PREDISPOSING FACTORS OF ADRs

There are many risk factors which predispose a patient to get Adverse Drug Reactions.
Knowing about these factors will eliminate or reduce the risk of developing the ADRs, by
informing the physician while individualizing the dosage regimen. Although many
susceptibilities are not know, a number of factors which affect susceptibility to ADRs , can
be categories into 3 groups:-

I. Predisposing factors associated with Patient,

II. Predisposing factors associated with Drug and
III. Predisposing factors associated with environment.

I. Predisposing Factors Associated With Patient

Patients related predisposing factors which makes patients more susceptible to ADRs are
given below:
1) Age
2) Gender
3) Race
4) Genetics
5) Ethnicity
6) Multiple and co-morbid disease conditions

II. Predisposing Factors Associated With Drug

Drug related predisposing factors which makes patients more susceptible to ADRs are given
below:
1) Polypharmacy
2) Drug characteristics and drug formulations
3) Dose and duration of therapy

III. Predisposing Factors Associated With Environment

Environment related predisposing factors which makes patients more susceptible to ADRs
are given below:
1) Tobacco use
2) Alcohol or other drug

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 3) Diet
4) Medicines of other systems

I. Predisposing Factors Associated With Patient

1) Age
Both paediatrics and geriatrics patients are more vulnerable to get ADRs, because of their age
related conditions. Geriatrics patients (≥60 years) are more prone to get ADRs, because of
physiological changes (pharmacokinetics and pharmacodynamic changes) i,e., decline in
metabolism and elimination rate and on multiple drug therapy for age related conditions. As
the age increase the mitigation to preventable ADRs in elderly will become increasingly
important.

Example:-

a) ACEIs induced postural hypotension in elderly patients (reaction may be exacerbated

by age related impaired baro-receptors response to change in posture).
b) Flucloxacillin induced jaundice and hepatitis is more common ADR in elderly
patients.

Paediatrics may develop serious ADRs to some drug when compare to adult, as their system
handling capacity of a drug differ. The organs which participate in drug metabolism and
elimination were not fully developed, due to which they are more prone to ADRs.
Additionally, children are more prone to ADRs because of dosing errors (as there is a
increased number of fixed dose formulation), lack of safety and efficacy.

Example:-

a) Chloramphenicol induced grey-baby syndrome in children.

b) Aspirin associated with Reye’s syndrome in children.

2) Gender
Women are more likely to suffer with ADRs compare to men, because of number of reasons
like physiological and hormonal changes etc. Pregnant women’s are generally at high risk for
ADRS.

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 Example:-

a) Aplastic anemia associated with usage of Chloramphenicol.

b) Agranulocytosis associated with usage of Chloramphenicol or phenlybutazone are
three time more common in women.
c) Psychiatric adverse events associated with usage of mefloquine (anti-malarial drug)
are more common in women.
d) Phocomelia (sea limbs disorder) associated with usage of thalidomide in pregnant
women’s.

3) Race
Certain population from Africa and South East Asia who are deficient in glucose-6-
phosphate-dehydrogenise are more susceptible to get ADRs for certain drugs. Such people
are at substantial risk of developing haemolytic crisis.

Example:-
a) Primaquine induced rapid haemolysis in patients with G6PD deficiency.

4) Genetics
Genetics factors play a major in drug handling and response to a drug, as well as
susceptibility to ADRs in each individual. Based on which a new era of individualisation of
dosage regimen has evolved. As we already know major genetic variations is found in the
cytochrome CYP450 group of isozymes (CYP2D6, CYP2C9, CYP2C19 and CYP3A5).
CYP2C9 accounts for 20% of total hepatic CYP450 content and which leads to a large effect
on metabolism of drugs.

Example:-

a) Anti epileptic drugs (carbamazepine, oxcarbamazepine and phenytoin) are associated

with Stevens -Johnson syndrome and toxic epidermal necrolysis more common in
South East Asian population , includes china, Thailand, Malaysia and Indonesia
(presence of HLA allele, HLA-B*1502 indicates an increased risk of skin reactions ),
to a lesser extent in India and Japan.
b) The risk of nephrotoxicity from penicillamine is increased in patients with the HLA
types B8 and DR3, whereas patients with HLA-DR7 may be protected.

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 c) The risk of a hypersensitivity reaction to the HIV-1 reverse transcriptase inhibitor
abacavir is associated with HLABs5701, HLA-DR7 and HLA-DQ.

5) Ethnicity
Ethnicity also linked to ADRs, due to inherited traits of metabolism. As we already
cytochrome p450 genotype involved in drug metabolism , has varied distribution in different
ethnic groups. ADR susceptibility based of ethnicity could be associated with genetic , but
ethnicity can be argued to be poor marker for a patients genotype.

