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Clinical pharmacology and therapeutics > S8: immunosuppressants & NSAIDs > Flashcards

S8: immunosuppressants & NSAIDs Flashcards

1
Q

Describe rheumatoid arthritis

A

Inflammatory change and proliferation of synovium leading to dissolution of cartilage and bone
Increase of pro-inflammatory substances compared to anti-inflammatory substances

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2
Q

Describe the treatment strategy of rheumatoid arthritis

A 
Early use of disease-modifying drugs 
Aim to achieve good disease control 
Use of adequate dosages 
Use of combinations of drugs
Avoidance of long-term corticosteroids
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3
Q

Describe the treatment strategy of SLE and vasculitis

A

Symptomatic relief
Reduction in mortality
Prevention of organ damage
Reduction in long term morbidity caused by disease & by drugs

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4
Q

Describe the mechanism of action of corticosteroids

A

Prevent interleukin IL-1 and IL-6 production by macrophages

Inhibit all stages of T-cell activation

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5
Q

List indications for azathioprine

A

SLE & vasculitis – maintenance therapy
Inflammatory bowel disease
Other uses include use as ‘steroid sparing’ drug

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6
Q

Describe the mechanism of action of azathioprine

A

Cleaved to 6-MP, which is converted to TIMP

-decreases DNA and RNA synthesis

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7
Q

Outline the adverse effects of azathioprine

A

Bone marrow suppression
Increased risk of malignancy
Increased risk of infection
Hepatitis

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8
Q

List examples of calcineurin inhibitors

A

Ciclosporin

Tacrolimus

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9
Q

List indications and contraindications for calcineurin inhibitors

A

Widely used in transplantation
Also atopic dermatitis & psoriasis
Not often used in rheumatology – renal toxicity (check BP & eGFR regularly)
Drug interactions with CYP450 drugs

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10
Q

Describe the mechanism of action of calcineurin inhibitors

A

Active against helper T cells

Prevent production of IL-2 via calcineurin inhibition

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11
Q

List indications for mycophenolate mofetil

A

Used primarily in transplantation
Good efficacy as induction and maintenance therapy for lupus nephritis
Maintenance therapy for vasculitis

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12
Q

Describe the mechanism of action and adverse effects of mycophenolate mofetil

A

Prodrug
Inhibits inosine monophosphate dehydrogenase, which impairs B and T cell proliferation
Adverse effects: nausea, vomiting, diarrhoea & myelosuppression

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13
Q

Describe cyclophosphamide

A

Alkylating agent – cross links DNA so that it cannot replicate
Suppresses T and B cell activity
Indications: lymphoma, leukaemia, solid cancers, lupus nephritis

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14
Q

Describe adverse effects of cyclophosphamide

A

Increased risk of bladder cancer, lymphoma & leukaemia
Infertility
Adjust dose in renal impairment
(mycophenolate mofetil safer & as effective in lupus nephritis)

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15
Q

List indications for methotrexate

A

Gold standard treatment for RA

Other indications: malignancy, psoriasis & Crohn’s disease

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16
Q

Describe the mechanism of action of methotrexate in malignancy & as a DMARD

A

In malignancy – inhibit dihydrofolate reductase -> reducing FH4 needed for DNA and protein synthesis
DMARD – inhibition of inflammatory mediators, T cells and adenosine

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17
Q

List adverse effects of methotrexate

A

Mucositis, marrow suppression (both respond to folic acid supplementation)
Hepatitis, cirrhosis, pneumonitis, infection risk
Highly teratogenic, abortifacient

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18
Q

Describe sulfasalazine

A

Relieve pain, stiffness & fights infection
Inhibition of T cell and neutrophil activity
Release 5-aminosalicylic acid (5-ASA) – immunosuppressive

19
Q

Outline adverse effects of sulfasalazine

A

Myelosuppression, hepatitis, rash
Milder side effects: nausea, abdo pain/vomiting
Very few drug interactions & safe in pregnancy

20
Q

Describe biologicals

A

Monoclonal antibodies made specifically to block any given substance in the body or to target any specific cell type
Act by TNF-alpha inhibition
ADR: test for latent TB as inhibition of TNF-alpha may reactivate latent disease (TNF is essential in granuloma formation so that TB bacilli are walled off)
Caution with other immunosupressants
Eg. infliximab, golimumab & adalimumab

21
Q

Describe rituximab

A

Causes B cell apoptosis – binds specifically to a unique cell-surface marker CD20
Very effective in RA

22
Q

Describe prostanoids

A

Prostanoids = prostaglandins, prostacyclin & thromboxanes (PGE2, PGF2a, PGD2, PGI2 & TXA)
Produced locally on demand – different enzymes, different prostanoids, short half lives so fine local control
Act locally at GPCRs & action is often enhanced by local autacoids including bradykinin and histamine
TXA2 and PGI2 have apposing vascular effects; imbalance to prostanoids plays significant role in hypertension, MI and stroke risk

23
Q

Describe arachidonic acid and prostanoid synthesis

A

Arachidonic acid derived primarily from dietary linoleic acid – incorporated into phospholipids
Found throughout the body – particularly in muscle, brain, liver & kidney

