LOGO Drug allergy of Antipsychotic By By Tunggul Adi P. (5137150/M/PYCP) ADR CASE STUDY.

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Drug allergy of Antipsychotic Drug allergy of Antipsychotic

By

By Tunggul Adi P. (5137150/M/PYCP)

ADR CASE STUDY

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Male, 46 years old28/12: He came to ER of

Ramatibodhi hospital no bed available refer to another hospital refer back to Ramatibodhi hospital at 7 Jan 08

Known case schizoprenia since 5 years ago.

No other underlying disease, no other medication

ADR CASE STUDY 16 Jan 09


Physical examination: GA: Thai male, normal consciousness,

appropriate dressing, no dyspneaVital sign: T: 36.2oC; HR: 94/minute; RR:

20/minute; BP: 140/100 mmHg Lung: no wheezingSkin: multiple papule and plaque on redness

skin, both arms Mental status examination:Appropriate affect; no loose of association;

denie paranoid delusion; denie suicidal idea; denie visual and auditory hallusination



Haloperidol 5mg

History of skin rash

Perphenazine 4 mg bid

Change to Trihexylpenidil and Haloperidol

Perphenazine 8 mg od hs and Chlorpromazine

Perphenazine 8 mg bidAnd Chlorpromazine 50 mg/day

Change to Trifluoperazine 5 mg 1x2 andDiazepam 10 mg 1x1 hs

Skin rash

skin rashItching

No skin

disorder

Rash

disappear

May-June 07June 07

-August 08

August -

28 Dec 08 28 Dec-7 Jan 087-10 Jan 09

10 Jan 09-

now



Drug On Hospitalization

7 Jan 8 Jan 9 Jan 10 Jan 11 Jan 12 Jan

Trifluoperazine 3 mg 1x2

v v v v Off

Diazepam 10 mg 1x1 v v v v v vChlorpeniramin 4 mg stat

v

Calamin lotion prn vAtarax 10 mg 1x2 v v Off0.1% TA lotion 1x2 v v v vHaloperidol 5 mg 1x2

v v v

Benadryl 25 mg 1x1 v v



Perphenazine, Trifluoperazine and Chlorpromazine

Phenotiazines group, propylamino derivates (Chlorpromazine) and propylpiperazine derivate (Perphenazine and Trifluoperazine) are conventional (prototypical, first generation) antipsychotic agent


Perphenazine Trifluoperazine Chlorpromazine


Type A:Predictable, dose dependant(ex: toxicity from medication, unavoidable side effects, pharmacologic actions, and drug-drug interactions)

Spectrum of ADR

Type B: Unpredictable, not dose dependant(ex: drug allergy/drug hypersensitivity)



Onset and duration of maculopapulo rash

Usually occurs between 4 to14 days after initiation of new therapy, but may begin later or even few days after the drug has been discontinued. In sensitized individuals who are re-exposed to the causative drug, skin lesions usually develop within 1-3 days. The reaction usually fades with desquamation within 1 or 2 weeks after withdrawal of the causative drug

Pichler WJ (ed): Drug Hypersensitivity, Basel, Karger,

2007, pp 242-250ADR CASE STUDY


Lesion/rash features





2007, pp 168-189


Clinical features of drug-induced exanthems and their relation to the distinct type IV reactions Various immune mechanisms may occur together or sequentially,

leading to different forms of delayed drug hypersensitivity reactions.

(Lerch: Curr Opin Allergy Clin Immunol, Volume 4(5).October 2004.411-419)

ADR CASE STUDY


Common causes of a maculopapular rash

(Taylor, R.B., 2000, The 10-minute diagnosis manual: symptoms and signs in the time-limited encounter, Lippincott Williams & Wilkins) ADR CASE STUDY


Mechanism of ReactionType IV/T-cell-mediated/delayed-type hypersensitivity




T cells recognize the antigen by their antigen receptors, which are heterodimers of 2 chains designated as either αβ T-cell receptors (the majority of T cells) or γδ T-cell receptors (about 5% of circulating T cells). Each T cell displays thousands of identical T-cell receptors, which bind a bimolecular complex displayed at the surface of another cell called an antigen-presenting cell. This complex consists of a fragment of a protein antigen (peptide) bound in the groove of a major MHC molecule. Two classes of MHC molecules present peptides of different origin and stimulate different T cells. Peptides that are derived from proteins synthesized and degraded in the cytosol are presented by MHC class I molecules and activate CD8+ T cells. The reactive CD8+ T cells secrete cytokines and are able to kill cells displaying foreign peptides derived from cytosolic pathogens, such as viruses. In contrast, MHC class II molecules present peptides derived from proteins degraded in endocytic vesicles. These structures interact with CD4+ T cells, which activate other immune effector cells as dictated by their cytokines (for example, macrophages, B cells,). CD4+ T cells can also be cytotoxic

