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Pharmacology > SPR L2 Inflammation, NSAIDS and DMARDS > Flashcards

SPR L2 Inflammation, NSAIDS and DMARDS Flashcards

1
Q

SPR L2 Inflammation and NSAIDS and DMARDS

Learning Outcomes

for general perusal

A
  1. Understand what NSAIDs are and their mechanism of action
  2. Appreciate the different roles of COX-1 versus COX-2 inhibition
  3. Be able to list the main medical uses of NSAIDs with examples
  4. Be familiar with the potential side-effects/contraindications of NSAIDs
  5. be able to describe DMARDs, giving three examples and their MOA
  6. have sufficient information on NSAIDs/DMARDs/Steroids to understand clinical cases presented in the Tutorials
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2
Q

Non-Steroidal Anti-Inflammatory Drugs

  1. Generally describe this class of drug
  2. What are they used to treat?
  3. However, what is seen with this class of drug?
A
  1. Very widely used, aspirin-like drugs, greater than 50 NSAIDS on the market - diverse range
  2. a range of conditions such as inflammation, fever, pain, muscle injury, sprains, fractures etc.
  3. significant side-effects
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3
Q

Give examples of Important NSAIDs commonly in use in medicine

A
  • aspirin
  • ibuprofen
  • Naproxen (Alleve)
  • Indomethacin - powerful NSAID with wide ranging use/side-effects
  • Diclofenac
  • Paracetamol
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4
Q

What is the mechanism of action of NSAIDs?

A

NSAIDs work by inhibition the action of cyclooxygenase (COX) enzymes, lowering levels of prostaglandins e.g. PGE2, PGI2

2 main isoforms: COX-1 and COX-2

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5
Q

Mechanism of Action of NSAIDS

What do prostaglandins cause?

A
  • vasodilation
  • oedema
  • pain (increasing Bradykinin-mediated nociception)
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6
Q

Cyclooxygenase (COX) Enzymes

  1. What are the two main isoforms?
  2. What action do these enzymes have?
  3. Where is COX-1 expressed?
    1. What does it do?
    2. Prostaglandins produced by COX-1 are involved in what?
  4. Where is COX-2 expressed, what is it?
A
  1. COX-1 (constitutively active) and COX-2 (inducible)
  2. use arachidonic acid to generate PGs and TXA2
  3. expressed in most tissues including platelets
    1. general “housekeeping” COX enzyme
    2. a) protection of gastric mucosa
      b) platelet aggregation
      c) renal blood flow autoregulation
  4. expressed in activated inflammatory cells e.g. basophils, eosinophils, inducible form of enzyme
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7
Q

Cyclooxygenase Enzymes

  1. COX-1 and COX-2 have approximately __% sequence identity?
  2. What similar ability do both have?
  3. What defines their different roles/side-effects?
  4. What are most NSAIDs?
A
  1. 60%
  2. ability to induce arachidonic acid oxidation
  3. differences in COX tissue expression
  4. non-selective between COX-1 versus COX-2
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8
Q

NSAIDs work by inhibiting COX-1 and COX-2

General Rule of Thumb

  1. What do the majority of anti-inflammatory effects of NSAIDs occur via?
  2. What do most side-effects of NSAIDs occur via?
A
  1. COX-2 inhibition
  2. COX-1 inhibition
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9
Q

Main Pharmacological Actions of NSAIDs

  1. What are these?
  2. What are the main side-effects?
A
  1. anti-inflammatory, analgesic, anti-pyretic
  2. gastric irritation, compromised renal blood flow, increased bleeding, increase risk of MI (COX-2).

