B/29. Immunopharmacology I. (cytotoxic agents, retinoids). Pharmacotherapy of autoimmune diseases.

Question 1

Drugs need to know in this topic

Answer 1

Cyclophosphamide, Methotrexate, Leflunomide, Azathioprine, Mycophenolate-mofetil

Question 2

Cyclophosphamide

Answer 2

Alkylating agent (attacks guanine N7 position, dysfunctional DNA)

Ora, parenteral Requires hepatic P450 activation

1. Hematological malignancies, breast and ovarian cancers
2. Autoimmune diseases (SLE, GN, vasculitis)
3. Myelosuppression 2. GI distress 3. Hemorrhagic cystitis

*Damage to the bladder is mediated by acrolein

Mesna is given as an antidote

Question 3

Methotrexate

Answer 3

Anti-metabolite (inhibitor of dihydrofolate reductase)

Oral, parenteral

Renal elimination

1. Hematological malignancies, CNS and other solid tumors
2. Autoimmune disease
   (RA, psoriasis)

*Toxic effects on normal cells may be reduced by
administration of folinic acid (Leucovorin)

Question 4

Leflunomide

Answer 4

Inhibit de-novo pyrimidine synthesis

Oral

1. Autoimmune diseases (RA, multiple sclerosis)
2. GI irritation
3. Hepatotoxicity
4. Teratogenic

Question 5

Azathioprine

Answer 5

Inhibit de-novo purine synthesis

Azathioprine is rapidly converted to 6-MP

Oral, parenteral

1. Hematological malignancies
2. Autoimmune diseases (RA, SLE)
3. IBD
4. Myelosuppression
5. Hepatotoxicity
   *Allopurinol inhibits 6-MP metabolism
   → elevated levels with increased risk for toxicity

Question 6

Mycophenolate-mofetil

Answer 6

Inhibits de-novo GTP synthesis (inosine monophosphate dehydrogenase enzyme)
B- and T-cells are suppressed

Oral, parenteral

1. Solid-organ transplantation
2. Autoimmune diseases
   (SLE, GN, myasthenia, psoriasis)
3. Myelosuppression
4. GI distress
   *Used in combination with cyclosporine → allows dose
   reductions to limit toxicity

Question 7

Rheumatoid arthritis

Answer 7

• *Management of acute flare-ups**
  1. NSAID’s (no effect on disease progression)
  2. Corticosteroids (short course of oral treatment or intra-articular injection)
• *Disease-modifying anti-rheumatic drugs (DMARD’s)**
  1. Methotrexate (1st-line agent)
  2. Chloroquine, hydroxychloroquine
  3. Leflunomide
  4. Sulfasalazine (5-ASA)
  5. Cyclosporin
  6. Tofacitinib
• *Biological therapy**
  1. Anti-TNF-α (infliximab, adalimumab, etanercept)
  2. CTLA-4 fusion protein (abatacept)
  3. IL-1 receptor antagonist (anakinra)
  4. IL-6 receptor antagonist (tocilizumab)
  5. Anti-CD20 (rituximab)

Question 8

Inflammatory bowel disease (IBD)

Answer 8

• *Mild disease**
  1. 5-ASA
  2. Glucocorticoids – budesonide (topical, oral)
• *Moderate disease**
  1. Glucocorticoids – prednisone (oral, IV)
  2. Azathioprine, 6-mercaptopurine
  3. Methotrexate
• *Severe disease**
  1. Cyclosporin
  2. Anti-TNF-α (infliximab, adalimumab)
  3. Anti-IL-12 and IL-23 (ustekinumab)
  4. Anti-integrin α4β1 (natalizumab), anti-integrin α4β7 (vedolizumab)

Question 9

Psoriasis

Answer 9

• *Topical** agents
  1. PUVA therapy (psoralen and ultraviolet A)
  2. Glucocorticoids (topical)
  3. Vitamin D (topical) – inhibits keratinocyte proliferation
  4. Retinoids – Vitamin A (inhibition of cell proliferation and differentiation via binding to nuclear retinoid receptors)
• *Systemic agents**
  1. Acitretin (inhibits synthesis of keratin precursors) – vitamin A derivative
  2. Dimethyl fumarate
  3. Apremilast (PDE-4 inhibition → decreased expression of TNF-α, IL-23, IL-17, and other inflammatory cytokines)
  4. Immunosuppressive agents – cyclosporin, methotrexate, leflunomide
• *Biological therapy**
  1. Anti-IL-12 and IL-23 (Ustekinumab)
  2. IL-17 antagonists
  3. Anti-TNF-α (infliximab, adalimumab, etanercept)

Question 10

Atopic dermatitis (eczema)

Answer 10

• *Topical agents**
  1. Pimecrolimus (topical calcineurin inhibitor)
  2. Glucocorticoids (topical)
• *Systemic agents**
  1. Glucocorticoids (only in severe, refractory disease)
  2. Cyclosporin
  3. Anti-IL-4 receptor α (dupilumab)

Question 11

Multiple sclerosis

Answer 11

• *Antimetabolites**
  1. Teriflunomide
  2. Cladribine (purine analogue chemotherapeutic agent)
• *Leukocyte suppression:**

1. Anti-CD52 (alemtuzumab)
   * *T-cell suppression**
2. Anti-integrin α4β1 (natalizumab)
3. Sphingosine-1-phosphate receptor modulator (fingolimod)
   * *B-cell suppression:** Anti-CD20 (ocrelizumab)
   * *Others**
4. Interferon-β
5. Glatiramers (mixture of short peptides corresponding to myelin building blocks)
6. Dimethyl-fumarate (anti-oxidant effect)
7. Fampridine (K+ channel inhibition – improves motor function)