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PR3154 > IC13 Analgesics & drugs for gout, rheumatoid arthritis & osteoarthritis > Flashcards

IC13 Analgesics & drugs for gout, rheumatoid arthritis & osteoarthritis Flashcards

1
Q

What are some examples of non-selective COX inhibitors?

A
  1. Aspirin - irreversible
  2. Ibuprofen
  3. Naproxen
  4. Diclofenac
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2
Q

What are some examples of selective COX-2 inhibitor?

A
  1. Celecoxib
  2. Etericoxib
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3
Q

What is an example of CNS-selective COX inhibitor?

A

Paracetamol

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4
Q

What some examples of opioids?

A
  1. Tramadol
  2. Codeine
  3. Morphine
  4. Oxycodone
  5. Fentanyl

Potency increases down the group

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5
Q

What is pain?

A

Pain is the unpleasant sensory & emotional experience associated w actual or potential tissue damage.

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6
Q

What are the 2 main MOA of modulating pain?

A
  1. Blocking signals along the pain pathway
  2. Alter the interpretation of signal in the brain
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7
Q

What is the process of producing eicosanoids when there is tissue injury?

Eicosanoids are molecules that are involved in inflammation and immune responses.

E.g of eicosanoids - Lipoxins, Prostaglandins, Leukotrienes

A

When there is damage to the cells, the lipids in the cell membrane present are mobilised.

Phospholipase A2 act on these lipids to produce Arachidonic Acid (AA).

AA is then acted on by 3 enzymes:
1. 15-lipoxygenase → lipoxins
2. COX → prostanoids
3. 5-lipoxygenase → Leukotrienes

https://nusu-my.sharepoint.com/:i:/r/personal/e0725451_u_nus_edu/Documents/Pharmacy/Year%203/Y3S2/PR3154/ICs/IC13%20-%20Analgesics%20and%20Drugs%20for%20Rheumatoid%20Arthritis%20and%20Gout/Production%20of%20inflammatory%20agents%20.png?csf=1&web=1&e=g22fNx

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8
Q

What is the MOA of steroids?

A

Steroids block phospholipase A2 enzyme from converting lipids to Arachidonic Acid (AA).

This prevents the production of all 3 types of eicosanoids.

This leads to a potent anti-inflammatory response, but it also causes immune suppression.

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9
Q

What is the MOA of NSAIDs?

A

NSAIDs inhibit COX, which prevents the synthesis of prostanoids.

Prostanoids include:
1. Prostacyclin (PGI)
2. Prostaglandins (PGE) ***
3. Thromboxane A2 (TXA2)

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10
Q

Prostanoids include:
1. Prostacyclin (PGI)
2. Prostaglandins (PGE) ***
3. Thromboxane A2 (TXA2)

What are the effects of each type of prostanoid?

A

Prostacyclin:
- Vasodilation
- Inhibition of platelet aggregation

Prostaglandins:
- Vascular permeability
- Pain

Thromboxane A2:
- Vasoconstriction
- Platelet aggregation

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11
Q

NSAIDS block the production of your prostanoids.

Knowing the effects of each prostanoid, what do you think are the effects of using NSAIDs?

Prostacyclin:
- Vasodilation
- Inhibition of platelet aggregation

Prostaglandins:
- Vascular permeability
- Pain

Thromboxane A2:
- Vasoconstriction
- Platelet aggregation

A

Normally, the vasodilation of prostacyclin is greater than vasoconstriction of TbA2 vasoconstriction effect.

When NSAIDs are used, they will block vasodilation. This leads to vasoconstriction, which reduces heating, redness and swelling. [Can be used for fever]

NSAIDs also reduce vascular permeability, which in turn reduces swelling.

***NSAIDs block production of prostaglandin, which reduces pain.
- PGE sensitizes the nociceptive fibres to stimulation by inflammatory mediators

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12
Q

Why does NSAIDs have a “analgesic ceiling”, where there is a limit to how much pain they can block?

A

NSAIDs blocks sensitization of nociceptors rather than activation.

This means that nociceptors can still be activated, just not as easily. This brings pain stimulation to the basal level.

This in turn translates to NSAIDs being effective for mild-moderate pain, but not severe pain.

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13
Q

Aspirin is CI in children as it causes Reye’s syndrome.

What is Reye’s syndrome?

A

Reye’s syndrome is a rare but life-threatening condition.

It causes the swelling of brain and liver.

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14
Q

What are other common NSAIDs that we have learnt?

A
  1. Aspirin (OTC)
  2. Naproxen (OTC)
  3. Ibuprofen (OTC)
  4. Diclofenac (prescription)
  5. Celecoxib (prescription)
  6. Etericoxib (prescription)
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15
Q

What are common ADRs of using NSAIDs?

