Methotrexate

Question 1

What is methotrexate?

Answer 1

A folic acid analogue

(Immunosupressent)

Question 2

True or False:

Methotrexate irreversibly binds dihyrdofolate reductase to inhibit its action.

Answer 2

TRUE

Question 3

True of False

Methotrexate is excreted by the kidneys

Answer 3

True

By 4 hours after ingestion the kidneys have excreted the plasma portion of the drug (50% is protein bound)

over the next 10 -27 hours the remaining is slowly released

Question 4

What is MTx Mechanism of action?

Answer 4

Irreversibly and competitively binds Dihydrofolate reductase.

Dihydrofolate reductase converts dihydrofolate to tetrahydrofolate

This is a necessary factor in nucleotide syntheses (necessary for DNA synthesis)

THEREFORE
- inhibits DNA synthesis in immunologically active cells

Also increases the concentrations of anti-inflammatory mediators (such as adenosine)

Question 5

True or false

Methotrexate absorption is affected by food intake.

Answer 5

False

Question 6

What is the standard Methotrexate starting dose?

Answer 6

In low risk patients (normal kidney function etc)
- 10 -15 mg a week
- gradual increase by 2.5 - 5mg every 2 -4 weeks

In higher risk patients - may start at 2.5 / 5mg and slowly titrate.

Standard dose in psoriasis is 10 - 15mg a week, up to 25mg weekly

Question 7

What pre-treatment Ix are required for Mtx?

Answer 7

FBC
UEC
LFTs

bHCG

Pre-immunosupression screen

Question 8

What monitoring is required for MTx?

Answer 8

FBC, UEC, LFTs

Every 2 weeks for 4 weeks
Then monthly for 3 months
Then 3 monthly if dose is stable

Fibroscan yearly

If WCC count drops or transaminitis, then reduce or stop.

Question 9

What are the risk factors for hepatic toxicity in patients taking methotrexate?

Answer 9

Persistent abnormal liver function tests

History of liver disease (inc Hep B and C)

Previous or concurrent excessive alcohol intake

FHx of heritable liver disease

Diabetes Mellitus

Obesity

Hyperlipidaemia

History of significant exposure to hepatotoxic drugs

Lack of folate supplementation

Question 10

What are the side effects of Methotrexate?

Answer 10

Myleosupression and pancyotpaenia

Hepatic Fibrosis

Pulmonary toxicity (pneumonitis / fibrosis)
- idiosyncratic

Fatigue
Headache
Dizzyness

GI upset (Nausea, Anorexia, D/ V)
- reduced with concominant folic acid
- or subcut injections

Reproductive:
- teratogen
- reversible oligospermia (in high doses)

Malignancy risk (rare)
- Lymphoma

Cutaneous:
- Photosensitivity
- Alopecia
Accelerated Rheumatoid nodulosis
- Acral erythema
- allergic reactions
- oral ulcers

Question 11

Pregnancy classification of Methotrexate?

Answer 11

Category X

Question 12

Is Methotrexate safe for breastfeeding?

Answer 12

No

Immunosuppression and growth concerns and carcinogenesis

Question 13

How long do you need to be on Methotrexate to see the full dose benefit?

Answer 13

2 -3 months

Question 14

What are the absolute and relative contraindications to MTx?

Answer 14

Absolute - Pregnancy and lactation

Relative
- liver disease
- abnormal LFTs
- significant alcohol intake (or Hx of)
- active serious infection
- desire for imminent pregnancy

Question 15

How long does MTx need to be ceased before you can conceive?

Answer 15

3 months

Question 16

Main drug interactions for MTx?

Answer 16

Elevate MTx levels:
- NSAIDs
- salicylates
- Sulfonamides
- chloramphenicol
- phenothiazines
- phenytoin
- tetracyclines

Increase MTx accumulation in cells
- Dipyridamole
- Probenicid

Inhibits folate metabolic pathway and increase risk for myelosupression
- Dapsone
- Sulfonamides
- Trimethoprim

Question 17

Are there any PBS restrictions on Mtx?

Answer 17

No

Question 18

What conditions is MTx commonly used?

Answer 18

Psoriasis
LYP
PRP (higher doses)
PLEVA (lower doses)
DM
Bullous Pemphigoid