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Year : 2015 | Volume : 3 | Issue : 3 | Page : 196 - 199  


Original Articles
Assessment of the causality of drug induced cutaneous manifestations

Janardan Upadhyay1, Raghvendra Rao B2

1Consultant Dermatologist

2Professor, Department of Dermatology, Venereology, and Leprosy, Malla Reddy Institute of Medical Sciences, Hyderabad

Corresponding Author

Dr. Raghvendra Rao B

Email: ravera1955@gmail.com

Abstract:

Background: A wide spectrum of cutaneous manifestations ranging from Maculopapular rash to severe Toxic Epidermal Necrolysis (TEN) can be produced by different classes of drugs. Some severe ACDRs may result in serious morbidity and even death.

Objective: To assess the causality and identify the offending drug.

Methods: The present hospital based study was carried out for a period of one year at Mahatma Gandhi Memorial Hospital, Warangal. The study subjects were those who had adverse cutaneous drug reactions. Patients willing to participate in the study with ACDR were included. Any cases with doubtful drug reaction were excluded. Complete history was taken and detailed clinical examination was done. Regular follow up of cases was done. Data was entered in the Microsoft Excel Worksheet and analyzed.

Results: Maculopapular rash and FDE were commonly caused by Antibiotics, while urticaria was due to NSAIDs and Acneiform eruptions was caused by Steroids. Severe Cutaneous Adverse Reactions (SCARs) was seen in 7 patients.

Amongst SCARs, SJS followed by TEN and AGEP was seen in 4, 2 and 1 case respectively. Antibiotics were the commonest offending agent for SCARs. Antimicrobials were the commonest offending group of drugs responsible for the adverse cutaneous drug reactions; however when individual drugs were considered, Diclofenac was leading drug followed by Amoxicillin and Phenytoin. Commonest reaction caused by NSAIDs was Urticaria followed by Maculopapular rash. Antiepileptics and Antipsychotics commonly caused Maculopapular rash whereas FDE was commonly seen with Antibiotics. Acneiform eruption was commonly caused by Systemic Steroids followed by SSRIs.

Conclusion: Antimicrobials as a group were the most common offending agents. However, when individual drugs were taken into considerations then Diclofenac (15%) followed by Amoxicillin (9%) and Phenytoin (8%) in the order were the offending drugs.

Key words: Cutaneous manifestations, drugs, morbidity

INTRODUCTION:

A wide spectrum of cutaneous manifestations ranging from Maculopapular rash to severe Toxic Epidermal Necrolysis (TEN) can be produced by different classes of drugs. Some severe ACDRs may result in serious morbidity and even death. 1, 2 Among various types of Adverse Cutaneous Drug Reactions (ACDRs), Maculopapular rash is the commonest (35%) 2, 3 followed by fixed drug eruptions in 30% and Urticaria in 14%. 3

Antimicrobials are implicated in majority of the patients (42.6%) followed by Anticonvulsants (22%) and NSAIDs (18%). Anticonvulsants were responsible for 43.8% of the life

 

 

 

 

 

 

 

 

 

 

 

 

 

 

threatening reactions like TEN and Stevens - Johnson syndrome (SJS). 3

It is most challenging and practically difficult to identify the offending drug when the patient is on multiple drugs because of myriad clinical symptoms, poorly understood mechanisms of drug-host interaction; relative paucity of laboratory testing that is available for any definite and confirmatory drug-specific testing. Therefore in practice, diagnosis of ACDR is purely based on clinical judgment. 4

Although ACDRs are common, comprehensive information regarding their incidence, severity and ultimate health effects are often not available as many cases go unreported. In India, drug reactions are uncommonly reported on a regular basis, except by a few departments of dermatology or pharmacology affiliated to tertiary care centers.

Present study was undertaken to assess the causality and identify the offending drug.

METHODS:

The present hospital based study was carried out for a period of one year at Mahatma Gandhi Memorial Hospital, Warangal. The study subjects were those who had adverse cutaneous drug reactions. Patients willing to participate in the study with ACDR were included. Any cases with doubtful drug reaction were excluded. Complete history was taken and detailed clinical examination was done. Regular follow up of cases was done. Data was entered in the Microsoft Excel Worksheet and analyzed.

