B/29. Immunopharmacology I. (cytotoxic agents, retinoids). Pharmacotherapy of autoimmune diseases. Flashcards
Drugs need to know in this topic
Cyclophosphamide, Methotrexate, Leflunomide, Azathioprine, Mycophenolate-mofetil
Cyclophosphamide
Alkylating agent (attacks guanine N7 position, dysfunctional DNA)
Ora, parenteral Requires hepatic P450 activation
- Hematological malignancies, breast and ovarian cancers
- Autoimmune diseases (SLE, GN, vasculitis)
- Myelosuppression 2. GI distress 3. Hemorrhagic cystitis
*Damage to the bladder is mediated by acrolein
Mesna is given as an antidote
Methotrexate
Anti-metabolite (inhibitor of dihydrofolate reductase)
Oral, parenteral
Renal elimination
- Hematological malignancies, CNS and other solid tumors
- Autoimmune disease
(RA, psoriasis)
*Toxic effects on normal cells may be reduced by
administration of folinic acid (Leucovorin)
Leflunomide
Inhibit de-novo pyrimidine synthesis
Oral
- Autoimmune diseases (RA, multiple sclerosis)
- GI irritation
- Hepatotoxicity
- Teratogenic
Azathioprine
Inhibit de-novo purine synthesis
Azathioprine is rapidly converted to 6-MP
Oral, parenteral
- Hematological malignancies
- Autoimmune diseases (RA, SLE)
- IBD
- Myelosuppression
- Hepatotoxicity
*Allopurinol inhibits 6-MP metabolism
→ elevated levels with increased risk for toxicity
Mycophenolate-mofetil
Inhibits de-novo GTP synthesis (inosine monophosphate dehydrogenase enzyme)
B- and T-cells are suppressed
Oral, parenteral
- Solid-organ transplantation
- Autoimmune diseases
(SLE, GN, myasthenia, psoriasis) - Myelosuppression
- GI distress
*Used in combination with cyclosporine → allows dose
reductions to limit toxicity
Rheumatoid arthritis
- *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)
Inflammatory bowel disease (IBD)
- *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)
Psoriasis
- *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)
Atopic dermatitis (eczema)
- *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)
Multiple sclerosis
- *Antimetabolites**
1. Teriflunomide
2. Cladribine (purine analogue chemotherapeutic agent) - *Leukocyte suppression:**
- Anti-CD52 (alemtuzumab)
* *T-cell suppression** - Anti-integrin α4β1 (natalizumab)
- Sphingosine-1-phosphate receptor modulator (fingolimod)
* *B-cell suppression:** Anti-CD20 (ocrelizumab)
* *Others** - Interferon-β
- Glatiramers (mixture of short peptides corresponding to myelin building blocks)
- Dimethyl-fumarate (anti-oxidant effect)
- Fampridine (K+ channel inhibition – improves motor function)