Effects and side-effects arise from the primary action of the NSAIDs in different tissues

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10
Q

Main Pharmacological Actions of NSAIDs

1. Anti-inflammatory

  1. How does this come about?
  2. What is this clinically useful in?
A
  1. NSAID inhibition of COX-2 predominantly
  2. Inflammatory arthritis Dental pain Oro-facial pain Post operative pain Bone metastases in cancer

NOTE: NSAIDs have no effect on the disease causing the inflammation e.g. RA

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11
Q

Main Pharmacological Actions of NSAIDs

2. Analgesic (for mild/moderate pain due to inflammation or tissue damage)

  1. What is the mechanism for this action?
  2. What are they effective in?
  3. How do they help headaches?
  4. How are they useful in surgery?
A
  1. decreased Prostaglandins, reduced sensitization of Bradykinin nociception
  2. Effective in arthritis, muscle pain, toothache, dysmenorrhea, postpartum pain, cancer metastasis in bone pain
  3. NSAIDs reduce PG-induced vasodilation in brain
  4. reduce postoperative pain, reduce the amount of opioids needed by up to 30 %
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12
Q

Main Pharmacological Actions of NSAIDs

3. Anti-pyretic

  1. How is this brought about?
  2. How?
  3. Outline the pathological pyretic response that brings about a fever?
A
  1. decreased PG production in the hypothalamus. “NSAIDs reset the body’s thermostat” (paracetamol primarily used)
  2. vasodilation, sweating. NB - no effect on normal body temperature
  3. Bacteria => endotoxin => increased IL-1 from macrophages (pyrogen) => Increased PGE2 production in the hypothalamus via COX-2 action => fever
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13
Q

Other Clinical Uses of NSAIDs

  1. ​Outline the main clinical uses of NSAIDS

Give TWO other uses

A
  1. Anti-inflammatory, Analgesic, Anti-pyretic
    * Anti-platelet: Aspirin (COX-1 inhibition)
    • Stroke prevention
    • MI prevention
    • Unstable angina
    • Deep venous thrombosis (DVT) prevention
      * Colon cancer prevention: low dose, long-term (5 years) aspirin may reduce the risk of colon and other GI cancers
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14
Q

Aspirin: Nature’s miracle drug

  1. What is it derived from?
  2. Aspirin is the only NSAID that…?
    1. Which does it inhibit?
    2. Which does it have more affinity for?
  3. Summarise the history of the drug
A
  1. the bark of the willow tree
  2. irreversibly inhibits COX
    1. Inhibits both COX-1 and COX-2
    2. but has a greater affinity for COX-1
  3. See picture
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15
Q

Side-effects of NSAIDS

high burden of side-effects with NSAIDs

  1. What are these side effects due to?
  2. What do common side effects include?
A
  1. due to the inhibition of COX activity and PG production in non-inflammatory tissues
    • GI disturbances
    • Adverse Renal Effects
    • Rashes
    • CNS effects
    • Bone Marrow effects
    • Aspirin sensitive asthma
    • Liver toxicity (paracetamol)
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16
Q

Side-effects of NSAIDS

Gastrointestinal Disturbances

  1. What are these usually in the form of?
  2. What occurs in approroximately 1/3 of patients on NSAIDS
  3. What is the cause of the GI disturbance seen?
  4. How can this effect be limited?

approx 100,000 people in the USA hospitalised as a result of GI effects of NSAIDs.

  1. 15 % of these people die - who do these tend to be?
A
  1. perforations, ulcers, bleeds
  2. diarrhoea, constipation, nausea, vomiting
  3. NSAIDs inhibit gastric COX-1 which generates PGE2 that inhibits acid secretion from the parietal cells in the stomach
  4. limit this effect by giving Misoprostol which is a PGE2 analogue (avoid in pregnancy!!) other types of ulcer protection also used (PPIs, antacids)
  5. older patients taking NSAIDs for arthritis
17
Q

Side-effects of NSAIDS

Adverse Renal Effects

In healthy patients, there is no risk to kidney function

  1. Who is at risk? Of what?
  2. What is the cause?
  3. What is the mechanism?
  4. What does the NA+ retention lead to?
  5. What was also seen with Phenacetin (now withdrawn)
A
  1. patients with compromised renal function - NSAIDs can cause acute renal failure. ALSO: Neonates, elderly, heart, liver, kidney disease patients at risk of this side-effect
  2. COX inhibition, reduced PGE2, PGI2 production, altered renal blood flow
  3. see picture
  4. Hypertension
  5. analgesic nephropathy also seen
18
Q

Drug Interactions of NSAIDS

  1. What is there increased risk of when using more than one NSAID, especially if one is aspirin?
  2. When is there increased risk of GI bleeding?
  3. What shows reduced effectiveness with NSAIDs?
A
  1. increased risk of bleeding
  2. with anticoagulants, and anti-depressants (aspirin and SSRIs ,venlafaxine)
  3. diuretics and antihypertensive agents
19
Q

Drug Interactions of NSAIDs

Stevens-Johnson Syndrome-an rare allergic drug reaction (Erythema multiforme major))

  1. What is this?
  2. What NSAID is most likely to be administered to young children?
A
  1. Hypersensitivity reaction to drugs-penicillin, sulfonamides. Can be fatal.
  2. ibuprofen or paracetamol
20
Q

When are NSAIDS contraindicated?

