2 - Azathioprine Flashcards by My Co Tran

Azathioprine was synthesised from its parent drug 6-mercaptopurine

True (AZA is a prodrug which is then rapidly converted into 6-MP in erythrocytes once it is absorbed from the GI tract)

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Azathioprine has immunosuppressant but also anti-inflammatory properties

True (drug of choice for organ transplantation during the 1960s and 1970s)

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Prior to starting Azathioprine, thiopurine methyltransferase (TPMT) testing may help guide proper dosing and prevent catastrophic myelosuppression

True (genetic polymorphisms of TPMT exists)

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Myelosuppression is an adverse effect of AZA

True (FBC is needed to monitor for myelosuppression throughout the course of treatment)

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Hepatotoxicity is an adverse effect of AZA

True (LFTs are needed to monitor for hepatotoxicity throughout the course of treatment)

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GI symptoms is an adverse effect of AZA

True

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Hypersensitivity reaction is an adverse effect of AZA

True

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Infections is an adverse effect of AZA

True

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Pancreatitis is an adverse effect of AZA

True

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Lymphoproliferative malignancy is an adverse effect of AZA

True

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Cutaneous SCC is an adverse effect of AZA

True

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AZA dosing can be based on TPMT level

True (high TPMT = up to 2-2.5mg/kg daily, medium TPMT = up to 1mg/kg daily, low TPMT = do not use AZA)

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88% of orally administered AZA is absorbed through the GI tract

True

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AZA does not cross the blood brain barrier

True (but crosses the placenta)

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AZA crosses the placenta

True

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AZA is rapidly and extensively metabolised

True (reaches peak plasma levels in < 2 hours)

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AZA reaches peak plasma levels in < 2 hours

True

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6-Thioguanine is the active metabolite of AZA which is converted from 6-MP via the hypoxanthine guanine phosphoribosyltransferase (HGPRT) anabolic pathway

True

AZA (prodrug) > 6-MP > 6-TG (active metabolite through HGPRT anabolic pathway)

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6-Thioguanine (active metabolite of AZA) slowly accumulates in tissues and slowly provides maximal clinical immunosuppression at around 8-12 weeks

True

AZA (prodrug) > 6-MP > 6-TG (active metabolite through HGPRT anabolic pathway)

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30% of of AZA is protein bound

True

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Upon absorption, AZA is rapidly converted to 6-mercaptopurine (6-MP) in the erythrocytes

True (AZA is a prodrug)

AZA (prodrug) > 6-MP > 6-TG (active metabolite through HGPRT anabolic pathway)

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AZA is a prodrug which is then converted to 6-MP in erythrocytes

True

AZA (prodrug) > 6-MP > 6-TG (active metabolite through HGPRT anabolic pathway)

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There are 3 metabolic pathways of AZA

True (2 pathways that yield inactive non-toxic metabolites and 1 anabolic pathway that yields active metabolites)

TPMT Inactive pathway = AZA > 6-MP > degraded to inactive non-toxic metabolites
Xanthine oxidase Inactive pathway = AZA > 6-MP > degraded to inactive non-toxic metabolites
Hypoxanthine guanine phosphoribosyltransferase anabolic pathway = AZA > 6-MP > anabolised to active 6-TG

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The 2 metabolic pathways of AZA that yield inactive non-toxic metabolites are the TPMT pathway and the xanthine oxidase pathway

True

TPMT Inactive pathway = AZA > 6-MP > degraded to inactive non-toxic metabolites
Xanthine oxidase Inactive pathway = AZA > 6-MP > degraded to inactive non-toxic metabolites
Hypoxanthine guanine phosphoribosyltransferase anabolic pathway = AZA > 6-MP > anabolised to active 6-TG

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The AZA anabolic pathway leads to active metabolites including 6-TG

True 1. TPMT Inactive pathway = AZA > 6-MP > degraded to inactive non-toxic metabolites 2. Xanthine oxidase Inactive pathway = AZA > 6-MP > degraded to inactive non-toxic metabolites 3. Hypoxanthine guanine phosphoribosyltransferase anabolic pathway = AZA > 6-MP > anabolised to active 6-TG