Example:-

a) Angioedema associated with use of ACE Inhibitors in black patients.

b) CYP2C9 alleles associated with poor metabolism can leads poor metabolism of
warfarin and causes warfarin toxicity.

6) Multiple and co-morbid disease conditions

Presence of multiple and intercurrent disease’s will increase the patients susceptibility to
ADRs. As their a increase in number of disease condition, patient have to use number of
drugs, which is directly propositional to increase risk of ADRs. A recent study reported that,
the repeated admission of old age patients are linked to presence of co-morbidities like
diabetes, kidney, liver and malignant diseases, than advanced age.

Example:-

a) Nephrotoxicity associated with the use of aminoglycosides in patents whose renal

function (excretory function) is reduced.
b) Ciprofloxacin given in patient with reduced renal clearance leads to nephrotoxicity.

II. Predisposing Factors Associated With Drug

1) Polypharmacy

Patients on multiple drug therapy are more susceptible to ADRs, due to alteration in the drug
effects through an interaction mechanism like, synergism and antagonism. Increase in
number of drugs use directly propositional to increased risk of ADRs.

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 Example:-

a) Aspirin along with warfarin may leads to anemia by excessive bleeding(synergistic

effect).
b) Ciprofloxacin taken (orally) along with iron or calcium or magnesium may interfere
with absorption of ciprofloxacin and leads altered outcomes.

2) Drug characteristics and drug formulations

Some drug are highly toxic in nature and patients who treat with those are at highly
susceptible to Change in drug formulation i.ie., when unsuitable molecules are combined in a
single drug formulation ADRs.

Example:-

a) Nausea and vomiting associated with use of cytotoxic anti-cancer drugs.

b) Dizziness associated with use digoxin and gentamicin (narrow therapeutic index
drugs).
c) Change in Phenytoin formulations from Phenytoin + Calcium sulphate dehydrate to
Phenytoin + Lactose develops Phenytoin toxicity.

3) Dose and duration of therapy

If the dose of any drug given more the max recommended dose per day or per single dose, it
can leads to ADRs. If duration of the therapy increased than the max recommendable
duration it will leads to a patient susceptible to ADRs.

Example:-

a) Liver toxicity if given paracetamol more that 4 gm per day.

b) Benzodiazepine dependence occurs when the treatment last longer and stopped giving
the drug without symptoms appear.
c) Increased number of seizers episodes, when stopped giving anti-epileptic (Phenytoin
and carbamazepine drug suddenly without dose tapering.

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 III. Predisposing Factors Associated With Environment

1) Tobacco use
Smoking increase the enzyme activity in liver and leads to alter in drug metabolisms and
which predispose a patient to ADRs.

Example:-

a) Smoking increase the removal of theophyline required dose adjustment and

absorption of insulin leading to delayed effects.

2) Alcohol or other drug

As we already known alcohol with medicine will leads to unwanted effects.

Example:-

a) Alcohol with aspirin increase risk of gastric irritation and bleeding.

3) Diet
ADRs will also happen when the certain food items along with medicine.

Example:-

a) Grape fruit juice increase the plasma concentration of calcium channel blockers,
when taken together and leads to ADRs.
b) Paracetamol taken with Alcohol causes liver damage.

4) Medicines of other systems

When a patient uses two systems of medicine together, it predispose a patient ADRs.

Example:-

a) Herbal medicine, st. John’s wort is a enzyme inducer, when taken with cyclosporine,
reduce the effectiveness of cyclosporine.

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Bibliography:-

1. Clinical pharmacy and therapeutics by Roger Walker and Cate Whittlesea: 5th edition;
chapter 5;Churchill livingstone Elsevier; 2012; pg.no 64-67

2. Stephens’ Detection of New Adverse Drug Reactions; john Talbot and Patric Waller;
chapter 2;john wiley & sons,ltd;2004; pn.no 93-107

3. A text book of clinical pharmacology and therapeutics by James M Ritter , Lionel D

Lewis, Timothy GK Mant and Albert Ferro; 5th edition; chapter 12: hodder Arnold –a part of
Hachette liver UK;2008; pg.no 62-68

4. A text book of clinical pharmacy practice: G. Parthasarathi, K.N. Hansen, M.C. Nahata-
Ed-2nd ; chapter 9: universities press; 2012;pg.no 106-107

5. Clinical Pharmacy by HP Tippins and Amrita Bajaj; 2nd edition; chapter 9;career
publications;2011; pg.no 271-272

6. Textbook of Pharmacovigilance : concept and practice by GP Mohanta and PK Manna;

chapter 4;pharmamed press;216; pg.no 43-45

7. Adverse Drug Reaction by By Stephanie N. Schatz and Robert J. Weber in PSAP 2015 •
CNS/Pharmacy Practice;2015; Pg.no 11-15

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