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HAEM/IMMUNOLOGY > Pharmacology > Flashcards

Pharmacology Flashcards

1
Q

How is iron absorbed?

A

Absorbed as haem (red meat) and Fe2+ (ferrous) but not as Fe3+ (oxidised). Stomach acid is reductive so maintains Fe2+ in its reduced state

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2
Q

How is iron replacement therapy given?

A

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

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3
Q

What are adverse effects of iron?

A

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

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4
Q

What is the action of folic acid?

A

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.)

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5
Q

How is folic acid replaced?

A

Oral: once a dat, no adverse effects, essential in pregnancy

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6
Q

How can MTX toxicity lead to megaloblastic anaemia?

How is it treated?

A

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

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7
Q

How is Vitamin B12 (cobalamin) involved in folic acid metabolism?

A

Removes methyl group from ‘blocked folic acid molecules, and transfers it to homocysteine to make methionine. This allows FH4 to contribute to DNA synthesis

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8
Q

How is B12 replaced?

A

Hydroxocobalamin via IM injection, weekly for 4 weeks then mostly every 1-3 months for maintenance

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9
Q

How can chronic renal failure affect haematopoeisis? and how is it treated

A

EPO deficiency, replaced by SC injections

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10
Q

What is G-CSF?

A

G-CSF: increases proliferation of granulocyte progenitors, increase maturation rate
- produced in BM stem cells

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11
Q

What is the recombinant form of G-CSF used in therapy and when is it given?

A
  • filgastrin = recombinant form in therapy
  • used to treat inadequate granulocyte production
  • suppressed myeloid growth in chemo
  • bone marrow transplant to rebuild populations
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12
Q

What is the action of thrombopoetin and what is a thrombi-poetin mimetic?

A

Binds to megakaryocytic to increase platelet production
Romiplostim: treats thrombocytopenia
- idiopathic thrombocytopenia purpura
- post BM transplant

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13
Q

What is the process of T cell activation?

A
  1. antigen presentation to APC (macrophage or DC)
  2. Processes antigen and mounts peptide on MHC I/II
  3. CD4+ (helper) activation requires: MHC II and TCR interaction, MHC II and CD4 receptor interaction and costimulatory signal
  4. 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
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14
Q

What is the main target of immunosuppressant drugs?

A

IL-2, because it regulates T cell survival and proliferation

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15
Q

What are the 4 phases in allograft rejection?

A
  1. APC migration/presentation of antigens activated by tissue damage in transplant
  2. Priming and activation of naive T cells
  3. IL-2 driven clonal expansion and differentiation
  4. migration of effector lymphocytes into graft (CD8, CD4, macrophages and B cells)
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16
Q

When are immunosuppressant drugs used?1

A
  1. Prevent/reduce transplant rejection
  2. Treat AI diseases
  3. Treat resistant inflammatory disease
17
Q

What are some calcineurin inhibitors and how do they act?

A

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

18
Q

What are some differences between cyclosporin and tacrolimus?

A

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

19
Q

How do calcineurin inhibitors increase rate of chronic transplant dysfunction?

A 
1- immune suppression 
2- nephrotoxicity
3- HT
4- Hyperglyaemia 
5- dyslipidaemia 
6- neurotoxicity

2-5 lead to CVD and graft failure

20
Q

What are DDI’s for calcneurin inhibitors?

A

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)

21
Q

What are anti-proliferative drugs and what is their action?

A

Prevent mitogenic response to IL-2: Mycophenolate, azathioprine, sirolimus

22
Q

What is the mechanism of action of mycophenolate and side effects of it?

A

M.O.A - inhibits DNA and RNA synthesis and pathways requiring GTP or cGMP (guanine)
Side effects - GI, myelosupression, infections and malignancy

23
Q

How does azathioprine act and what are common side effects?

A

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

24
Q

How do glucocorticoids act as immunosuppressants?

A
  • 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
25
Q

How does sirolimus act? adverse effects?

A

Binds mTOR to inhibit IL2 driven T cell proliferation

Adverse effects - hyperlipidaemia, BM and wound healing

26
Q

What is induction, consolidation, adjuvant and neoadjuvant chemotherapy?

A

Induction - cytoreduction, and complete or partial remission
Consolidation - after induction
Adjuvant - following surgery or radiotherapy
Neoadjuvant - given before to shrink tumour

27
Q

What genetic mutations are associated with malignancy?

A
  1. driver mutations accumulate over time
  2. gain of function (RTK - receptor tyrosine kinase)
  3. loss of function in tumour suppressor (p53, Rb)
  4. RAS/RAF/MAPK and PI3K/Akt pathways affected - signals for growth, survival and maturation
28
Q

What are the ways in which traditional chemotherapies interfere with DNA synthesis/function

A
  1. cross linking - alkylating, platinum
  2. impaired DNA synthesis - 5FU, MTX
  3. Inhibit gene transcription - topoisomerase inhibitors
  4. disrupt mitosis (microtubules) - taxanes, vinca alkaloids
29
Q

Common side effects of traditional chemotherapy drugs?

A
  • hair loss
  • GI
  • myelosuppression
30
Q

How does combination chemotherapy maximise tumour cell killing?

A
  • different modes of action
  • different times of cell cycle
  • dissimilar toxicities = lower doses and reduced side effects
31
Q

What is the traditional therapy for AML?

A

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

32
Q

What is the therapy given for CLL?

A 
- mature B cell clonal malignancy 
Traditional chemo + immunotherapy + targeted therapy 
trad: fludarabine +cyclophosphamide
immuno: rituximab
Targeted: against B cell (ibrutinib)
33
Q

What 2 mechanisms are targeted to switch off proliferation and survival signalling?

A

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

34
Q

Gain of function or increased expression mutations in which pathways can cause increased kinase activity and proliferation, survival, maturation and angiogenesis?

A
  1. RAS/RAF/MAPK
  2. PI3K/Akt
  3. JAK/STAT
35
Q

What is the targeted therapy for CML?

A

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

36
Q

What small molecule inhibitors and antibodies are used in targeted therapy of tumours?

A 
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
37
Q

What are targeted serine/threonine kinase therapies?

A

B-RAF mutation in 50% melanoma

Vemurafenib - targets B-RAF mutant protein, however resistance develops after 6 months

38
Q

What are the limitations of targeted therapies?

A 
Side effects - usually tolerated 
- rash with EGFR/ErbB2 inhibitors 
- GI
- Skin/hair 
- Cardio - HTN, thrombosis
- Liver 
- endocrine 
Drug resistance 
Cost
39
Q

How do immune checkpoint inhibitor drugs work in cancer therapy?

A

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

HAEM/IMMUNOLOGY (5 decks)

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