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MSS > MSS08 Drugs Used In The Management Of Arthritis > Flashcards

MSS08 Drugs Used In The Management Of Arthritis Flashcards

1
Q

2 types of Arthritis

A
  1. Degenerative (OA)
  2. Inflammatory (RA)

NO cure for both

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2
Q

Paracetamol

A
  1. Analgesic effect
    - preferred against mild to moderate pain
  2. ***Lack of anti-inflammatory effect
    - therefore limited to OA
  3. Therapeutically safe
    - skin rash and minor allergic reactions
  4. Liver +/- Kidney damage
    - only at toxic dosage
    - risk increased:
    —> **Cytochrome enzyme induction (heavy alcohol consumption) —> formation of reactive toxic intermediate NAPQI
    —> **    Glutathione (GSH) depletion (fasting / malnutrition)
    —> risk reduced by treatment with ***N-acetylcysteine
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3
Q

Anti-inflammatory drugs

A
  1. NSAIDs
    - traditional NSAIDs
    - selective COX-2 inhibitors
  2. Steroids
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4
Q

***Mechanism of NSAIDs

A

Inhibit activity of cyclooxygenase (COX)
—> ↓ ***Prostanoids production

  1. Anti-inflammatory effect —> ***↓ Vasodilatation and vascular permeability —> ↓ oedema, swelling and redness
  2. Analgesic effect —> ***↓ Sensitisation of pain nerve endings —> ↓ low to moderate pain arisen from integumental structures
  3. Anti-pyretic effect —> ***↓ Set-point of the hypothalamic thermoregulatory centre —> relieve fever
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5
Q

***Mechanism of glucocorticoids

A

Intracellular action: bind to **Glucocorticoid receptor
—> receptor-ligand complex translocate into nucleus
—> **prevent transcription from gene to mRNA
—> regulate protein synthesis (enzymes, mediators)
—> Take time for full effect (hrs - days)

Effect on Eicosanoid production
1. **↑ Lipocortin (Annexin-1) synthesis —> **inhibit Phospholipase A2 —> ↓ cell membrane phospholipid -X-> Arachidonic acid —> ↓ Prostanoids

  1. ***↓ COX-2 induction —> ↓ Prostanoids

Effect on inflammatory response
3. ↓ Pro-inflammatory cytokines production (TNF-α, IL-1)
—> ***↓ vasodilatation, ↓ vascular permeability, ↓ expression of adhesion molecules

  1. ***Inhibit Macrophages and other APC function
    —> ↓ phagocytosis, ↓ cytokine production, ↓ T cell activation
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6
Q

***Arachidonic acid pathway

A

Cell membrane phospholipid
—(Phospholipase A2)—>
Arachidonic acid
1. —(Lipoxygenase)—> Leukotriene
2. —(COX-1: GI, platelets, kidneys)—> Prostanoid (TXA2 in platelet)
3. —(COX-2: inflammatory sites)—> Prostanoid

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7
Q

Synthetic glucocorticoids

A
  1. Hydrocortisone, Prednisolone
    - Short - Medium acting
  2. Cortisone, Prednisone
    - Pro-drug
    - converted to hydrocortisone and prednisolone in the liver by **11β-hydroxysteroid dehydrogenase type 1 (*11β-HSD1)
    - avoid in patients with impaired 11β-HSD1 activity (severe hepatic failure)
  3. Betamethasone, Dexamethasone
    - Long-acting
    - less common for oral therapy
    —> avoid adverse effects
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8
Q

Synthesis of glucocorticoid in the body

A

Hypothalamus: Corticotrophin-releasing factor CRF
—> Anterior pituitary: Adrenocorticotrophic hormone ACTH
—> Adrenal ***cortex:
1. Glucocorticoids (metabolic, anti-inflammatory, immunosuppressive)
2. Mineralcorticoids (peripheral actions on salt and water metabolism)

Glucocorticoid —(-ve feedback)—> Hypothalamus

Vasopressin / Anti-diuretic hormone (ADH) —(stimulate)—> Anterior pituitary

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9
Q

Physiological effect of glucocorticoids

A
  1. Direct actions in the cells
    - occur in response to threatening environment
  2. Permissive effects
    - permit / facilitate the actions of other hormones
    - occur primarily in the resting state
    - normal functions of cells become deficient in their absence
    —> **lipolytic reponses of fat cells to catecholamines (NA/A)
    —> **    vascular responses to catecholamines (NA)
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10
Q

***Metabolic effects of glucocorticoids

A
  1. Glucose: (maintenance of adequate glucose supply to the brain and heart: glucose-dependent tissues)
    - ↑ Gluconeogenesis (phosphoenolpyruvate carboxykinase, glucose-6-phosphatase, glycogen synthase)
    - ↓ Glucose uptake and utilisation (by translocation of glucose transporter from plasma membrane to intracellular)
  2. Protein:
    - ↑ Protein breakdown + ↓ Protein synthesis (amino acids for gluconeogenesis in liver)
  3. Lipid:
    - ↑ Lipolytic responses to various hormones (glycerol for gluconeogenesis in liver)
    - ***BUT subsequently ↑ blood glucose level —> ↑ insulin —> ↑ Lipogenesis —> fat re-distribution in the trunks (back of neck, face, supraclavicular area: less sensitive to glucocorticoid action)
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11
Q