RESULTS:

Table 1: Distribution of various SCARs and causative agents

 

Drugs

SJS

TEN

AGEP

DRESS

Co-trimoxazole

2

-

-

-

Ciprofloxacin

1

-

-

-

Nevirapine

1

-

-

-

Nimusulide

-

1

-

-

Mesalamine

-

-

1

-

Phenytoin

-

1

-

-

Total

4

2

1

-

SJS = Stevens - Johnson syndrome, TEN = Toxic Epidermal Necrolysis, AGEP =Acute Generalized Exanthematous Pustulosis, DRESS = Drug Reaction with Eosinophilia and Systemic Symptoms  

 

Table 2: Distribution of the various drugs observed in the study

 

Drug

Number

Percentage

Antibiotics and ATT

35

35

NSAIDs

29

29

Anti epileptics

12

12

Steroids

9

9

Psychiatric drugs

5

5

ART

4

4

Anti malarial

2

2

Miscellaneous

4

4

Total

100

100

ATT = Anti-tuberculosis treatment, ART = Anti-Retroviral treatment

Overall, as a group of drugs, Antibacterials including ATT (35%), were the commonest offending agent, followed by NSAIDs (29%), and AntiEpileptics (12%). However, when individual drugs were considered Diclofenac (15%), followed by Amoxicillin (9%), and Phenytoin (8%), were the commonest offending agent.

 

 

 

 

 

Table 3: Antimicrobials and ACDRs

 

Drug class

Number of ACDRs

Percentage

Penicillins

12

29.26

Fluoroquinolones

10

24.39

Cephalosporins

8

19.51

Sulfonamides

4

9.75

Anti retroviral therapy

4

9.75

Antimalarials

2

4.87

Anti tuberculosis therapy

1

2.43

 

Among the Antimicrobials, the commonest offending /drug group was Penicillins (29.26%) followed by fluoroquinolones(24.91%), Cephalosporins (19.51%), Sulfonamides & ART (9.75% each), Antimalarials(4.87%) and ATT(2.43%).

 

Table 4: NSAIDs and ACDRs

 

Drug

Number of ACDRs

Percentage

Diclofenac

15

51.72

Ibuprofen

5

17.24

Nimesulide

5

17.24

Aceclofenac

3

10.34

Naproxen

1

3.44

Total

29

100

 

Among the NSAIDs the commonest offending agent was Diclofenac (51.72%) followed by Ibuprofen (17.24%) same as Nimesulide (17.24%), Aceclofenac (10.34%) and Naproxen (3.44%).

 

Table 5: Antiepileptics & Psychiatric drugs

 

Drug

Number of ACDRs

Percentage

Phenytoin

8

47.05

Carbamazepine

3

17.64

Chlorpromazine

2

11.76

Escitalopram

2

11.76

Phenobarbitone

1

5.88

Lithium

1

5.88

Total

17

100

 

Among the antiepileptics, antipsychotics and antidepressants; Phenytoin (47.05%) was the most common offending agent followed by carbamazepine (17.64%), Chlorpromazine & Escitalopram (11.76% each) and Phenobarbitone & Lithium (5.88%). The commonest offending agents for Maculopapular rash were Antibacterials including ATT followed by NSAIDs. Urticaria was commonly seen due to NSAIDs, followed by antibacterials. FDE was commonly caused by antibacterials followed by NSAIDs. Common sites involved were oral cavity, face, genitalia and extremities. Four cases of Bullous

form of FDE were seen in our study, were caused by Amoxicillin, Ampicillin,

Aceclofenac and Ibuprofen (one each). Acneiform eruption was commonly caused by Systemic Steroids followed by Escitalopram, Phenobarbitone, Isoniazid and Lithium. The drugs found to cause severe cutaneous adverse reactions were antibiotics followed by Nevirapine, Nimesulide, Phenytoin and Mesalamine.

Other ACDRs seen in our study were Exfoliative dermatitis, Vasculitis, Photosensitivity, AGEP, Hyperpigmentation and striae. Other drugs causing ACDRs included Antiretrovirals, Antimalarials, PPI and Oral hypoglycemic agent.

DISCUSSION:

Amongst the reactions, Maculopapular rash was the commonest (26%) caused by Antibiotics 12 (46.15%) followed by NSAIDs 8 (30.76%) and Antiepileptics and Antipsychotics 5 (23.07%). Urticaria was the second most frequent (20%) reaction caused by NSAIDs followed by Antibiotics.

FDE was the third commonest reaction with 15 cases (15%) which is in contrast to a recent study by M. Patel Raksha et al. 62which showed FDE to be the commonest reaction. In our study, the offending agents for FDE were commonly Antibiotics (8 cases) followed by NSAIDs (6 cases). This was in contrast to earlier studies 2, 4, 62 which showed sulphonamides to be the commonest offending drug for FDE. This may be due to decreased use of Sulfonamides in these days. Four cases of bullous variant of FDE were seen in our study, which were caused by Aceclofenac, Amoxicillin, Ampicillin and Ibuprofen.