Mechanism of ReactionType IV/T-cell-mediated/delayed-type

hypersensitivity

Pichler,W.J., 2003, Delayed Drug Hypersensitivity Reactions, Annals of Internal Medicine, Vol 139,(8),683-693 ADR CASE STUDY


Cross-Reactivity of Drug-Specific T Cells

There is no data about the phenotiazines cross reactivity. From other, in vitro, data suggest that T cells recognize primarily the core structure and, to a variable degree, the side chain.

# In the sulfamethoxazole model, the complete sulfanilamide core structure is always required to elicit cross-reactivity to other anti-infectious drugs. Thus, the presence of a sulfonamide (SO2–NH2) structure, as found in furosemide or celecoxib, is never sufficient to stimulate T-cell clones originally stimulated by sulfamethoxazole; conversely, celecoxib-stimulated T cells do not recognize sulfamethoxazole. On the other hand, if the sulfanilamide core structure is present, certain T-cell clones tolerate large alterations of the side chain of related antibiotics, while other T cells react exclusively with sulfamethoxazole itself.

# Similar bindings have been observed with lidocaine, which has no cross-reactivity with ester compounds

#Cross-reactivity of amoxicillin-specific or penicillin G–specific T-cell clones with various cephalosporins in vitro has never been observed, even if the same side chain was present

Pichler,W.J., 2003, Delayed Drug Hypersensitivity Reactions, Annals of Internal Medicine, Vol 139,(8),683-693 ADR CASE STUDY


Case Report of ChlorpromazineA 32 year old white man with the Eaton-Lambert syndrome and a

longstanding history of obsessive compulsive disorder with unipolar depression was prescribed chlorpromazine (250 mg daily) for an acute psychotic episode. The dose was increased to 700 mg over the next 10 days. Three weeks later he developed a fever (38,5°C) and a macular eruption on his trunk, which was itchy and erythematous. The rash spread to his limbs and face and developed with widespread follicular and non-follicular pustules. His other drug treatment had not been altered: 3,4-diaminopyridine (60 mg daily), pyridostigmine bromide (180 mg daily), prednisolone (15 mg on alternate days), azathioprine (275 mg daily), and ranitidine (150 mg daily). Urea and electrolyte concentrations and viral titres were normal. The following investigations yielded normal or negative results: liver function tests, blood culture, monospot test, and culture of throat and skin swabs. His haemoglobin concentration was 111 g/l (normal range 130-180), with normal indices, and his eosinophil count was 0.98x 109/L (0.04-4.0). A skin biopsy specimen showed a mixed perivascular infiltrate in the upper dermis, with collections of neutrophils around hair follicles resembling folliculitis. There was no evidence of vasculitis, and direct immunofluorescence gave negative results for IgG, IgM, IgA, and C3. The rash cleared within two weeks after chlorpromazine was withdrawn.

Burrows, N.P., Ratnavel, R.C., Norris, P.G., 1994, Pustular eruptions after chlorpromazine, BMJ, vol 309, p 97ADR CASE STUDY


A 49 year old white woman with schizophrenia started chlorpromazine treatment (100 mg three times a day) to control her psychotic symptoms. two days later she developed a fever (37.5°C) and an erythematous macular rash that was confined to her face and the dorsum of her hands in a photosensitive distribution. Pustules appeared after a further 24 hours, predominantly on the cheeks and forehead. Urea and electrolyte concentrations, erythrocyte sedimentation rate, viral titres, and concentrations of nuclear antibodies, extractable nuclear antibodies, immune complexes, and complement were normal. The results of urine analysis, liver function tests, and culture of skin swabs were normal or negative. The neutrophil and eosinophil counts were raised (8.3x10/L (4-11) and 0.7x109/L respectively). Complete resolution of the rash was seen within 10 days after stopping chlorpromazine.

