Clinical Pharmacology

"Adverse Drug Event of the month"

A patient of malaria with itching: Chloroquine induced pruritus

Case report:
RSJ a 25 yearr old male, nondiabetic, normotensive, construction worker by occupation was admitted with complaints of high-grade fever with rigor and chills of 4 days duration. General examination showed pallor. Systemic examination was within normal limits. Peripheral blood smear was positive for Plasmodium vivax trophozoites with an asexual count of 2345/ul and sexual count of 43/ul. He was treated with Chloroquine 25mg/kg over 3 days along with symptomatic treatment. On the 2nd day of admission, he developed intense itching of the palms and soles, which later progressed to involve his lower limbs also. Clinical examination showed wheal marks due to scratching. He was treated with T. chlorpheniramine maleate 6 mg/day and local application of calamine lotion for 3 days. A diagnosis of probable Chloroquine induced Pruritis was made. A causality analysis using the Naranjo's algorithm was done and the adverse event was scored at 7 out of a possible total of 13 (score for a probable adverse event being 5-8). The patient was negative for malarial parasites on day 3. His itching was better on the 4th day of admission and he was discharged. Chlorpheniramine maleate was discontinued on day 5. He did not have any itching while on follow up.

Discussion
A high percentage of patients develop itching within 24 hours of ingestion of Chloroquine (1). It is commonly seen in black skinned African patients. The frequency and severity of Chloroquine induced pruritus is low in Asian patients treated with chloroquine for Plasmodium. vivax malaria in comparison with black-skinned Africans (2). This may be related to lower affinity of chloroquine for less pigmented skin. Pharmacogenetic factors, viz poor metabolism of Chloroquine in some patients and thus persistence of Chloroquine in blood may be the reason for the itch (3). Itching is also due to extensive sequestration of Chloroquine in melanin containing tissue (skin) including palms and soles (4). G 6-PD deficiency was also found to be relatively more common among itchers than non-itchers. This indicates that G 6-PD deficiency may perhaps increase susceptibility to Chloroquine induced pruritus (5). Other studies have shown reduced frequency of the sickle cell trait (HbAS) among itchers compared to non-itchers. This suggests that this trait may be protective against Chloroquine induced pruritus (5).

From current data and the records of previously-published reactions to chloroquine, during fever or malarial chemotherapy in man and some mammals, the possible involvement of racial and skin pigment factors, histamine factor, other peripheral mediators of itch, tissue pharmacokinetic factors, central mediators of itch, pyrogenic haemodynamics, and 'gateway' modulation in producing enhanced pruritic reaction during chloroquine antimalarial chemotherapy, showed aggravating role of ischaemia on itch excitability (6).

The pruritus seen usually does not interfere with daily activity and is reduced in intensity by anti-histamine therapy and usually does not affect the patient's willingness to complete the chloroquine regimen, which is important for majority of the endemic countries like India (7). It is also frequently seen in treatment defaulters. The defaulting rate attributable to Chloroquine induced pruritus ranges from 30-60% in several studies. There was no difference in the distribution of itchers among the different ABO blood groups. Other antimalarials like halofantrine also induce itch, but the intensity and duration of halofantrine-induced pruritus is significantly lower than Chloroquine induced pruritus (8). Malaria infection appears to enhance chloroquine-induced pruritus but not halofantrine-induced pruritus and this may be of therapeutic importance (9).

Treatment
Several authors have studied antihistaminics and corticosteroids for the management of pruritus. Concurrent administration of chloroquine (2.1 g base total dose) with prednisolone caused a statistically significant reduction in the pruritus compared with the antihistamine promethazine alone. A single oral dose of prednisolone (10 mg) may be preferable to the antihistamine promethazine (25 mg) as an antipruritic agent for concurrent prescription with chloroquine in individuals predisposed to severe itching (9). Pruritus-prone subjects can be subsequently given antihistamine therapy either 30 min before or along with chloroquine administration (initial dose, 600 mg base oral, or 200 mg base i.m.). Malaria parasite clearance and clinical amelioration has been shown to be unaffected by any of the treatments. The success rates obtained with the following antihistamines as follows 49% (chlorpheniramine maleate, 4-8 mg oral), 46% (mepyramine maleate, 50-100 mg oral), and 60% (Promethazine hydrochloride, 50 mg oral or i.m.) (10). Promethazine appears to be the most effective in the prevention of chloroquine-induced pruritus but the differences were not significant.

Conclusion
If pruritus is observed in dark skinned patients within 24 hours of ingestion of Chloroquine, a probable diagnosis of Chloroquine induced pruritus should be considered using the Naranjo's algorithm. The pruritus is usually generalized and involves the palms and soles. The pruritus usually does not interfere with daily activity. Decreased metabolism of Chloroquine and thus persistence of Chloroquine in blood and deposition of Chloroquine in melanin containing tissues is thought to be responsible for itching. The itching is reduced by administration of antihistamine / corticosteroid therapy.

References
1. Bussaratid V, Walsh DS, Wilairatana P, Krudsood S, Silachamroon U, Looareesuwan S. Frequency of pruritus in Plasmodium vivax malaria patients treated with chloroquine in Thailand. Trop Doct. 2000; 30:211-4

2. O.G. Ademowo, O. Walker & Sodein prevalence of chloroquine-induced pruritus evidence for heredo-familial factors http://www.chez.com/malaria/08ansu02.htm

3. Onyeji CO, Ogunbona FA. Pharmacokinetic aspects of chloroquine-induced pruritus: influence of dose and evidence for varied extent of metabolism of the drug.Eur J Pharm Sci. 2001; 13:195-201

4. Ducharme, J and Farinotti R . Clinical pharmacokinetics and metabolism of Chloroquine. Focus on recent advancement. Clin. Pharmacokinet. 1996; 31:257-274

5. Ademowo OG, Sodeinde O Certain red cell genetic factors and prevalence of chloroquine-induced pruritus. Afr J Med Med Sci. 2002; 31:341-3.

6. Osifo NG. Mechanisms of enhanced pruritogenicity of chloroquine among patients with malaria: a review. Afr J Med Med Sci. 1989; 18:121-9

7. Dua VK, Gupta NC, Kar PK, Nand J, Edwards G, Sharma VP, Subbarao SK. Chloroquine and desethylchloroquine concentrations in blood cells and plasma from Indian patients infected with sensitive or resistant Plasmodium falciparum.Ann Trop Med Parasitol. 2000; 94:565-70

8. Ezeamuzie IC, Igbigbi PS, Ambakederemo AW, Abila B, Nwaejike IN. Halofantrine-induced pruritus amongst subjects who itch to chloroquine. J Trop Med Hyg. 1991; 94:184-8

9. Adebayo RA, Sofowora GG, Onayemi O, Udoh SJ, Ajayi AA. Chloroquine-induced pruritus in malaria fever: contribution of malaria parasitaemia and the effects of prednisolone, niacin, and their combination, compared with antihistamine. Br J Clin Pharmacol. 1997; 44:157-61.

10. Okor RS. Responsiveness of chloroquine-induced pruritus to antihistamine therapy--a clinical survey. J Clin Pharm Ther. 1990;15:147-50.

Department of Clinical Pharmacology
Department of Medicine
Seth G S Medical College and KEM Hospital,
Mumbai.