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PA MS > MSPA: Pharmacology disease modifying drugs > Flashcards

MSPA: Pharmacology disease modifying drugs Flashcards

1
Q

What is citrulination in RA ?

A

It is the process in which peptidylarginine deiminase (PAD) released by neutrophils or bacteria convert L-arginine to Citruline

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2
Q

What are the Post-translational modifications seen in Rheumatoid arthritis ?

A

Citrulination, Carbamylation and auto-antibody production.

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3
Q

What is carbamylation in RA ?

A

It is the process in which L-Lysine is converted to homocitrulline with the help of anion cyanate. cyanate level are increased in renal disease, inflammation and smoking.

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4
Q

What are the antibodies in RA and how do they work?

A

The antibodies are RF, ACPA, Anti-carbamylated protein antibody they act by recognising the post translational modifications.

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5
Q

What is the mechanism of inflammation?

A

It is an essential mechanism to protect tissues from irritation and injury. It is mediated by the complex interactions between pro-inflammatory mediators which induce tissue leukocytic infiltration and increase in ROS hydrolytic enzymes causing apoptosis and phagocytosis.

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6
Q

what are the most common pro-inflammatory mediators ?

A

TNF, IL-1, IL-6, CCL2, CXCL8, histamine and prostaglandine.

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7
Q

What is inflammation resolution?

A

It is an important process to limit the tissue damage done by inflammatory process. It involves removal of pro-inflammatory mediators, Neutrophil apoptosis, release of pro-resolving mediators, transformation of proinflammatory M1 macrophages to Anti-inflammatory M2 macrophages. failure of inflammation resolution causes chronic inflammation.

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8
Q

How does COX-2 inhibitors cause cardiovascular disease ?

A

They reduce PGI2 production by vascular endothelium with no inhibitory effect on prothrombotic platelet thromboxane A2 production. Therefore an exaggerated prothrombotic effect will be observed in patients treated with Coxibs.

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9
Q

Which is the only NSAIDs that doesn’t increase CV risk ?

A

Naproxin.

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10
Q

What is the mechanism of action of glucocorticoids ?

A

It increase annexin (lipocortin) production which inhibits phospholipase A2 leading to reduced synthesis of IL-1 and 2, interferon, prostaglandins and leukotrienes. It also reduces the production of basophils, eosinophils, and monocytes. However, it increases neutrophils. The production of T lymphocyte are reduced greater than B lymphocytes with the the CD4+ reduction greater than CD8+. It adversely affects carbohydrate metabolism.

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11
Q

What is the structure of sulfasalazines ?

A

It is an anti-inflammtory drug consists of salicylic acid and sulfapyridine joined by an azo bond.

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12
Q

What is the MOA of sulfasalazine ?

A

It is reduced by the bacterial enzyme azoreductase to sulfapyridine and 5-aminosalicylic acid (5-ASA) in bowel. The Active moiety 5-aminosalicylic acid reduces neutrophil activity, reduces the synthesis of IL-1, reduces releases of TNF from monocytes and macrophages. It also inhibits T cell proliferation.

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13
Q

What are the side effects of sulfasalazines ?

A

The side effects are primarily due to sulfapyridine and these are skin reactions,
hepatitis, pneumonitis,
agranulocytosis, aplastic anemia, in Males - oligospermia and infertility, and gastrointestinal upset.

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14
Q

What are Hydroxychloroquine ?

A

These are anti-malarial medications used in the Tx of inflammatory arthritis. The exact MOA is not known, However, it penetrate cell walls and stabilize lysosomal membranes, Inhibit metabolism of deoxyribonucleotides, and Interferes with cell’s ability to degrade and process proteins.

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15
Q

What are the side effects of hydroxychloroquine ?

A

*Rash, nausea, diarrhea, depigmentation and myopathy.
*Ocular-retinopathy/colour vision - rare but requires monitoring.

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16
Q

What are the indications for Methotrexate ?

A

It is an anti-folate agent used to treat RA, psoriasis, and in combination with cyclosporin to prevent GvHD.

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17
Q

What is the MOA of methotrexate ?

A

MTX is polygultaminated therefore, it has long half life. It acts by inhibiting AICR transformylase and dyhydrofolate reductase enzyme. The inhibition of AICR transformylase causes increase in pro-inflammation resolution molecule adenosine. The inhibition of dyhydrofolate reductase enzyme inhibits purine and pyrimidine synthesis.