Case Report of Chlorpromazine

Burrows, N.P., Ratnavel, R.C., Norris, P.G., 1994, Pustular eruptions after chlorpromazine, BMJ, vol 309, p 97ADR CASE STUDY


NARANJO ALGORITHMNO Question Scoring Perphena

zineChlorpro

mazine

1 Are there previous conclusive reports on this reaction?

Yes (+1) No (0) Do not know or not done (0)

0 +1

2 Did the adverse event appear after the suspected drug was given?

Yes (+2) No (-1) Do not know or not done (0)

+2 +2

3 Did the adverse reaction improve when the drug was discontinued or a specific antagonist was given?


+1 +1

4 Did the adverse reaction appear when the drug was readministered?

Yes (+2) No (-2) Do not know or not done (0)

+2 0

5 Are there alternative causes that could have caused the reaction?

Yes (-1) No (+2) Do not know or not done (0)

0 0



NARANJO ALGORITHM

NO Question Scoring Perphenazine

Chlorpromazine

6 Did the reaction reappear when a placebo was given?

Yes (-1) No (+1) Do not know or not done (0)

0 0

7 Was the drug detected in any body fluid in toxic concentrations?


0 0

8 Was the reaction more severe when the dose was increased, or less severe when the dose was decreased?


+1 +1

9 Did the patient have a similar reaction to the same or similar drugs in any previous exposure?


+1 0

10 Was the adverse event confirmed by any objective evidence?


0 0

Total score 7 (probable ADR)

5 (probable ADR)

CONTINUED



Roussel Uclaf Causality Assessment Method (RUCAM)

Criteria Score Perphenazine

Chlorpromazine

1. Time to onset of the reaction

Highly suggestive +3Suggestive +2Compatible +1Inconclusive 0

0 0

2. Course of the reaction

Highly suggestive +3Suggestive +2Compatible +1Against the role of the drug -2Inconclusive or not available 0

0 0

3. Risk factor (s) for drug reaction

Presence +3Absence +2

+2 +2

4. Concomitant drug (s)

Time to onset incompatible 0Time to onset compatible but unknown reaction -1Time to onset compatible and known reaction -2Role proved in this case -3None or information not available 0

0 0



Roussel Uclaf Causality Assessment Method (RUCAM)

Criteria Score Perphenazine

Chlorpromazine

5. Non-drug-related causes

Ruled out +2Possible or not investigated +1 to-2Probable -3

0 0

6. Previous information on the drug

Reaction unknown 0Reaction published but unlabelled +1Reaction labelled in the product characteristics +2

0 +1

7. Response to readministration

or Plasma concentration of the drug known to be toxic or Validated laboratory test with high specifity, sensitivity, and predictive values

Positive +3Compatible +1Negative -2Not available or not interpretable 0

+3

Positive +3Negative -3Not interpretable or not available 0

+3

0

0

0

Total score +5 (possible)

+3(possible)

CONTINUED


Management




Plan

Withdraw the offending drug Improve the skin disorder: Oral antihistaminesTopical corticosteroid Alternative drug:Indication and efficacy: Atypical agents

(clozapine, risperidone, olanzapine) are at least as efficacious as typical agents for positive symptoms and that atypical agents may be more efficacious in regard to negative and cognitive symptoms

Safety: cross reaction may be happen with other phenotiazines. Typical agents has greater side effect related with EPS (extrapyramidal symptoms), and prolactin elevation, than atypical agents



Alternative drug:Adherence: to care patient with

nonadherence, there are available several i.m. long acting depot therapy: fluphenazine decanoat (every 1-2 weeks), haloperidol decanoat (every 4 weeks), long-acting risperidone (every 2 weks)

Cost: drug acquisition cost for atypical antipsychotics can be several 100-fold greater than atypical antipsychotics

Plan



References:

Bircher, A.J., Approach to the patient with a drug hypersensitivity reaction-clinical perspectives, in Drug Hypersensitivity, Pichler WJ (ed), Basel, Karger, 2007, pp 352-365

Lerch, M., Pichler, W.J., 2004, The immunological and clinical spectrum of delayed drug-induced exanthems, Current Opinion in Allergy & Clinical Immunology, 4(5):411-419

Gerber, B.O., Pichler, W.J., The p-i concept: evidence and implications, in Drug Hypersensitivity, Pichler WJ (ed), Basel, Karger, 2007, pp 66-73

Pichler W.J., Drug hypersensitivity reactions: Classification and relationship to T-cell activation, in Drug Hypersensitivity, Pichler WJ (ed), Basel, Karger, 2007, pp 168-189