24
Q

Describe PGE2 and gastric acid secretion

A

PGE2 contributes to regulation of acid secretion in parietal cells
Prostacyclin contributes to maintenance of blood flow and mucosal repair

25
Q

Describe cyclooxygenase enzymes

A

COX-1: constitutively active across most tissues

COX-2: inducible in chronic inflammation, constitutively in brain, kidney and bone

26
Q

List homeostatic functions of COX-1 and COX-2

A

COX-1: GI protection, platelet aggregation & vascular resistance
COX-2: renal homeostasis, tissue repair and healing, reproduction & inhibition of platelet aggregation

27
Q

List pathological functions of COX-1 and COX-2

A

COX-1: chronic inflammation, chronic pain & raised BP

COX-2: chronic inflammation, chronic pain, fever, blood vessel permeability

28
Q

Describe NSAIDs

A

Have antipyretic, analgesic and anti-inflammatory properties
Mode of action: inhibition of COX -> decreased prostaglandin, prostacyclin & thromboxane synthesis
Compete with arachidonic acid for hydrophobic site of COX enzymes

29
Q

Describe the analgesic action of NSAIDs

A

Local peripheral action at site of pain
Inhibition reduces peripheral pain fibre sensitivity by blocking PGE2
Decreased PGE2 synthesis in dorsal horn -> decreased neurotransmitter release -> decreased excitability of neurones in pain relay pathway
Full analgesia after several days dosing

30
Q

Describe the anti-inflammatory action of NSAIDs

A

NSAIDs reduce production of prostaglandins released at site of injury
Symptomatic relief with COX inhibition – little effect on underlying chronic condition

31
Q

Describe the antipyretic action of NSAIDs

A

Inhibition of hypothalamic COX-2 where cytokine induced prostaglandin synthesis is elevated
Results in a reduction in temperature

32
Q

Describe COX selectivity of NSAIDs

A

Differentiated by their selectivity
COX-2 selective compounds inhibit COX-2 with much greater selectivity than COX-1 at therapeutic doses
Aspirin, ibuprofen, naproxen, diclofenac, celecoxib, etericoxib (increasing COX-1 selectivity -> increasing COX-2 selectivity)

33
Q

What are the adverse effects, warnings, contraindications & important drug interactions of NSAIDs? (GI system)

A

Adverse effects: dyspepsia, nausea, peptic ulceration, bleeding and perforation, exacerbation of IBD
-decreased mucus & bicarbonate secretion, increased acid secretion
-decreased mucosal blood flow -> enhanced cytotoxicity and hypoxia
Warnings: elderly, prolonged use, smoking, alcohol, history of peptic ulceration, H. pylori
Important drug interactions: aspirin, glucocorticoid steroids, anticoagulants

34
Q

What are the adverse effects, warnings, contraindications & important drug interactions of NSAIDs? (renal)

A

Adverse effects: reversible decrease in GFR & decrease renal blood flow, increased BP due to inhibition of prostaglandins
Warnings, contraindications: underlying CKD, heart failure
Important drug interactions: ACEi, ARBs, diuretics

35
Q

Describe selective COX-2 inhibitors

A

Less GI ADRs, renal ADRs similar to non-selective
Do not share antiplatelet action but inhibit PGI2
Can be useful when monitored in severe osteo and rheumatoid arthritis for longer term treatment
(NB: ALL NSAIDs increase risk of MI)

36
Q

List examples of selective COX-2 inhibitors

A

Celecoxib

Etoricoxib

37
Q

Describe NSAIDs and protein binding

A

Displace other bound drugs -> increases free drug concentration
-sulfonylurea: hypoglycaemia
-methotrexate: accumulation and hepatotoxicity
-warfarin: increased risk of bleeding
Competitive displacement of some other drugs – likely dose adjustment needed & increased monitoring

38
Q

List indications for NSAID use

A 
Inflammatory conditions 
Osteoarthritis 
Postoperative pain 
Topical use on cornea
Menorrhagia
39
Q

Describe paracetamol

A

Antipyretic action, use for mild to moderate analgesia and fever
At therapeutic doses generally well tolerated with fewer common ADRs
COX-2 selective inhibition in CNS – decrease pain signals to higher centres
Very little anti-inflammatory action

40
Q

Describe NAPQI

A

Highly reactive metabolite
At normal therapeutic doses, conjugation with glutathione renders NAPQI harmless
When hepatic glutathione is limited, NAPQI causes cell death by necrosis and apoptosis

41
Q

Describe paracetamol overdose

A

Can be asymptomatic for many hours
First: nausea, vomiting, abdominal pain; maximal liver damage occurs at 3-4 days
Treatment: glutathione thiol replacement – i.v. N-acetylcysteine
Can’t give glutathione itself because it can’t get into the hepatocytes

42
Q

List mechanisms by which NSAIDs can cause GI adverse drug reactions

A

Decreased mucus secretion
Decreased bicarbonate secretion
Reduced mucosal blood flow
pH partitioning & accumulation of NSAID at gastric mucosa
-inhibition of PGE2 and PGI2 major factor in these ADRs

43
Q

Which prostanoids show apposing platelet aggregatory action?

A

PGI2 & TXA2
PGI2 inhibits platelet aggregation
TXA2 contributes to platelet aggregation

Clinical pharmacology and therapeutics (14 decks)

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