Pharmacology Flashcards
How is iron absorbed?
Absorbed as haem (red meat) and Fe2+ (ferrous) but not as Fe3+ (oxidised). Stomach acid is reductive so maintains Fe2+ in its reduced state
How is iron replacement therapy given?
Orally: FeSO4 or Fe fumarate
Foods to avoid: antacids (turns Fe2+ into Fe3+), foods that complex with iron and some antibiotics complex with iron
IV: fe-sucrose, Fe-polymaltose, Fe-carboxymaltose
What are adverse effects of iron?
Oral: Gi intolerance, pain, nausea and constipation
OD: Multi system failure and death, GI severe
Parenteral: hypersensitivity reaction
Chronic iron overload: may result in iatrogenic haemochromatosis
What is the action of folic acid?
Allows one carbon additions, but needs 4 protons attached to it in order to do so(gains 2 at each step):
1. folic acid reduced to Dihydrofolic acid by DHFR
2. FH2 reduced to tetrahydrofolic acid by DHFR
Folic acid = integral part of nucleic acid synthesis (purine and thymidine C1 groups are derived from F.A.)
How is folic acid replaced?
Oral: once a dat, no adverse effects, essential in pregnancy
How can MTX toxicity lead to megaloblastic anaemia?
How is it treated?
Inhibits DHFR - prevents nucleic acid synthesis
Often diagnosed early because it also blocks proliferation of short lived cells like leukocytes, enterocytes and platelets
Treatment: C1 substituted folic acid molecules - 5-formyl-FH4 acid, folinic acid, leucovorin
How is Vitamin B12 (cobalamin) involved in folic acid metabolism?
Removes methyl group from ‘blocked folic acid molecules, and transfers it to homocysteine to make methionine. This allows FH4 to contribute to DNA synthesis
How is B12 replaced?
Hydroxocobalamin via IM injection, weekly for 4 weeks then mostly every 1-3 months for maintenance
How can chronic renal failure affect haematopoeisis? and how is it treated
EPO deficiency, replaced by SC injections
What is G-CSF?
G-CSF: increases proliferation of granulocyte progenitors, increase maturation rate
- produced in BM stem cells
What is the recombinant form of G-CSF used in therapy and when is it given?
- filgastrin = recombinant form in therapy
- used to treat inadequate granulocyte production
- suppressed myeloid growth in chemo
- bone marrow transplant to rebuild populations
What is the action of thrombopoetin and what is a thrombi-poetin mimetic?
Binds to megakaryocytic to increase platelet production
Romiplostim: treats thrombocytopenia
- idiopathic thrombocytopenia purpura
- post BM transplant
What is the process of T cell activation?
- antigen presentation to APC (macrophage or DC)
- Processes antigen and mounts peptide on MHC I/II
- CD4+ (helper) activation requires: MHC II and TCR interaction, MHC II and CD4 receptor interaction and costimulatory signal
- IL-2 produced from activated CD4 cells, which acts on naive T cells to
–with IL-4 to produce TH2 cells
– with IL-12 to produce TH1 cells
IL-2 also produced by CD8 cells
What is the main target of immunosuppressant drugs?
IL-2, because it regulates T cell survival and proliferation
What are the 4 phases in allograft rejection?
- APC migration/presentation of antigens activated by tissue damage in transplant
- Priming and activation of naive T cells
- IL-2 driven clonal expansion and differentiation
- migration of effector lymphocytes into graft (CD8, CD4, macrophages and B cells)
When are immunosuppressant drugs used?1
- Prevent/reduce transplant rejection
- Treat AI diseases
- Treat resistant inflammatory disease
What are some calcineurin inhibitors and how do they act?
Cyclosporin and tacrolimus: prevents TCR signalling pathway from TCR to activation of IL-2
- block calcineurin so pNFAT cannot be dephosphorylated to NFAT, and IL-2 cannot be transcribed
What are some differences between cyclosporin and tacrolimus?
Cyclosporin - oral, metabolised in liver by CYP3a, half life 24 hours
Tacrolimus - also anti fungal, 100x more potent, oral/IV/topical, 7 hour half life, metabolised through liver by CsA
How do calcineurin inhibitors increase rate of chronic transplant dysfunction?
1- immune suppression 2- nephrotoxicity 3- HT 4- Hyperglyaemia 5- dyslipidaemia 6- neurotoxicity
2-5 lead to CVD and graft failure
What are DDI’s for calcneurin inhibitors?
Absorption - grapefruit juice and st johns wort
CYP3A4 induction - increase metabolism of immunosuppressant (antibiotics and anticonvulsants)
CYP3A4 inhibition - decrease metab of immunosuppressant = increased levels (grapefruit juice, antibiotics, calcium channel blockers, statins, H2 blockers)
What are anti-proliferative drugs and what is their action?