A
  1. GI effects:
    - Dyspepsia
    - N&V
    - PUD

*** Risk of PUD is greatly increase if NSAIDs are used for > 5 days

  1. Renal effects:
    - Hyponatremia
    - Water retention
    - Peripheral oedema
    - HTN
    - Hyperkalaemia
    - Acute renal failure
  2. Allergic reaction
  3. Asthma
  4. Bleeding
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16
Q

How does NSAIDs increase likelihood of having asthma and allergies?

A

NSAIDs block COX, which leads to an accumulation of arachidonic acid (AA).

An increase in AA will lead to an increased production of the other eicosanoids.

Leukotrienes is an eicosanoid that will increase in amount when AA increases.

Excess leukotriene can lead to bronchospasm and allergic symptoms.

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17
Q

Why does Aspirin cause stronger ADRs compared to other NSAIDs?

A

Aspirin is a irreversible COX inhibitor.

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18
Q

What are the drugs involved in Triple Whammy?

A
  1. NSAIDs
  2. Diuretics
  3. ACEi/ARBs

Avoid using these drugs tgt as they can lead to AKI.

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19
Q

In the newer generation NSAIDs, they are more specific to reduce certain ADRs.

Which COX are the newer NSAIDS more specific at inhibiting?

A

The newer NSAIDs are more specific in inhibiting COX-2 enzyme.

The more specific the NSAID for COX 2, there will be lesser GI ADR.

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20
Q

Down the group, are the NSAIDs more specific at blocking COX 2?

  1. Ketoprofen
  2. Aspirin
  3. Naproxen
  4. Ibuprofen
  5. Diclofenac
  6. Celecoxib
  7. Etericoxib
A

Yes, the NSAIDs are more COX-2 selective down the group.

  1. Ketoprofen (COX 1&raquo_space;> COX 2)
  2. Aspirin
  3. Naproxen
  4. Ibuprofen
  5. Diclofenac
  6. Celecoxib
  7. Etericoxib (COX 2&raquo_space;> COX 1)
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21
Q

COX 2 enzymes are present in the kidneys, female reproductive tract and etc.

What do you think will happen if COX 2 enzymes are inhibited?

A

It can lead to:
1. Renal toxicity
2. Delayed ovulation
3. -ve effects in 3rd trimester of pregnancy

All COX-2 inhibitors, including non-selective NSAIDs, are contraindicated in 3rd trimester of pregnancy.

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22
Q

What other conditions is NSAID CI in?

A
  1. Poorly controlled asthma
  2. Pt with GI ulcers
  3. Post-surgery pt
  4. Pt at increased risk of MI and stroke

NSAIDs can impair wound healing. This means that ulcers and wounds may not heal properly with the use of NSAIDs.

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23
Q

Why does COX-2 selective NSAIDs increase risk of MI and stroke?

A

COX 1 is involved in the production of Thromboxane A2 (TbXA2).

When COX-2 is block, more arachidonic acid will be metabolised by COX-1, producing more TbXA2. This leads to increase platelet aggregation and increased risk of thrombosis.

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24
Q

We have covered many conditions that NSAIDs are CI in.

Can you list all 7 of them?

A
  1. Severe kidney impairment (eGFR<30ml/min)
  2. Severe heart failure
  3. Active GI ulcer or GI bleed
  4. Bleeding disorders
  5. Use of antiplatelet agents, anticoagulants, systemic corticosteroid
  6. Pregnancy
  7. NSAID hypersensitivity - asthma, elderly and etc.)
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25
Q

What do we counsel patients on NSAIDs?

A
  1. Take NSAIDs as prescribed
  2. Use for shortest duration (≤5 days)
  3. To combine w NSAIDs w paracetamol initially, then stop NSAIDs & continue paracetamol
  4. Seek medical advice if NSAIDs use is needed after 5 days
  5. Not to take NSAID w food
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26
Q

What are the advantages of using paracetamol?

A
  1. few DDI
  2. Few SE
  3. GI sparing
  4. Potent antipyretic
  5. Good analgesic
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27
Q

What are the disadvantages of paracetamol?

A
  1. Weak anti-inflammatory effects
  2. Toxic doses can cause liver damage
  3. Can cause skin allergy rxn sometimes
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28
Q

What is the reversal agent used in paracetamol toxicity?

A

N-acetylcysteine - NAC

29
Q

Key things to note when using paracetamol:

  1. Does it have anti-inflammatory effects at clinical doses?
  2. Can we use in pt w hepatic dysfunction and alcohol abuse?
  3. Will overdose be problem free?
A
  1. Paracetamol does not have anti-inflammatory effects at clinical doses
  2. We must use w caution, or avoid in pt w hepatic dysfunction & alcohol abuse
  3. Overdose will lead to liver damage
30
Q

What are the 3 big risk when using opioids?

