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MBBS II MSS > L08 - Drugs Used in the Management of Arthritis > Flashcards

L08 - Drugs Used in the Management of Arthritis Flashcards

• Identify the rationale behind the selection and the regimen of steroidal anti-inflammatory drugs in the management of joint disorders • Describe the risk for chronic usage of anti-inflammatory steroids • Describe the different categories of DMARDs • Explain the pharmacological differences between nonbiological and biological DMARDs • Recognize the benefits and the risks associated with the use of non-biological and biological DMARDs

1
Q

Name a non-opioid analgesic used to treat arthritis?

A

Paracetamol (Acetaminophen)

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2
Q

List 2 advantages and 2 disadvantages of using Paracetamol for arthritis?

A

Advantages:
• Analgesic effect: preferred drug against mild to moderate pain
• Therapeutically safe - RARE skin rash and minor allergic reactions

Disadvantages:
• Liver and/or kidney damage - only at toxic dosage
• Lack of anti-inflammatory effect - limited to osteoarthritis

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3
Q

What can increase the risk of liver and/or kidney damage under high dose paracetamol consumption?

A

Risk increased with cytochrome enzyme induction (e.g. heavy alcohol consumption)

or GSH depletion (e.g. fasting or malnutrition)

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4
Q

What can decrease the risk of liver and/or kidney damage under high dose paracetamol consumption?

A

risk reduced by treatment with N-acetylcysteine (Mucolytic)

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5
Q

What are the 2 classes of NSAIDs?

A

Non-steroidal anti-inflammatory drugs (NSAIDs)

  • traditional NSAIDs (tNSAIDs)
  • selective cyclooxygenase-2 inhibitors
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6
Q

What 2 classes of drugs can be used to treat inflammation caused by arthritis?

A

NSAIDs

Steroids

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7
Q

Why do Glucocorticoids take time to achieve therapeutic effects?

A

MoA: bind to intracellular cytoplasmic receptors

> > induce / repress gene transcription in nucleus

> > affect level of mRNA, proteins

Long process, full effect comes after several hours, weeks

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8
Q

What are the effects of NSAIDs?

A
  • Anti-inflammatory
  • Analgesic effect
  • Antipyretic effect
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9
Q

Explain the overall MoA of NSAIDs?

A

Inhibit the activity of cyclooxygenase&raquo_space; decrease production of prostanoids

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10
Q

Explain how NSAIDs have anti-inflammatory effect?

A

Decrease production of prostanoids

> > decrease vasodilation and vascular permeability

> > Decrease edema and swelling and redness

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11
Q

Explain how NSAIDs have analgesic effect?

A

Decrease production of prostanoids

> > Decrease sensitization of pain nerve endings
decrease low to moderate pain from integumental structures

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12
Q

Explain how NSAIDs have antipyretic effect?

A

Decrease production of prostanoids

Decrease set-point of hypothalamic thermoregulatory center

> > relieve fever

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13
Q

What are the 2 ways that Glucocorticoids can impact synthesis of eicosanoids?

A

Affect synthesis of eicosanoids/ arachidonic metabolites by:
a) Increase expression of lipocortin (annexin-1) to INHIBIT phospholipase A2&raquo_space; less cell membrane phospholipids converted to arachidonic acid to make leukotrienes

b) Decrease expression of cyclooxygenase 1 and 2&raquo_space; LESS CONVERSION of arachidonic acid to prostaglandins and Thromboxane respectively

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14
Q

How does glucocorticoid impact inflammatory response by cytokines?

A

Decrease pro-inflammatory cytokines (tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1))

  • Decrease vasodilation and vascular permeability
  • Decrease expression of adhesion molecules between WBC and endothelial cells
  • Inhibit function of macrophages and APCs
  • Inhibit production of prostaglandins, leukotrienes and platelet-activating factor
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15
Q

Name 6 synthetic glucocorticoids and group them into functional groups.

A

1) Hydrocortisone and Prednisolone = short to medium acting
2) Cortisone and Prednisone = Inactive pro-drug
3) Betamethasone and Dexamethasone (long- acting) ( less commonly used for oral therapy to avoid adverse effects)

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16
Q

Advantages of Hydrocortisone, Prednisolone?

