Pharma 6 -2😂 Flashcards
Gc mechanism of action
- prevent interleukin (IL)–1 and IL-6 production by macrophages
- inhibit all stages of T-cell activation
Azathioprine mechanism of action
Purine antimetabolite, converted to 6-MP; may inhibit synthesis of DNA, RNA, and proteins; interferes with cellular metabolism; may inhibit mitosis
Azathioprine immunosuppressants side effect
• Bone marrow suppression
– Monitor FBC
• Increased risk of malignancy All immunosuppressants
– Esp transplanted patients -NHL
- Increased risk of infection
- Hepatitis
– Monitor LFT
Ciclosporin & tacrolimus mechanism of action
- active against helper T cells, preventing the production of IL-2 via calcineurin inhibition
- Ciclosporin binds to cyclophilin protein
- Tacrolimus binds to tacrolimus-binding protein
- Drug/protein complexes bind calcineurin
- Calcineurin normally exerts phosphatase activity on the nuclear factor of activated T cells. This factor then migrates to the nucleus to start IL-2 transcription
Calcineurin inhibitors: adverse effects
- Nephrotoxicity
- Hypertension
- Hyperlipidemia
- Nausea, vomiting, diarrhea
- Hypertrichosis, gingival hyperplasia,
- Hyperuricemia.
- Multiple drug interactions are possible, primarily with agents affecting the cytochrome P-450 system
Mycophenolate mofetil mechanism of action
I • Is a prodrug derived from fungus Penicillium stoloniferum
- inhibits the enzyme inosine monophosphate dehydrogenase (required for guanosine synthesis)
- impairs B- and T-cell proliferation
- spares other rapidly dividing cells (because of the presence of guanosine salvage pathways in other cells)
Cyclophosphamide
- Alkylating agent -cross links DNA so that it cannot replicate
- Many immunological effects:
– suppresses T cell activity
– suppresses B cell activity
🔫🔫🔫Indications:
– lymphoma, leukaemia
– lupus nephritis
– Wegener’s granulomatosis
– Polyarteritis nodosum
Methotrexate: mechanism of action in malignant
- Methotrexate competitively and reversibly inhibits dihydrofolate reductase (DHFR)
- The affinity of methotrexate for DHFR is 1000X that of folate for DHFR.
- Dihydrofolate reductase catalyses the conversion of dihydrofolate to the active tetrahydrofolate the key carrier of one-carbon units in purine and thymidine synthesis
- Methotrexate, therefore inhibits the synthesis of DNA, RNA and proteins
- Methotrexate acts specifically during DNA and RNA synthesis, and thus it is cytotoxic during the S-phase of the cell cycle. It therefore has a greater toxic effect on rapidly dividing cells (such as malignant and myeloid cells, and GI & oral mucosa), which replicate their DNA more frequently
Methotrexate: mechanism of action non malignant
- Mechanism of action in non-malignant disease e.g. RA, psoriasis is not clear
- Mechanism is not via anti-folate action
- Possible mechanisms include – inhibition of enzymes involved in purine metabolism, leading to accumulation of adenosine, a purine nucleoside that is elaborated at injured and inflamed sites. Adenosine is a regulatory autocoid that is generated as a result of cellular injury or stress, interacts with specific G protein-coupled receptors on inflammatory and immune cells to regulate their function.
– the inhibition of T cell activation activation
– suppression of intercellular adhesion molecule expression by T cells
Methotrexate: pharmacokinetics
- Mean oral bioavailability is 33% (13-76%)
- Mean intramuscular bioavailability is 76%
- Administered PO, IM or S/C
- In patients taking PO with partial response or with nausea then swap to s/c
- WEEKLY NOT DAILY DOSING, metabolized to polyglutamates with long half lives
- 50% protein bound -NSAIDs displace
- Renal excretion
Sulfasalazine (sulphasalazine)
- A conjugate of a salicylate (5aminosalicylic acid, 5ASA) and a sulfapyridine molecule
- Developed in 1940s
- RA or ‘rheumatic polyarthritis’ believed to be infectious
- Designed to relieve pain & stiffness (5-ASA = anti-inflammatory)
- And to fight infection (sulfapyridine = sulfonamide)
Sulfasalazine: immunological effects
• T cell
– inhibition of proliferation
– possible T cell apoptosis
– inhibition of IL-2 production
• Neutrophil
– reduced chemotaxis
– reduced degranulation
Sulfasalazine: immunological effects
• T cell
– inhibition of proliferation
– possible T cell apoptosis
– inhibition of IL-2 production
• Neutrophil
– reduced chemotaxis
– reduced degranulation
Effects of blocking TNF-α
Etanercept ,infliximab ,
Adalimumab
اتنر اكسبت تو يوز ماب لان يخاف يموت بالصحراء
ETANER acCEPT to use MAB”
👾👾• ↓ Inflammation
Cytokine cascade Recruitment of leukocytes to joint
- elaboration of adhesion molecules
- production of chemokines
- ↓ Angiogenesis
VEGF and IL-8 levels
• ↓ Joint destruction
MMPs and other destructive enzymes Bone resorption and erosion Cartilage breakdown
Etanercept ,infliximab ,
Adalimumab
- anti-TNF therapy does not appear to increase the overall risk of malignancy in RA
- increased risk of new malignancy in those anti-TNF treated patients with prior malignancy
- risk of serious infections
- Anti-TNF increases risk of skin/soft tissue infections
- ✨TB reactivation and other intracellular bacterial infections –post marketing surveillance
