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
1

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
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

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

4

transporting through biological membranes

deceleration or acceleration of absorption

distribution
biotransformation

excretion
Interactions during absorption can lead to:

decreasing or increasing the amount of drug

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
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 ADIs occurence:

anaesthetic drugs
drugs have an influence on blood coagulation system
oral antidiabetic drugs

NSAIDs
cardiovascular drugs
hypolipemic drugs
theophilline
psychotropic drugs
antiepileptic drugs
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
Therapeutical range of drug
CARDIAC GLYCOSIDES

digoxin

0,8 2,2 g/l

digitoxin

10 25 g/l

ANTI-ARRHYTMIC DRUGS

amiodaron

chinidine

dizopiramide

lidocaine

procainamid

propranolol
ANTIEPILEPTIC DRUGS

phenytoin

0,5 2,5 mg/l

2 5 mg/l
2 5 mg/l
1,5 5 mg/l
4 10 mg/l
50 100 g/l

10 20 mg/l

phenobarbital

10 40 mg/l

carbamazepine

4 11 mg/l

ethosuximide

40 100 mg/l

valproic acid

50 100 mg/l

ANTIBIOTICS

amikacine

20 30 mg/l

gentamycine

5 12 mg/l

netylmycine

5 12 mg/l

tobramycine

5 12 mg/l

streptomycine

15 40 mg/l

vancomycine

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