A
  1. Addiction & abuse
  2. Sedation
  3. Respiratory depression - occur on overdose
31
Q

Answer the following questions:

  1. Are opioids 1st line for pain?
  2. Are opioids anti-inflammatory?
  3. How should we use opioids?
A
  1. Opioids are NOT 1st line for pain
  2. Opioids are NOT anti-inflammatory
  3. Opioids should be used for the shortest duration, at the lowest effective dose
32
Q

What are some opioid ADRs?

A
  1. GI effects - constipation*
  2. Sedation / drowsiness
  3. Addiction
  4. Respiratory depression
33
Q

What is the only central muscle relaxant that we know?

A

Orphenadrine

34
Q

What is the MOA of orphenadrine?

A

It is a muscarinic receptor antagonist.

It can also block H1 histamine receptors as well

35
Q

Knowing that orphenadrine blocks muscarinic and histamine receptors, what are the common SE pt will likely present?

A
  1. N&V
  2. Dry mouth, blurred vision, constipation
  3. Weight gain, sedation
36
Q

We will now move on to gout.

What are the 6 common medications used to manage gout?

A
  1. NSAIDs
  2. Glucocorticoids
  3. Colchicine
  4. Allopurinol
  5. Febuxostat
  6. Probenecid
37
Q

What is gout and how does it come about?

A

Gout is a type of arthritis and it is caused by accumulation of urate in the body, resulting in the formation of urate crystals in the synovial joints.

38
Q

What is the normal urate concentration in the body?

A

2-7mg/dL

Above this concentration, urate crystals may precipitate.

It can also lead to the formation of kidney stones.

39
Q

What are the 5 common risk factors for gout?

A
  1. Diet
  2. Ageing (>40yo)
  3. HTN
  4. DM
  5. Hyperlipidaemia
  6. Gender (Men : Women = 5:1)
  7. Drugs - thiazide/loop diuretics, low-dose aspirin, ciclosporin
40
Q

What are the goals of therapy when treating gout?

A
  1. Relieve acute gout attack
  2. Prevent recurrent gout attacks
41
Q

What is the process of a gout attack to inflammation?

A
  1. When pt has hyperuricaemia, urate crystals start to precipitate in the joints.
  2. Neutrophils & monocytes are activated, leading to release of inflammatory chemicals and enzymes.
  3. This leads to tissue injury and inflammation.
42
Q

Which of these 5 agents are used for:

(a)Acute gout attack
(b)Prevention of gout attack

  1. NSAIDs
  2. Glucocorticoids
  3. Colchicine
  4. Allopurinol
  5. Febuxostat
  6. Probenecid
A

Acute gout attack (anti-inflammatory agents):
- NSAIDs
- Glucocorticoids
- Colchicine

Prevention of gout attack (Urate lowering therapy):
- Allopurinol
- Febuxostat
- Probenecid

43
Q

What is the MOA of the 6 agents?

  1. NSAIDs
  2. Glucocorticoids
  3. Colchicine
  4. Allopurinol
  5. Febuxostat
  6. Probenecid
A

NSAIDs & glucocorticoids:
- Anti-inflammatory & analgesic

Colchicine:
- ↓ migration of leukocytes into joints

Allopurinol & febuxostat:
- Inhibit uric acid synthesis

Probenecid:
- Increase uric acid excretion

We do not use Allopurinol, Febuxostat & Probenecid when patient has an acute gout attack. It can lead to mobilisation of uric crystals & increase likelihood of kidney stone formation.

44
Q

There is one NSAID that is contraindicated in the treatment of gout.

What is that NSAID?

A

Aspirin.

Do not use aspirin as it is CI with gout.

45
Q

What is an example of a glucocorticoid that we can use?

A

Prednisolone

46
Q

We need to be careful with the use of allopurinol.

What are the ADRs that allopurinol can cause?

A

Allopurinol can cause severe cutaneous adverse reaction (SCAR).

This is most common in HLA-B*58:01 genotype

47
Q

When would you consider the use of probenecid?

A

We would consider probenecid when pt is not able to tolerate allopurinol.

Probenecid is often started 2-3 weeks after an acute attack.

48
Q

What are the 3 main classes of drugs used in osteoarthritis?

A
  1. Paracetamol
  2. NSAIDs
  3. Glucocorticoids
49
Q

What are the 5 main classes of drugs to use in Rheumatoid Arthritis (RA)?

