileptic drugs
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•anticancer drugs
•cyclosporin
•takrolimus
Monitoring therapy
If the pharmacological effect of a drug is difficult to measure during the therapy, and the range
between the therapeutic dosage and toxic dosage is narrow, the safety and effectiveness of the
therapy can be improved through a method called TDM – therapeutic drug monitoring, which
consists in monitoring of medication levels in blood.
TDM uses pharmacokinetic methods for the treatment of individual patients.
TDM is based on an assumption that there is a correlation between a pharmacological effect
and medication level in blood or in another biological material available for analysis.
Criteria of choosing medication for monitoring
•narrow therapeutic index, i.e. a narrow range between therapeutic and toxic doses
•dangerous toxic effects and final clinical effect difficult to detect
•significant correlation between concentration and effect
•application in long-term therapy
•application in life-threatening diseases
•significant individual differences in respect of pharmacokinetics
•non-linear pharmacokinetics (minor changes of the dose may cause disproportionately big
changes of medication level and dangerous toxic effects)
•large distribution volume
Basic recommendations for TDM:
•Lack of expected treatment results or appearance of unexpected toxic effects despite the planned
dosage schedule
•Lack of
possibility for proper clinical or laboratory monitoring of pharmacological
effectiveness and impact, especially when the drug is administered for a long time or
prophylactically
•Morbidity whose symptoms connected with an ineffectively treated disease resemble toxic
effects of the drug
•Individual differences of pharmacokinetics, dependent first of all on age and genotype
Co-existence of organic diseases responsible for LADME in the body
Simultaneous taking other drugs especially when there is a danger of interaction between them
Protection against toxic effects of some substances used purposefully in high doses to receive a
better therapeutic effect
Assesment of therapeutic value of new drugs
Severe general condition of the patient which requires especially precise dosing
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Therapeutical range of drug
CARDIAC GLYCOSIDES
•digoxin
•digitoxin
0,8 – 2,2 μg/l
10 – 25 μg/l
ANTI-ARRHYTMIC DRUGS
•amiodaron
0,5 – 2,5 mg/l
•chinidine
2 – 5 mg/l
•dizopiramide
2 – 5 mg/l
•lidocaine
1,5 – 5 mg/l
•procainamid
4 – 10 mg/l
•propranolol
50 – 100 μg/l
ANTIEPILEPTIC DRUGS
•phenytoin
•phenobarbital
•carbamazepine
•ethosuximide
•valproic acid
10 – 20 mg/l
10 – 40 mg/l
4 – 11 mg/l
40 – 100 mg/l
50 – 100 mg/l
ANTIBIOTICS
•amikacine
•gentamycine
•netylmycine
•tobramycine
•streptomycine
•vancomycine
20 – 30 mg/l
5 – 12 mg/l
5 – 12 mg/l
5 – 12 mg/l
15 – 40 mg/l
2- 40 mg/l
New patterns of dosaging
MODIFICATED previous
=
X
DOSAGE
dosage
recommended drug concentration in blood
-------------------------------------------------------determined drug concentration in blood
MODIFICATED previous
determined drug concentration in blood
DOSAGE =
dosage X ---------------------------------------------------RANGE
range
recommended drug concentration in blood
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