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18
Q

What is the dose of MTX in RA ?

A

15 mg once per week.

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19
Q

What is the dose of MTX in cancer remission therapy ?

A

45 mg twice weekly.

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20
Q

How does pro-inflammation resolution molecule adenosine works ?

A

It acts on G-protein coupled adenosine receptors such as the A1, A2A, A2B, and A3 which are found on multiple immune cells and promote pro inflammation resolution processes.

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21
Q

What are the side effects of MTX?

A

*Folate deficiency
*Pulmonary damage – pulmonary fibrosis/pneumonitis
*Myelosuppression/blood dyscrasias
*Gastrointestinal problems such as nausea, stomach upset, and loose stools.
*Stomatitis or soreness of the mouth
*Infection
*Alopecia

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22
Q

What are the indications for leflunomides ?

A

These are DHODH inhbitiors used to treat RA. Its Active metabolite teriflunomide also approved for MS.

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23
Q

What is the action of leflunomides ?

A

It inhibits dihydroorotate dehydrogenase (DHODH) which is an essential enzyme for the de novo synthesis of pyrimidines. It also inhibits B and T cell proliferation.

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24
Q

What are the side effects of leflunomide ?

A

the side effects are increased liver enzymes and mild GI disturbance.

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25
Q

what is the structure and action of TNF superfamily enzymes ?

A

These are pro-inflammatory cytokines released as trimers of 17 kDa monomers. In low concentrations they activate host defence and in high concentration they causes organ damage.

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26
Q

What are the enzymes in TNF superfamily ?

A

TNFa
Lymphotoxin a (formerly TNFb)
Lymphotoxin b

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27
Q

What are the TNF alpha receptors ?

A

There are TNF receptor 01 and 02. The TNF-1 R are constitutively expressed in all cells except RBCs and they are p55 and CD120a. TNF receptor 02 are inducible on endothelial & haematopoietic cells and they are p75 and CD120b.

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28
Q

What are LTb receptors?

A

These are the selective receptors for Lymphotoxin alpha and beta.

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29
Q

What are the key actions of TNF alpha ?

A
  • It increases inflammation by increasing pro-inflammatory cytokines and chemokines on macrophages.
  • It increases cell infiltration by increasing adhesion molecules.
  • It increases angiogenesis by increasing endothelial VEGF.
  • It increases serum CRP by increasing hepatic acute response.
  • It increases articular cartilage degradation by increasing metaloproteanase synthesis in synovocytes.
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30
Q

what are the modes of inhibiting TNF ?

A

Three approaches to blocking TNF:
*Bind to receptor and block TNF binding.
* Bind to TNF and block it form binding to receptor.
* Block TNF synthesis.
* No TNF receptor inhibitors available.

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31
Q

What is the action of Thalidomide ?

A

Inhibition of TNF synthesis.

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32
Q

What is the action of TNF alpha inhibitor Etanercept?

A

Etanercept, a dimeric fusion protein consisting of the extracellular ligand-binding domain of the 75 kDa receptor for TNF-α and the constant portion of human IgG1. It is the first specific anticytokine therapy approved for rheumatoid arthritis. It inhibits binding of TNF to cell surface TNFRs, rendering TNF biologically inactive.

33
Q

What is the MOA of Infliximab?

A

Chimeric whole IgG1k monoclonal antibody that binds to soluble and transmembrane forms of TNF-α with high affinity to disrupt the pro-inflammatory signalling cascades.

34
Q

What is the MOA of Adalimumab & golimumab?

A

They are the fully human recombinant immunoglobulin1 monoclonal antibodies that bind and neutralize soluble and membrane-bound tumor necrosis factor (TNF), so that it cannot interact with p55 and p75 cell-surface TNF receptors. It also induces apoptosis in mononuclear cells with TNF receptors.

35
Q

What is the MOA of Certolizumab?

A

Certolizumab pegol binds and neutralizes both soluble and transmembrane TNFα and inhibits signaling through both the p55 and p75 TNFα receptors. It is used for the Tx of RA.

36
Q

What is the risk of TNF alpha inhibitors ?

A

Higher risk of infection and reactivation of TB. Therefore, Pre-screening of patients is recommended.

