Week 3- Pharmacology of methotrexate, ciclosporine, leflunamide

Question 1

12:48am what are some examples of novel anti-infalmmatory thearies?

Answer 1

• Non-Steroidal Anti-Inflammatory Drugs (NSAIDS)
• Steroids
• Immunosuppressive agents
• More novel therapies
• Anti-cytokine – TNF antibodies
• Anti-adhesion molecules – Abs to Integrins, ICAM-1 etc
• MMP Inhibitors
• Other small molecules

Question 2

what does DMARD stand for?

Answer 2

DISEASE-MODIFYING ANTIRHEUMATIC DRUGS

Question 3

whats the difference between DMARDS and NSAIDS?

Answer 3

-DMARDS aim to halt or reverse the underlying disease itself but NSAID which only reduce the symptoms

Question 4

what type of drug is methotrexate?

Answer 4

• DMARD

- is a folic acid antagonist with cytotoxic and immunosuppressant activity

Question 5

what is the common first line drug for rheumatoid artheritis?

Answer 5

methatrexate

Question 6

why does methatrexate need to be closely monitored?

Answer 6

It has a more rapid onset of action than other DMARDs, but treatment must be closely monitored
because of bone marrow depression, causing a drop in white cell and platelet counts (potentially
fatal) and liver cirrhosis

Question 7

what other class of drug is it often given in conjunction with?

Answer 7

anticytokine drugs

Question 8

what are folates role and importance?

Answer 8

synthesis of purine nucleotides and thymidylate, which in turn are essential for
DNA synthesis and cell division.

Question 9

what is the main role of folate anatgonsits?

Answer 9

interfere with thymidylate synthesis

Question 10

what is methatrexates lipophilicity like?

Answer 10

low lipid solubility and thus does not readily cross the blood– brain barrier

Question 11

how comes ciclosporin doesnt obey lipinskis rule but still be orally avaible?

Answer 11

But orally bioavailable as balance
of hydrophilicity and
hydrophobicity is sufficient to
cross gut membrane
Main metabolism is through P450
leading to drug interactions

Question 12

what are the key infor about ciclosporin?

Answer 12

-its a fungal metabolite
-has potent
immunosuppressive activity but no effect on the acute inflammatory reaction per se.

Question 13

what are some of its numerous actions?

Answer 13

• decreased clonal proliferation of T cells, primarily by inhibiting IL-2 synthesis and possibly also by decreasing
expression of IL-2 receptors
• reduced induction and clonal proliferation of cytotoxic T cells from CD8+ precursor T cells
• reduced function of the effector T cells responsible for cell-mediated responses (e.g. decreased delayed-type
hypersensitivity)
• some reduction of T cell-dependent B-cell responses

Question 14

why may you have drug still in tissues after its eben administered?

Answer 14

Ciclosporin accumulates in most tissues at concentrations three to four times that seen in the plasma.
Some of the drug remains in lymphomyeloid tissue and remains in fat depots for some time after
administration has stopped.

Question 15

what is the unwanted side effect of ciclosporin?

Answer 15

-nephrotoxicity
-Hepatotoxicity and hypertension can also occur
Ciclosporin has no depressant effects on the bone marrow

Question 16

what is leflunomide mainly used to treat?

Answer 16

to treat rheumatoid arthritis and occasionally to

prevent transplant rejection

Question 17

how does leflunomide?

Answer 17

transformed to a metabolite that inhibits de novo synthesis of
pyrimidines by inhibiting dihydro-orotate dehydrogenase

Question 18

what is leflunomides oral avaiblitiy like?

Answer 18

It is orally active and well absorbed from the GI tract.

Question 19

what are some unwanted side effects of leflunomide?

Answer 19

include diarrhoea, alopecia, raised liver enzymes and a risk of
hepatic failure

Question 20

why can there be a risk of cumulative toxicity with leflunomide?

Answer 20

It has a long plasma halflife, and the active metabolite undergoes enterohepatic circulation.The long half-life increases the risk of cumulative toxicity