A
  1. NSAIDs
  2. Glucocorticoids
  3. csDMARDs
  4. bDMARDs
  5. tsDMARDs
50
Q

What is rheumatoid arthritis?

A

Rheumatoid arthritis is a chronic inflammatory autoimmune disease.

RA is more common in women than men
(3:1 ratio).

51
Q

What are the goals of therapy in treating RA?

A
  1. Remission of symptoms involving joints
  2. Maintenance of remission w DMARD therapy
  3. Return of full function
52
Q

What are some examples of conventional synthetic DMARDs (csDMARDs)?

A
  1. Methotrexate - 1st line
  2. Sulfasalazine
  3. Leflunomide
  4. Hydroxychloroquine
53
Q

What are some examples of biologic DMARD (bDMARD) ?

A
  1. Infliximab - anti-TNF mAb
  2. Anakinra - IL-1R antagonist
  3. Tocilizumab - anti-IL-6 receptor mAb
54
Q

We know that infliximab is an anti-TNF biologics.

What other anti-TNF biologics are there?

A
  1. Infliximab
  2. Adalimumab
  3. Etanercept
  4. Golimumab
55
Q

What is an example of targeted synthetic DMARDs (tsDMARD)?

A

Jak inhibitors:
1. Tofacitinib

56
Q

What is the MOA of methotrexate in reducing inflammation in RA?

A

Methotrexate helps to increase adenosine production by inhibiting ATIC enzyme.

An increase in adenosine levels will lead to anti-inflammatory effects via:
1. Downregulation of inflammatory cytokines

      2. Inhibition of apoptosis

      3. Inhibition of chemotaxis
57
Q

Methotrexate can cause side effects such as:
1. N&V
2. Mouth & GI ulcers
3. Hair thinning

What can be supplemented to help reduce SE?

A

Folic acid can be give to help reduce SE from MTX.

Folic acid should be taken 12-24 hours after MTX to reduce toxicity.

58
Q

What is the MOA of MTX that leads to folic acid deficiency?

A

Methotrexate inhibits dihydrofolate reductase, in addition to ATIC enzyme.

Inhibition of dihydrofolate reductase leads to decrease production of folinic acid - which is a substrate needed to produce nucleic acids in the body.

59
Q

The 4 main csDMARDs are:
1. MTX
2. Sulfasalazine
3. Leflunomide
4. Hydroxychloroquine

What do we have to watch out for in Leflunomide?

A

Leflunomide has a very long half-life.

It can still be detected years after last dosing.

We must use Colestyramine (a bile salt binding resin) to help wash out the leflunomide.

60
Q

How are tsDMARDs (e.g tofacitinib) used in treatment of RA?

A

Tofacitinib is used together with MTX for moderate to severe RA.

If pt has intolerance to MTX, you can use tofacitinib as monotherapy.

61
Q

What is the MOA of tofacitinib?

A

It is a JAK inhibitor. By inhibiting the JAK pathway, it blocks cytokine production.

62
Q

What are the ADRs of tofacitinib?

A
  1. Cytopenia - lower than normal cell count
    - Immunosuppression
    - Anaemia
  2. Hyperlipidaemia
  3. MACE
  4. Malignancy

DO NOT COMBINE bDMARDs w tsDMARDs.

63
Q

When do we use bDMARDs?

  1. Infliximab - anti-TNF mAb
  2. Anakinra - IL-1R antagonist
  3. Tocilizumab - anti-IL-6 receptor mAb
A

When RA patients do not respond to csDMARDs & tsDMARDs.

bDMARDs are often used together with MTX.

64
Q

What is contraindicated with the use of bDMARDs?

A
  1. Live vaccination
  2. Hepatitis
65
Q

What are some side effects associated with the use of bDMARDs?

A

As bMARDs suppresses the immune system, it can lead to:
- Respiratory infection & skin infection
- Leukopenia
- Aplastic anaemia
- Increased risk of lymphoma

66
Q

A gout patient reported that it has been 2 days since his gout attack.

What would be the appropriate treatment for the patient?

A

NSAIDs + glucocorticoids.
- Celecoxib + Prednisolone

We would want to avoid the use of colchicine after 36 hours since the start of the acute gout attack.

67
Q

What is the side effect of colchicine?

A

Diarrhoea, N&V, GI bleeding

68
Q

A gout patient’s acute gout attack has been resolved.

He is currently on Colchicine. He will be starting allopurinol soon.
Can he still take colchicine with allopurinol?

A

Yes. However, he must take colchicine at low dose and slowly taper off.

69
Q

Methotrexate can cause GI ADR.

What drug can be given to help reduce these GI ADRs?

A

Folic acid can be given 12-24hrs after taking methotrexate.

PR3154 (19 decks)

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