A
  • Oral intake, convenient

- Short acting, avoids long-lasting adverse effects

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17
Q

Which glucocorticoids cannot be given to patients with severe liver failure and why?

A

Cortisone and Prednisone:

  • inactive (Pro-drug) converted by 11β-HSD1 in the liver to biologically active forms (hydrocortisone and prednisolone)
  • Severe hepatic failure = impaired 11β-HSD1 activity
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18
Q

Where are glucocorticoid and Mineralocorticoid made naturally in body?

A

Adrenal Cortex

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19
Q

What stimulates the production of Glucocorticoids and Mineralocorticoids in the body?

A

Hypothalamus&raquo_space; Corticotrophin- Releasing Factor (CRF)&raquo_space; Corticotrophs @ Anterior Pituitary&raquo_space; Adrenocorticotrophic Hormone (ACTH)&raquo_space; Adrenal Cortex

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20
Q

How is Glucocorticoid production regulated in the body?

A

Production by Adrenal Cortex&raquo_space; Glucocorticoid level increases&raquo_space; NEGATIVE FEEDBACK ONTO HYPOTHALAMUS&raquo_space; cease release of CRF …etc

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21
Q

Compare the mode of action of glucocorticoids on cells at low level and high level in body?

A

Low level = Permissive effect: permit the actions of other hormones in its presence (occur primarily in the resting state)

High level = Direct action in cells in response to threat

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22
Q

What is the metabolic effect of Glucocorticoids at low dose?

A

Increase adrenergic- receptor-mediated lipolysis in fat cells (e.g. under increased NE/E levels)

> > fat lysis to glycerol for gluconeogenesis in liver

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23
Q

Overall normal physiological Metabolic effect of Glucocorticoids?

A

Maintenance of adequate glucose supply to the brain and heart (glucose-dependent tissues)

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24
Q

What is the metabolic effect of Glucocorticoids at HIGH dose?

A

1) Increase activity of PEP carboxykinase and G6P to increase gluconeogenesis in liver
2) Translocate glucose transporters internally to decrease glucose uptake in muscles
3) Increase protein breakdown to use amino acid for gluconeogenesis

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25
Q

Explain why high dose glucocorticoid treatment can cause fat redistribution?

A

High dose glucocorticoids increases Blood Glucose levels massively

Cause increase in insulin and Lipogenesis

Cause fat deposition to trunk, back of neck, face …etc

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26
Q

Explain effect of chronic high dose glucocorticoid intake on fat redistribution?

A

Chronic intake = decrease fat cell responsiveness = fail to breakdown fat

Cause further fat accumulation and redistribution

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27
Q

Compare Electrolyte and water balance effects between low and high dose glucocorticoid intake?

A

Low = Maintain glomerular filtration rate, facilitate water excretion by the kidney (permissive effects on tubular function)

High = Decrease calcium absorption in GIT, Increase Calcium excretion by kidney = BONE LOSS (attempt to compensate for low plasma Ca)

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28
Q

Vascular and Neuronal effects of glucocorticoid intake?

A

Vascular = Enhance vascular reactivity to other vasoactive substances = Hypertension

Neuronal = mood elevation, euphoria, insomnia, restlessness, increase motor activity

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29
Q

List the 7 adverse effects of glucocorticoid intake?

A
  • Immunosuppression = Infection and peptic ulcer (H. pylori)
  • Impaired inflammatory response = impaired wound healing
  • Impaired carbohydrate metabolism = hyperglycemia → diabetes mellitus
  • Impaired protein metabolism = muscle
    wasting, weakness
  • Impaired lipase activity, insulin secretion = redistribution of fat to trunk
  • Impaired calcium metabolism = osteoporosis
  • Abnormal CNS effects = insomnia, euphoria, depression
30
Q

Why is chronic glucocorticoid use not recommended for children?

A

Growth inhibition

Only give short term, not oral preparation

31
Q

What pre-existing conditions are contraindicated against use of glucocorticoids?

A

infectious illnesses, peptic ulcer, heart disease, diabetes, psychoses, osteoporosis, hepatic dysfunction

32
Q

Glucocorticoids can be quickly withdrawn after chronic admin. True or False?