A
  • Patients with Peptic Ulcer Disease
  • Patients with a history of GI bleed
  • Those receiving anticoagulants
  • caution in patients with renal impairment, heart failure or hypertension
  • used with caution in pregnancy, especially during the third trimester (can cause closure of the ductus arteriosus in utero, PH in baby) => EOP 3
    • ibuprofen can be used to close the PDA in premature infants (JAMA)
  • Those with a previous history of allergic reactions e.g. asthma
21
Q

Paracetamol: NSAID or not?

Paracetamol (acetaminophen)

  1. What actions does it have?
  2. What may it be related to?
  3. Are there any GI effects?
  4. What is a problem with this drug?
  5. What is the toxic dose of paracetamol?
    1. What does it cause?
    2. How long does this take to occur?
    3. What can overdose be treated with?
A
  1. excellent analgesic and anti-pyretic effects, little anti-inflammatory effects
  2. the inhibition of COX-3 (a splice variant of COX-1) in the CNS
  3. no real side-effects in the GIT, platelets-so is it an NSAID at all?
  4. problems related to “over the counter” availability of the drug
  5. 10-15 grams = > fatal hepatotoxicity
    1. depletion of glutathione (GSH), accumulation of toxic intermediates in liver, necrosis and liver failure
    2. fatal hepatotoxicity after 24-48hr
    3. can be treated within 12 h of ingestion with acetylcysteinse (↑GSH)
22
Q

Selective versus non-selective COX inhibitors

if the side-effects of NSAIDs are due to COX-1 inhibition, why not make COX-2 specific inhibitors?

A
  • 2 COX-2 specific inhibitors developed for arthritis, colon cancer
    • rofecoxib (Vioxx, Merck)
    • celecoxib (Celebrex, Pfizer)
  • rofecoxib reduced the incidence of GI bleeds by 50 %
  • increased risk of myocardial infarction/stroke - drug withdrawn by Merck in 2004
    • Why? Increased arterial BP, increased platelet count
    • Merck paid $5 billion in class action lawsuit (2007), $1 billion in civil and criminal fines (2011)
23
Q

Reminder of Drug Class Recognition

Give examples of the following drugs:

  1. ACE Inhibitors
  2. ARBs
  3. Ca2+ Channel Blockers
  4. COX-2 Inhibitors
A
  1. Enalapril, Lisinopril
  2. Losartan, Valsartan
  3. Amlodipine, Aranidipine
  4. Celecoxib, Paracoxib
24
Q

Selective versus non-selective COX inhibitors

Question: if the side-effects of NSAIDs are due to COX-1 inhibition, why not make COX-2 specific inhibitors?

  1. Give examples ofC OX-2 inhibitors in use today
  2. What are they used for?
  3. What needs to be observed?
    1. Why?
A
  1. Celecoxib (Celebrex, rare cases of RA)

Parecoxib

Etoricoxib

  1. used for the treatment of arthritis
  2. monitor for adverse CV events, still get some effects on GIT (ulcers), kidney, skin
    1. probably due to some inhibition of COX-1 (selective, not specific)
25
Q

NSAID selectivity for COX enzymes

  1. Give an example of a COX-1 Inhibitor?
  2. and of COX 1&2 Inhibitors?
  3. and of COX 2 Inhibitors?
A
  1. Aspirin
  2. Ibuprofen**, Naproxen**, Indometacin***
  3. Celecoxib

Etoricoxib

26
Q

Disease-Modifying Anti-Rheumatic Drugs (DMARDs)

diverse set of unrelated agents that have different mechanisms of action, all have the potential to improve the symptoms of rheumatoid arthritis