Acneiform eruption was seen in 12(12%) cases. A study done by Shinila Sehgal et al 5 showed 6 cases of acneiform eruptions out of 80 ACDRs.63 Common offending agents were prednisolone (5), SSRIs (2), followed by Dexamethasone, Methylprednisolone, Phenobarbitone, ATT like Isoniazid and Lithium accounting for one each.

Severe cutaneous adverse reactions (SCARs) 72, 73 i.e. SJS 4 cases (57.14%),

TEN 2 cases (28.57%) and a case of AGEP (14.28%) comprised 7 (7%) of the total cases. The frequency seen in various studies 1, 2, 6, 7, 8 ranged from 7-25%. The most common offending group of drugs for such severe reactions were Antibiotics (42.85%) followed by NSAIDs and antiepileptics (14.28% each).

In our study 4 cases of SJS were observed 3 were due to Antibiotics (Cotrimoxazole -2 and one to Ciprofloxacin) and one was to Nevirapine, which is in contrast to earlier study of Noel MV et al 2 in which antiepipleptics accounted for majority and in M. Patel Raksha et al 6 it was to NSAIDs mainly. There were 2 cases of TEN to Phenytoin and Nimesulide (one each)

The commonest offending group of drugs as a whole was Antibacterials including ATT (35%) followed by NSAIDs (29%) and Antiepileptics along with Psychiatric drugs (17%). Antibacterials were the leading offending group causing cutaneous ADRs to earlier studies. 1, 3, 7, 9, 8, 10, 11 Antimicrobials comprised of Penicillins (12) followed by fluoroquinolones (10), Cephalosporins (8), Sulfonamides & ART (4 each), Antimalarials (2) and ATT (1). Note: Number in parenthesis denotes no. of ACDRs observed in present study.

However, when individual drugs were considered, then Diclofenac with 15 no. of ACDRs was the commonest offending agent similar to a recent study. 6, 5 This could be attributed to common over the counter (OTC) prescription. This drug commonly resulted in urticaria followed by maculopapular rash, FDE and exfoliative dermatitis.

Antiepileptics and Psychiatric drugs (Antipsychotics, Antidepressants and Mood stabilizing drugs) were responsible for 17% of the reactions, most common agents amongst them being phenytoin followed by carbamazepine and chlorpromazine. These drugs caused maculopapular rash most commonly, similar to other studies. 2, 3, 7 Second common reaction seen was exfoliative dermatitis. Other ACDRs seen with these drugs were urticaria, FDE, TEN, vasculitis and acneiform eruption.

Penicillins caused 12% of cutaneous reactions. This group was commonly found to cause maculopapular rash, urticaria, and FDE.

Fluoroquinolones were responsible for 10% of the cutaneous ADRs. The commonest adverse effects seen were FDE followed by urticaria, maculopapular rash and SJS. The commonest offending agent amongst this group was ciprofloxacin followed by levofloxacin and norfloxacin.

Cephalosporins caused 8% of all the cutaneous reactions, commonly causing

maculopapular rash followed by urticaria. The common individual drugs were

ceftriaxone, cefotaxim, cefixime, cefadroxil and cefoperazone.

Steroids were responsible for 9% of cutaneous ADRs. The commonest ACDR seen was acneiform eruption. The other reactions were purpura (due to topical steroid i.e., Clobetasol propionate in our study) and striae.

Sulfonamides which included co-trimoxazole caused 4% of all the reactions, commonly causing SJS followed by FDE and maculopapular rash.

ATT was responsible for 1% of all the reactions causing acneiform eruption.

One case of Acneiform eruption to Isoniazid similar to a recent study 62 was seen.

In the current era of HAART, ART medications (Nevirapine and Zidovudine) caused 4% of total ACDRs namely SJS, EMF, Exfoliative dermatitis (Nevirapine induced) and Hyperpigmentation of skin and nails (Zidovudine induced)

Other drugs causing ACDRs include Antimalarial drugs (chloroquine and sulfadoxine-pyremethamine) accounted for 2% of total cases, oral hypoglycaemic agents (glipizide), PPI (pantoprazole), topical depigmenting agent (Hydroquinone) and Mesalamine were seen to cause ACDRs in 1% each.

CONCLUSION:

Antimicrobials as a group were the most common offending agents. However, when individual drugs were taken into considerations then Diclofenac (15%) followed by Amoxicillin (9%) and Phenytoin (8%) in the order were the offending drugs.

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