A

False

Immediately withdrawal Cause Adrenal insufficiency (Body cannot make glucocorticoids for normal processes)

33
Q

What are the consequences of adrenal insufficiency?

A
  • disturbances in fluid and electrolyte balance
  • hypoglycaemia
  • impaired responses to the stress of illness or trauma → circulatory shock and even death
34
Q

How to stop glucocorticoid treatment after long term admin?

A

Graded reduction of glucocorticoid therapy

  • 2-12 months for recovery of adrenal function
  • another 6-9 months for recovery of corticosteroids level
  • close monitoring due to individual differences
35
Q

What are the 3 considerations when admin. glucocorticoids?

A

1) Duration of action = preferably medium-acting for large doses
2) Route of admin = preferably topical preparation, local therapy to reduce systemic effects
3) Dosage regimen= lowest possible dosage to reduce side effect + Alternate day therapy for normal adrenal function

36
Q

DMARDs can be given to cure Rheumatoid arthritis over chronic admin. True or False?

A

False

Only Modify disease activity and retard progress of bone and cartilage damage, not cure RA

37
Q

Explain the mechanism of glucocorticoid intake causing adrenal insufficiency?

A

Due to negative feedback, when glucocorticoids are given as drugs, their plasma level is enough to suppress the hypothalamic-anterior pituitary-adrenal cortex (HPA) axis

> > body cannot synthesize glucocorticoids

38
Q

What drugs are given to treat Rheumatoid arthritis?

A

Disease-modifying anti-rheumatic drugs (DMARDs)

39
Q

Function of DMARDs?

A

Modify disease activity: retard the progress of bone and cartilage damage

achieve clinical remission, prevent irreversible damage to joints

40
Q

Why are DMARDs used in conjunction with anti-inflammatory drugs at the beginning of therapy?

A

Act Slowly - 2 weeks to 6 months

41
Q

Which is more toxic: DMARDs or NSAIDs? Why?

A

DMARDs

Affects more basic inflammatory mechanisms (immune response) than do glucocorticoids / NSAIDs

42
Q

What are some toxic effects of DMARDs?

A
  • Hematologic toxicity / bone marrow suppression

- Gastrointestinal disturbances, mucosal ulcers

43
Q

What types of drugs should be given against pain from arthritis?

A

Acetaminophen + NSAIDs

44
Q

What types of drugs should be given against inflammation from arthritis?

A

Glucocorticoids, NSAIDs

45
Q

What types of drugs should be given against joint damage from arthritis?

A

DMARDs, glucocorticoids

46
Q

List 4 groups of Conventional Synthetic DMARDs (csDMARDs)?

A

1) Cytotoxic agents
2) Sulfasalazine
3) Antimalarial drugs
4) Immunosuppressants

47
Q

What is Sulfasalazine used for?

A

Treating Ulcerative Colitis, Rheumatoid Arthritis and Crohn’s disease

48
Q

List 4 cytotoxic agent csDMARDs?

A

methotrexate most important

leflunomide, cyclophosphamide, azathioprine

49
Q

List 2 Antimalarial csDMARDs?

A

chloroquine, hydroxychloroquine

50
Q

List 2 Immunosuppressant csDMARDs.

A

cyclosporine

mycophenolate mofetil

51
Q

MoA of Methotrexate? (4)

A

Folic Acid Analog (Antifolate), Cytotoxic Agent

Polyglutamated in cells, block active site of dihydrofolate reductase*** > decrease FH4 production&raquo_space; Decrease methylation processes

  • Inhibit AICAR, nuclear factor kappa B (NFκB)&raquo_space;
    suppress neutrophils, macrophages, dendritic cells and lymphocytes at low dose
  • inhibit proliferation and stimulate apoptosis of immune-inflammatory cells
  • inhibit proinflammatory cytokines
52
Q

Adverse effects of Methotrexate? What drugs reduce adverse effects of Methotrextae?

A

1) GI disturbances, mucosal ulcers
2) Hypersensitivity reaction > Methotrexate lung fibrosis*
3) Hematotoxicity, Nephrotoxicity*
4) Dose - related hepatotoxicity

Concomitant use of leucovorin or folate

53
Q

What is the ONLY DMARD that can be given to pregnant women?