  1. What do Corticosteroids and NSAIDs do?
  2. What to DMARDS do?
A
  1. give reduced pain/inflammation associated with RA
  2. decrease disease severity, improve symptoms
    - decrease number of swollen joints
    - reduced pain score
    - decrease serum levels of IgG
27
Q

Examples of DMARDs

  1. Name the older drugs not commonly used for RA
  2. Name the common drugs for RA
A
  1. Gold, D-penicillamine, Sulfasalazine, Hydroxychloroquine
  2. Methotrexate, Leflunomide

Azathioprine-look up yourselves

Infliximab (anti-TNFa antibody)

28
Q

DMARDs

Methotrexate

  1. What is it? Outline its mechanism of action.
  2. What is it used as?
  3. What is the ROA?
  4. When is the onset of action?
  5. What are the potential side effects?
  6. What therapy is common?
  7. When is it NOT to be used? Why?
A
  1. folic acid antagonist with immunosuppressant activity. potent anti-rheumatoid activity, common first-choice DMARD. (see picture)
  2. used to treat Crohn’s disease, also used as an anti-metabolite in cancer therapy, inhibits DNA synthesis
  3. orally, im, iv
  4. 6 week onset of action
  5. blood disorders, liver cirrhosis, nephrotoxicity, GIT damage, neural tube defects
  6. long term therapy common (>5 years), most commonly used DMARD for RA
  7. not to be used in pregnancy/avoid conception 3 months post therapy due to teratogenic effects
29
Q

DMARDs

Leflunomide

  1. What is this?
  2. What is it’s mechanism of action?
  3. How is it absorbed orally?
  4. Describe the half life
  5. What are the main side effects?
  6. What is essential?
  7. What is the onset of action?
  8. Who can it be given to?
  9. When is it contraindicated
    1. What is the washout period? What is the general rule as a result?
A
  1. immunosuppresant drug, specific inhibitor of activated lymphocytes
  2. Inhibitor of dihydroorotate dehydrogenase, blocks pyrimidine production, blocks clonal expansion of T-cells, other cells can bypass this blockade
  3. well absorbed orally
  4. long half-life (4-28 days)
  5. anaemia, hepatotoxicity, diarrohea, nausea
  6. blood monitoring essential
  7. onset of action in 4 weeks
  8. patients who don’t respond to MTx
  9. pregnancy, breast feeding
    1. Needs a 2 year wash out period, best avoided in premenopausal women
30
Q

DMARDs

​Anti-tumour necrosis factor-a (TNFa) antibodies

  1. What is
    - Infliximab
    - Etanercept
  2. What is it used for?
  3. When are these drugs used?
  4. Infliximab can be used in combination with what?
  5. What are the s/e’s?
  6. What are the disadvantages
A
    • monoclonal antibody against TNFa - recombinant TNFa receptor-IgG fusion protein
  2. used for RA, Crohn’s Disease
  3. NICE guidelines-use these drugs after at least 2 DMARDs have been tried
  4. with MTx - If MTx cant be used due to C/I, use etanercept as monotherapy
  5. reactivation of TB, increased infections
  6. very expensive drugs: one year of therapy costs about £20,000 per patient, but has been a major therapeutic advance in the treatment of rheumatoid arthritis
31
Q

Steroid v NSAID v DMARD in RA

​How are the following drugs used in RA…

  1. NSAIDS?
  2. DMARDS?
  3. Steriods?
A
  1. can provide rapid pain relief
  2. could be started at the same time as NSAIDS, takes 4-6 weeks before effects seen
  3. can be used but care should be taken due to potential side-effects

remember the contraindications and potential side-effects

32
Q

Learning Outcomes

for general perusal

A
  1. Understand what NSAIDs are and their mechanism of action
  2. Appreciate the different roles of COX-1 versus COX-2 inhibition
  3. Be able to list the main medical uses of NSAIDs with examples
  4. Be familiar with the potential side-effects/contraindications of NSAIDs
  5. be able to describe DMARDs, giving three examples and their MOA
  6. have sufficient information on NSAIDs/DMARDs/Steroids to understand clinical cases presented in the Tutorials

Pharmacology (26 decks)

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