Prevent mitogenic response to IL-2: Mycophenolate, azathioprine, sirolimus
What is the mechanism of action of mycophenolate and side effects of it?
M.O.A - inhibits DNA and RNA synthesis and pathways requiring GTP or cGMP (guanine)
Side effects - GI, myelosupression, infections and malignancy
How does azathioprine act and what are common side effects?
Action - pro-drug metabolised to mercaptopurine and interferes with DNA synthesis, T+B cell prolif (mainly Th clonal expansion)
Side effects - GIT, BM, hair, infection and malignancies
How do glucocorticoids act as immunosuppressants?
- first line therapy
2 actions
1. directly affect immune system
2. anti-inflammatory - target many cells: T, B, macrophages, eosinophils, endothelial
- in T cells, reduce IL-2 production and clonal expansion of Th cells
How does sirolimus act? adverse effects?
Binds mTOR to inhibit IL2 driven T cell proliferation
Adverse effects - hyperlipidaemia, BM and wound healing
What is induction, consolidation, adjuvant and neoadjuvant chemotherapy?
Induction - cytoreduction, and complete or partial remission
Consolidation - after induction
Adjuvant - following surgery or radiotherapy
Neoadjuvant - given before to shrink tumour
What genetic mutations are associated with malignancy?
- driver mutations accumulate over time
- gain of function (RTK - receptor tyrosine kinase)
- loss of function in tumour suppressor (p53, Rb)
- RAS/RAF/MAPK and PI3K/Akt pathways affected - signals for growth, survival and maturation
What are the ways in which traditional chemotherapies interfere with DNA synthesis/function
- cross linking - alkylating, platinum
- impaired DNA synthesis - 5FU, MTX
- Inhibit gene transcription - topoisomerase inhibitors
- disrupt mitosis (microtubules) - taxanes, vinca alkaloids
Common side effects of traditional chemotherapy drugs?
- hair loss
- GI
- myelosuppression
How does combination chemotherapy maximise tumour cell killing?
- different modes of action
- different times of cell cycle
- dissimilar toxicities = lower doses and reduced side effects
What is the traditional therapy for AML?
Induction: high dose cytarabine (Ara-C, antimetabolite) + anthracycline
– if complete recovery, move onto consolidation, if partial give another dose
Consolidation: 2 cycles cytarabine+idarubicin + etoposide OR 3 cycles high dose cytarabine
Supportive care - transfusions, tumour lysis prophylaxis, G-CSF antibiotics
What is the therapy given for CLL?
- mature B cell clonal malignancy Traditional chemo + immunotherapy + targeted therapy trad: fludarabine +cyclophosphamide immuno: rituximab Targeted: against B cell (ibrutinib)
What 2 mechanisms are targeted to switch off proliferation and survival signalling?
Antibodies: humanised protein that attacks EC portion of receptor molecule, or soluble protein (VEGF) -ab
Small molecule inhibitors: diffuse through plasma membrane and target kinase domains, switching off their function inside the cell -ib
Gain of function or increased expression mutations in which pathways can cause increased kinase activity and proliferation, survival, maturation and angiogenesis?
- RAS/RAF/MAPK
- PI3K/Akt
- JAK/STAT
What is the targeted therapy for CML?
CML is driven by BRC-Abl (dysregulated tyrosine kinase) fusion protein, which is a product of the philadelphia chromosome. This causes uncontrolled myeloid proliferation.
Imatinib - sits in the BCR-Abl kinase domain catalytic cleft, switching off BCR-Abl signalling
What small molecule inhibitors and antibodies are used in targeted therapy of tumours?
EGFR - mutated in many cancers Small molecule inhibitors - gefitinib : EGFR - erlotinib : EGFR - lapatinib : EGFR/ErbB2 Humanised antibodies - trastazumab - ErbB2 (IV for breast cancer that is HER2+) - cetuximab - EGFR - panitummumab - EGFR
What are targeted serine/threonine kinase therapies?
B-RAF mutation in 50% melanoma
Vemurafenib - targets B-RAF mutant protein, however resistance develops after 6 months
What are the limitations of targeted therapies?
Side effects - usually tolerated - rash with EGFR/ErbB2 inhibitors - GI - Skin/hair - Cardio - HTN, thrombosis - Liver - endocrine Drug resistance Cost
How do immune checkpoint inhibitor drugs work in cancer therapy?
Ipilumimab: blocks CTLA-4 which would otherwise prevent DC activation/priming of T cells
Nivolumab: Cancer cells express PD-1L which stops activated T cell cytotoxicity, Nivolumab targets PD-1L