A

Hydroxychloroquine

Antimalarial agent ^

54
Q

What is the triple therapy of csDMARDs?

A

Methotrexate + Sulfasalazine + Hydroxychloroquine

55
Q

List 5 groups of Biological DMARDs?

A
  • Tumour necrosis factor (TNF)-a blocking agents
  • T-cell co-stimulation modulator
  • B-cell cytotoxic agent
  • Interleukin-1 receptor antagonist
  • Interleukin-6 receptor antagonist
56
Q

Give 5 examples of Tumour necrosis factor (TNF)-a blocking agents?

A

etanercept**,

infliximab, adalimumab, golimumab, certolizumab

57
Q

Give example of T-cell co-stimulation modulator?

A

Abatacept

58
Q

Give example of B-cell cytotoxic agent?

A

rituximab

59
Q

Give example of IL-1 and IL-6 receptor antagonists?

A

IL-1&raquo_space; Anikinra

IL-6&raquo_space; tocilizumab, sarilumab

60
Q

MoA of Abatacept?

A

Abatacept = T-cell co-stimulation modulator*
contains the endogenous ligand CTLA-4

> > binds to CD80 and CD86 of antigen-presenting cell
inhibit CD28 - CD80/86 complex formation
prevent activation of T-cells

61
Q

Administration and preparation of Abatacept?

A

intravenous infusion over 30 minutes (once every 2 weeks x 3, followed by monthly infusions)

62
Q

Adverse effects of Abatacept?

A

Injection site irritation / allergy/ hypersensitivity reaction

Modest increase in risk for infection

63
Q

What is the Rheumatoid arthritis regimen for latent TB positive patients?

A

start anti-TB drugs 1 month before biological DMARDs and JAK inhibitors

64
Q

What combo of bDMARDs are not recommended?

A

Do not combine:

T- cell co-stimulation modulator (Abatacept)/ B cell cytotoxic agent (rituximab)/ IL-1 receptor antagonist (anakinra)
+
TNF- a blocking agent (etanercept)

TNF - a blocking agents must not be given with any other bDMARDs, only give alone or with IL-6 receptor antagonist

65
Q

Why are certain combos of bDMARDs not recommended?

A

Massive decrease in pro-inflammatory cytokines = cannot vasodilate or express adhesion molecules = Huge increase in risk of infection

66
Q

List 4 general adverse effects of bDAMRDs?

A
  • Increase risk of infection
  • GI disturbances
  • Bone marrow suppression + hematologic toxicity
  • Allergy/ Hypersensitivity reaction/ Injection site irritation
67
Q

3 Precautions before administering bDMARDs?

A

Must screen for latent TB

NO live vaccines when on bDMARDs

Must not combo TNF-a blocking agent with other bDMARDs

No bDMARDs are allowed for pregnant woman

68
Q

Name one group of tsDMARDs and give 2 examples of these drugs?

A

Targeted Synthetic DMARDs (tsDMARDs)

Janus-Activated Kinase Inhibitors

Tofacitinib: more specific for JAK1, 3

Baricitinib: more specific for JAK1, 2

69
Q

MoA of JAK inhibitors?

A

binds to ATP binding site of the catalytic domain of JAK

> inhibit Janus-activated kinase (JAK)

> DECREASE SIGNALLING BY IL-6, IFN*****

> cytokines cannot activate immune cells to produce further pro-inflammatory signals = decrease joint damage

70
Q

When is JAK inhibitor chosen for treating RA?

A

Indicated for patients with inadequate responses to one or more DMARDs

orally bioavailable

71
Q

Precautions of JAK inhibitors?

A

1) INFECTION RISK, particularly for herpes virus
2) SKIN CANCER RISK
3) Increase plasma level of liver enzymes, lipoproteins
4) GI perforation

5) BONE MARROW TOXICITY:
Potential risk of anemia, leukopenia, neutropenia, lymphopenia and thrombocytopenia (many hematopoietic growth factors affected through JAK pathway)

MBBS II MSS (31 decks)

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