37
Q

What causes reduction in the efficacy of Monoclonal antibodies ?

A

These are antibodies against the monoclonal antibodies that reduce their efficacy. Therefore, more dose escalation will be needed. However, it is not a problem with Etanercept.

38
Q

What are theindications for Anti-TNFa Agents?

A

Used for treatment of a number of autoimmune diseases:
Rheumatoid arthritis
Polyarticular juvenile idiopathic arthritis
Psoriatic arthritis
Psoriasis
Ankylosing spondylitis
Crohn’s disease
Ulcerative colitis

39
Q

What is the action of abatacept and belatacept?

A

Abatacept and belatacept block CD86-CD28 interaction, but belatacept blocks them more powerfully. Abatacept has higher affinity for B7-1 (CD80) than B7-2 (CD86).

40
Q

What is the IL-1 receptor antagonist (IL-1Ra) approved for use in RA ?

A

Anakinra

41
Q

What is the action of canakinumab used in RA and many autoimmune diseases ?

A

blocking anti-IL-1β antibodies .

42
Q

What is the action of Rituximab ?

A

It is a monoclonal antibody to CD20 expressed on B cells specifically. It triggers complement formation and cell lysis. Indicated in B-cell lymphoma and RA resistant to anti-TNF therapy. Patients can develop fatal SIRS & PML

43
Q

What is Tofacitinib ?

A

These are small molecule JAK-1 inhibitors indicated in RA and psoriatic arthritis only use under Risk Evaluation and Mitigation Strategy (REMS).
https://youtu.be/ClkQ2FiVT8k?si=3EI-jw0HAVwNARn2

44
Q

What are the small molecule DMARDs in RA ?

A

Hydroxychloroquine
Leflunomide
Methotrexate
Minocycline
Sulfasalazine
Cyclosporine A
Tofacitinib (Janus kinase inhibitor)

45
Q

What are the Non-TNF biologics in RA ?

A

Abatacept
Rituximab
Tocilizumab
Anakinra

46
Q

What are the Anti-TNF
biologics in RA ?

A

Adalimumab
Etanercept
Infliximab
Certolizumab pegol
Golimumab

47
Q

What are the Therapeutic Strategies in RA ?

A

*Symptomatic treatment for immediate pain relief with NSAIDs
* Use Steroids for bridging therapy.
* Start early use of DMARDs. Start with Monotherapy – ideally Methotrexate.
*If Monotherapy doesn’t work Combinations of Conventional DMARDs
Combinations of DMARD plus Biologic agents.

48
Q

What are the Treatment Strategies for Gout?

A

*Prevention of inflammation
with NSAIDs or Colchicine which Inhibits microtubular depolymerisation in neutrophils.
*Decrease synthesis of urate (disease modifying strategy) with Allopurinol which Inhibits xanthine oxidase and Prevents synthesis of uric acid.
Increase excretion of urate using Probenicid
Rasburicase.

49
Q

What are the 5 types of opioid receptors ?

A

*m (MOP)
*k (KOP)
*d (DOP)
*nociceptin/orphan FQ (N/OFQ) (NOP)
*Opioid growth factor receptor

50
Q

How does opioid receptors work ?

A

They Promote opening of K+ channels and thereby
Reduces neuronal excitability.
They inhibit opening of voltage-gated Ca2+ channels thereby Reduces neurotransmitter release.

51
Q

How does Morphine work?

A

It is a m, k and d receptor agonist. Its effects are
Effects
*Marked elevation in pain threshold without loss of consciousness (m and k receptors).
*Euphoria
*dysphoria in some subjects (k receptors)
*Other sensory modalities not affected.

52
Q

What are the type of immune responses ?

A

The immune response can be divided into Th1,Th2 or Th17responses.

53
Q

What is Th1 response ?

A

It is the pro-inflammatory response.

54
Q

What is Th2 response ?

A

It is the anti-inflammatory response.

55
Q

What is Th17 response ?

A

It is thought to be the key player in autoimmune response.

56
Q

What are the four different mechanisms of immune suppression ?

A

1.Inhibition of cell division
2.Inhibition of cytokine actions 3.Inhibition of co-stimulation 4.Immune cell depletion.

57
Q

What is the action of cytotoxic drugs?

A

They inhibit cell division.