Both AZA degradation pathways lead to inactive non-toxic metabolites

Reduced activity of 1 of the 2 AZA TPMT or xanthine oxidase degradative pathways will shift more 6-MP into the anabolic HGPRT pathway, leading to excessive clinical immunosuppression with an increased risk of myelosuppression

TPMT enzyme activity is reduced or absent in certain patients with a genetic polymorphism

True

The 3 TPMT (degradative) enzyme activity patient groups are patients with (1) high activity, (2) intermediate activity, and (3) low activity

True (patients with low TPMT enzyme degradative activity have markedly increased accumulation of 6-TG active metabolites as more 6-MP is shifted to the anabolic HGPRT pathway, which increases the risk of myelosuppression and this patient group should not receive AZA)

Patients with low TPMT enzyme degradative activity have markedly increased accumulation of 6-TG active metabolites as more 6-MP is shifted to the anabolic HGPRT pathway, which increases the risk of myelosuppression and this patient group should not receive AZA

Patients with high TPMT enzyme degradative activity may be therapeutically under-dosed as less 6-MP goes into the anabolic HGPRT pathway

The TPMT enzyme function test measures the activity of TPMT in red blood cells and has been shown to correlate well with systemic TPMT activity

True

AZA is virtually completely metabolised

True (therefore negligible unmetabolised AZA is excreted)

Decreased activity of xanthine oxidase occurs as a result of allopurinol as a drug interaction

True (therefore allopurinol inhibits the xanthine oxidase degradative pathway and co-administration of allopurinol with AZA results in increased production of 6-TG active metabolites as more 6-MP is shifted to the anabolic HGPRT pathway, with excessive immunosuppression and increased risk for myelosuppression) 1. TPMT Inactive pathway = AZA > 6-MP > degraded to inactive non-toxic metabolites 2. Xanthine oxidase Inactive pathway = AZA > 6-MP > degraded to inactive non-toxic metabolites 3. Hypoxanthine guanine phosphoribosyltransferase anabolic pathway = AZA > 6-MP > anabolised to active 6-TG

Lesch-Nyhan syndrome affects the anabolic HGPRT pathway and the efficacy of AZA in these individuals

AZA's active metabolite 6-TG's structural similarity to the endogenous purines allows it to be incorporated into DNA and RNA, inhibiting purine metabolism and cell division

True (AZA also affects T cell and B cell function)

AZA affects T cell and B cell function

True (the altered B cell antibody production is of central importance to AZA therapy for immunobullous dermatoses such as Pemphigus vulgaris and bullous pemphigoid)

Pregnancy is an absolute contraindication for AZA

True

Active clinically significant infections is an absolute contraindication for AZA

True (AZA is immunosuppressive)

Prior use of alkylating agents is a relative contraindication for AZA use due to the theoretical increased malignancy risk

True

Allopurinol is a relative contraindication for AZA use as it interacts/inhibits xanthine oxidase which has a role in the xanthine oxidase degradation pathway of 6-MP which shifts more 6-MP towards the anabolic HGPRT pathway causing increased 6-TG active metabolites contributing to the immunosuppressive and myelosuppressive effect of AZA

True

AZA is contraindicated in patients with low TPMT enzyme activity

True (increased risk of AZA toxicity with immunosuppression and myelosuppression)

AZA may cause lymphoproliferative malignancies (especially non-Hodgkins B-cell lymphomas) and SCC of the skin

True (although the increased incidence of these malignancies have not been convincingly demonstrated in dermatology patients, regular physical examination with attention to detection of these malignancies in patients on long term AZA are important)

Severe myelosuppression is a rare adverse event resulting from excessive immunosuppression by AZA, including at relatively low dosages in patients with low or absent TPMT enzyme activity

True (neutropenia, and rarely agranulocytosis and pancytopenia)

Patients on AZA are at a higher risk of infection secondary to their immunosuppressive state

True (increased infection rate typically seen in patients on higher doses of AZA or those who are on multiple immunosuppressive agents such as organ transplant recipients)

The opportunistic infections seen in patients on AZA include HSV infections, HPV infections and scabetic infections