Pichler,W.J., 2003, Delayed Drug Hypersensitivity Reactions, Annals of Internal Medicine, Vol 139,(8),683-693

Taylor, R.B., 2000, The 10-minute diagnosis manual: symptoms and signs in the time-limited encounter, Lippincott Williams & Wilkins

Yawalkar, N., Maculopapular drug eruptions , in Drug Hypersensitivity, Pichler WJ (ed), Basel, Karger, 2007, pp 242-250


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Sa Wat Di Kab


Neurotransmitter-tract function and effect of typical versus atypical antipsychotics


Relative receptor-binding affinities of typical and atypical antipsychotic agents


Relative incidence of antipsychotic drug adverse effects


Antipsychotic relative potency and adult dosing


Recognizing common skin lessions

Springhouse, 2005, Handbook of Signs and Symptoms, 3rd Edition, Lippincott Williams & Wilkins


Differential Diagnosis

Maculo papularMaculo papularexanthemsexanthems

Viral infection

Drug-induced

Bacterial infection

Collagen vascular disease

Acute graft-versus-host

reaction


Mechanism of action

T cells recognize the antigen by their antigen receptors, which are heterodimers of 2 chains designated as either αβ T-cell receptors (the majority of T cells) or γδ T-cell receptors (about 5% of circulating T cells). Each T cell displays thousands of identical T-cell receptors, which bind a bimolecular complex displayed at the surface of another cell called an antigen-presenting cell. This complex consists of a fragment of a protein antigen (peptide) bound in the groove of a major MHC molecule. Two classes of MHC molecules present peptides of different origin and stimulate different T cells. Peptides that are derived from proteins synthesized and degraded in the cytosol are presented by MHC class I molecules and activate CD8+ T cells. The reactive CD8+ T cells secrete cytokines and are able to kill cells displaying foreign peptides derived from cytosolic pathogens, such as viruses. In contrast, MHC class II molecules present peptides derived from proteins degraded in endocytic vesicles. These structures interact with CD4+ T cells, which activate other immune effector cells as dictated by their cytokines (for example, macrophages, B cells,). CD4+ T cells can also be cytotoxic


Cross reactivity

The great majority of drug-specific T cells express the ß T-cell receptor.

Both CD4+ and CD8+ T cells can be activated with highly heterogeneous functions. In some instances, an oligoclonal T-cell reaction to a drug has been observed in vitro (56). However, most drug-specific T cells have a heterogeneous T-cell receptor repertoire (45, 56). This implies that many different T-cell receptors can interact with the same drug. The ability of these T-cell receptors to recognize structurally related compounds differs substantially (45, 56-59). In the sulfamethoxazole model, the complete sulfanilamide core structure is always required to elicit cross-reactivity to other anti-infectious drugs. Thus, the presence of a sulfonamide (SO 2–NH2) structure, as found in furosemide or celecoxib, is never sufficient to stimulate T-cell clones originally stimulated by sulfamethoxazole; conversely, celecoxib-stimulated T cells do not recognize sulfamethoxazole (45, 54). On the other hand, if the sulfanilamide core structure is present, certain T-cell clones tolerate large alterations of the side chain of related antibiotics, while other T cells react exclusively with sulfamethoxazole itself (45). Similar bindings have been observed with lidocaine, which has no cross-reactivity with ester compounds; however, there is reactivity with bupivacaine and mepivacaine (59). Cross-reactivity of amoxicillin-specific or penicillin G–specific T-cell clones with various cephalosporins in vitro has never been observed, even if the same side chain was present (56). These in vitro data suggest that T cells recognize primarily the core structure and, to a variable degree, the side chain.


Kamus

Figure 1. Revised Gell and Coombs classification of delayed drug hypersensitivity reactions TNF, tumor necrosis factor; Th, T helper; GM-CSF, granulocyte-macrophage colony stimulating factor; PMN, polymorphonucleocyte; AGEP, acute generalized exanthematous pustulosis.

Figure 2. Clinical features of drug-induced exanthems and their relation to the distinct type IV reactions Various immune mechanisms may occur together or sequentially, leading to different forms of delayed drug hypersensitivity reactions.

From: Lerch: Curr Opin Allergy Clin Immunol, Volume 4(5).October 2004.411-419

LOGO Drug allergy of Antipsychotic By By Tunggul Adi P. (5137150/M/PYCP) ADR CASE STUDY.

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