58
Q

What is the action of cytotoxic drug cyclophosphamide ?

A

It is metabolised
to phosphoramide mustard and acrolin in the liver which
alkylates DNA.

59
Q

what is the action Mitoxantrone and doxorubicin ?

A

These are drugs that intercalate into the DNA and inhibit topoisomerase II mediated DNA repair. They have significant cardiotoxicity.

60
Q

What is the indication for Mitoxanthorne ?

A

It is a last resort drug in MS.

61
Q

What is the action of Azathioprine ?

A

It is metabolised by the liver to 6-Mercaptopurine and it inhibits purine metabolism which causes inhibition of DNA, RNA, and protein synthesis.

62
Q

What is the action of Mycophenolate mofetil?

A

It is converted to the
active metabolite mycophenolic acid which inhibits inosine monophosphate dehydrogenase. IMPD is essential for DNA synthesis through Guanine nucleotide.

63
Q

What is the action of Caldribine ?

A

It is an analogue of deoxyadenosin which inhibit deamination of adenosine by adenosine deaminase. It mimics severe immunodeficiency disorder by selectively disrupting T-cell and B-cell mediated immune process. cladribine concentrations increase the expression of deoxycytidine kinase (DCK) which induce lymphocyte apoptosis.

64
Q

What is the mechanism of paracetmole induced analgesia ?

A

The metabolite of paracetamole called NAPQI activates TRPA1 or Wasabi receptors in spinal neurones to produce anti-nociceptive effect.

65
Q

What is the action of Zileuton?

A

It is a lipooxygenase inhibitor used to treat Asthma.

66
Q

What is the action of Meclofenamate ?

A

It is an inhibitor of COX and LOX used for the Tx of menstrual pain.

67
Q

What are the LT receptor antagonists approved for Asthma ?

A

Zafirlukast and Montilukast

68
Q

What is Cyclosporine?

A

It is a cytotoxic immuno- suppressant made from the fermentation product of the fungus Tolypocladium inflatum it inhibits the phosphatase enzyme calcinurine thereby inhibit IL-2 synthesis.

69
Q

What is the action of Tacrolimus ?

A

It is a cytotoxic macrolide metabolite from the fungus Streptomyces tsukubaenasis. It is a more potent inhibitor of calcinurine than cyclosporin.

70
Q

What is the action of Rapamycin also known as Sirolimus ?

A

It is isolated from the bacteria streptomyces hygroscopius. It inhibits IL-2 signalling through the PI3K-Akt-mTOR pathway causing cell cycle arrest at G1.

71
Q

What are the indications for Rapamycin family drugs ?

A

Rapamycin, Evrolimus and Temsirolimus are indicated for the tx of melanoma, breast ca, and renal cell carcinoma. It is also being used as a cot on the cardiac stents to prevent smooth muscle cell proliferation in it.

72
Q

What are the three ways to regulate IL-2 activity ?

A

*Inhibit activation of IL-2with Dacilizumab and Basiliximab.
* Inhibit synthesis with cyclosporin and tacrolimus.
* Inhibit IL2-PI3K-Akt-mTOR signeling with Rapamycine, Temsirolimus, and Everolimus.

73
Q

What is the action and indication of Interferon beta ?

A

It is an important cytokine in viral diseases and is a 22.5 kDa protein with 166 amino acids and is the first line Tx in MS.

74
Q

What are the indications for IL-6 inhibitor Tocilizumab ?

A

RA and Systemic Inflammatory Response Syndrome.

75
Q

What is IL-17A ?

A

It is a cytokine secreted by the Th-17 cells in response to IL-23 stimulation and is a key cytokine in Psoriasis.

76
Q

What are the monoclonal antibodies against IL-17A ?

A

Lxekizumab and Secukinumab.

77
Q

what is the monoclonal antibody against IL-17 receptor

A

Brodalumab.

78
Q

What is the mechanism of T-cell activation and proliferation?

A

The activation of CD3 by MHC antigen complex and co-activation of CD28 are necessary for T cell activation and proliferation.

79
Q

What is the action of check point inhibitors Nevolumab and Pembrolizumab ?

A

These are monoclonal antibodies that inhibit the de-activation of Programmed death-Ligand 01 on T cells which will ensure a T cell mediated response against tumor cells.

PA MS (44 decks)

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