True (although true opportunistic infections are uncommon for dermatologic indications)

AZA is found in breast milk and colostrum and is not recommended in breast feeding women

True

Caution is advised when administering live vaccines to immunosuppressed patients (such as those on AZA), as a potential atypical response may theoretically occur

True

The attenuated/killed virus vaccine of hepatitis B administered to patients on AZA and corticosteroids (and hence immunosuppressed) has shown a decreased response

True

AZA may potentially very rarely cause a drug-induced hypersensitivity syndrome

True (very similar to the anticonvulsant hypersensitivity syndrome, and the cutaneous presentation is diverse)

The rare drug-induced hypersensitivity reaction from AZA typically develop between 1 and 4 weeks after starting therapy

True (and more common in patients who are simultaneously receiving CsA or MTX therapy)

The rare drug-induced hypersensitivity reaction from AZA is more common in patients who are simultaneously receiving CsA or MTX therapy

True

Rechallenge of patients who have had a hypersensitivity reaction to AZA is contraindicated as this may cause a life-threatening reaction

True

The most common adverse effects of AZA are GI including nausea, vomiting and diarrhoea

True (often present between the 1st and 10th days of therapy)

The GI adverse effects of AZA including nausea, vomiting and diarrhoea often present between the 1st and 10th days of therapy

True

Reducing the dose of AZA often alleviates the GI adverse effect symptoms of nausea, vomiting and diarrhoea

True (dividing the dose and taking AZA with food also helps to alleviate these symptoms)

Dividing the dose of AZA often alleviates the GI adverse effect symptoms of nausea, vomiting and diarrhoea

True (reducing the dose and taking AZA with food also helps to alleviate these symptoms)

Taking AZA with food often alleviates the GI adverse effect symptoms of nausea, vomiting and diarrhoea

True (reducing or dividing the dose also helps to alleviate these symptoms)

Pancreatitis has rarely been reported in patients taking AZA

True

Chronic administration of AZA has been associated with uncommon but life-threatening hepatic damage

True (LFT should be monitored throughout the length of treatment regardless of TPMT status) N.B. MTX and systemic retinoids also causes liver toxicity

Routine monitoring of LFT (transaminases) is of significant importance in patients receiving AZA, regardless of TPMT status

True (as chronic administration of AZA has been associated with life-threatening hepatic damage, though this is uncommon)

The dose of AZA should be reduced in renal impairment

True

TPMT assay does not need to be repeated subsequent to baseline determination

True (enzyme function guides dosing strategy as this provides an indication for patient risk of immunosuppression and myelosuppression)

The best studied dermatologic uses of AZA are for the treatment of immunobullous diseases, most notably Pemphigus vulgaris and bullous pemphigoid

True

The most important drug interaction occurs between AZA and allopurinol

True (allopurinol inhibits the xanthine oxidase degradative pathway and co-administration of allopurinol with AZA results in increased production of 6-TG active metabolites as more 6-MP is shifted to the anabolic HGPRT pathway, with excessive immunosuppression and increased risk for myelosuppression)

5 other drug categories can potentially interact with AZA: (1) ACE-inhibitors (2) warfarin (3) sulfasalazine (4) neuromuscular blocker pancuronium (5) other myelosuppressive drugs

True

ACE-inhibitors with AZA may increase the risk of leukopenia due to increased myelosuppression

True

A significant increase in warfarin dose may be required in patients on AZA as AZA may reduce the anticoagulant effect

True

Sulfasalazine inhibits TPMT activity, and thus may potentiate AZA toxicity

True

AZA may reduce the efficacy or reverse the neuromuscular blockade of pancuronium

True (may require an increased dose of this paralytic agent)

Concomitant use of other known myelosuppressive agents I.e. MTX should be avoided with AZA as these potentiate the myelosuppressive effect

True (AZA itself is myelosuppressive)

Concomitant AZA and MTX may cause plasma levels of 6-MP to be increased and potentiate increased myelosuppression

True (more 6-MP for the anabolic HGPRT pathway yielding more 6-TG)

AZA may decrease plasma levels of CsA

True

2 - Azathioprine Flashcards

(73 cards)