***Effects of glucocorticoids on electrolyte and water balance

A

Calcium:
- **↓ Ca absorption from GI tract
- **↑ Ca excretion by the kidney
- ***inhibition of vitamin D activity in osteoblasts
—> bone loss

Water:
Maintain glomerular filtration rate —> facilitate water excretion by the kidney (due to permissive effects on tubular function)

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12
Q

***Other effects of glucocorticoids

A
  1. Enhance ***vascular reactivity to other vasoactive substances
    —> hypertension
  2. Affect ***neuronal survival and activity
    —> mood elevation, euphoria, insomnia, restlessness and ↑ motor activity
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13
Q

***Adverse effects of glucocorticoids

A

↑ risk with ↑ dose and ↑ duration

  1. Hyperglycaemia —> DM
    —> effects on carbohydrate metabolism
  2. Muscle wasting and weakness
    —> effects on protein metabolism
  3. Redistribution of fat
    —> effects on lipase activity and insulin secretion
  4. Osteoporosis
    —> effects on Ca metabolism
    —> inhibition of vitamin D activity in osteoblasts
  5. Insomnia, euphoria and depression
    —> effects on the nervous system
  6. Infections and peptic ulcer
    —> suppression of responses to infection
  7. Impaired wound healing
    —> suppression of responses to injury
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14
Q

Precautions with glucocorticoids

A

Children
- growth inhibition with chronic use

Pre-existing conditions
- diabetes
- peptic ulcer
- heart disease
- infectious illnesses
- psychoses
- osteoporosis
- hepatic dysfunction

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15
Q

Patients on long term glucocorticoid

A

Patients on long term glucocorticoid
—> suppress normal production of steroid by body
—> during adverse events such as surgery, medical illness, trauma
—> ***supplemental dose of glucocorticoid for patients must be given to save life

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16
Q

Withdrawal of glucocorticoids

A

**Adrenal insufficiency
- disturbances in fluid and electrolyte balance
- hypoglycaemia
- impaired responses to stress of illness / trauma
—> **circulatory shock and even death

Graded reduction of glucocorticoid therapy
- 2-12 months: recovery of adrenal function
- another 6-9 months for recovery of corticosteroid level
- close monitoring due to individual differences

17
Q

Choices with glucocorticoid therapy

A
  1. Duration of actions
    - ***Medium-acting glucocorticoid if large doses needed
  2. Route of administration
    - ***Topical preparation preferred for local therapy
    —> reduced systemic adverse effects
  3. Dosage regimen (for Large dose and Chronic treatment)
    - **Start at low dose —> then **lowest possible dosage by gradually lowering the dose —> reduced adverse effects
    - ***Alternate-day schedule (switch between NSAIDs and steroids) —> prevent suppression of adrenal functions
18
Q

Management of RA: DMARDs

A
  1. Modify disease activity
    - ***Retard the progress of bone and cartilage damage
    - achieve clinical remission + prevent irreversible damage to joints
  2. ***Act slowly
    - 2 weeks to 6 months
    - used in conjunction with anti-inflammatory drugs
  3. Diverse chemical structures
    - non-biological small molecules (conventional and targeted synthetic molecules)
    - biological agents (antibodies / binding proteins)
  4. Mechanisms of actions
    - conventional non-biological small molecules: not very clear —> long-term efficacy: controversial
    - **affects more basic inflammatory mechanisms than glucocorticoids or NSAIDs
    —> **    more toxic
19
Q

***Conventional Synthetic DMARDs (csDMARDs)

A
  1. Cytotoxic agents
    - Methotrexate —> Antimetabolite
    - Azathioprine / 6-MP —> Antimetabolite
    - Leflunomide
    - Cyclophosphamide —> Alkylating agent
  2. Sulfasalazine
  3. Antimalarial drugs
    - Chloroquine
    - Hydroxychloroquine
  4. Immunosuppressants
    - Cyclosporine —> Calcineurin inhibitor
    - Mycophenolate mofetil —> inhibit IMP dehydrogenase
  5. Gold (no longer recommended: toxicities vs efficacy)
    - Aurothiomalate
    - Auranofin
20
Q

Methotrexate

A
  • ***Folic acid analog (Antifolate)
  • Cytotoxic agent (CI in pregnancy)
  • Low dose —> treatment of RA

**MOA:
Block active site of **DHFR (dihydrofolate reductase)
—> Folate cannot be reduced to THF (active form)
—> inhibit **Nucleotide (Adenine, Guanine, Thymidine) + **Amino acid production (Methionine, Serine)

Effects:
1. Suppress inflammatory **functions of neutrophils, macrophages, dendritic cells and lymphocytes
2. Inhibit proliferation and stimulate **apoptosis of immune-inflammatory cells
3. Inhibit pro-inflammatory ***cytokines

Adverse effects:
1. GI disturbances, mucosal ulcers
2. Hypersensitivity reaction: Methotrexate lung
3. **Haematologic toxicity
4. **Hepatotoxicity (dose-related) —> regular liver function monitoring
5. Reduced by concomitant use of ***Leucovorin (folinic acid) / Folate

21
Q

Triple therapy for csDMARDs

A

Cytotoxic agents (Methotrexate)
+ Sulfasalazine
+ Antimalarial (Chloroquine / Hydroxychloroquine)

22
Q

Biological DMARDs (bDMARDs)

A
  1. TNF-α blocking agents
    - **Etanercept, **Infliximab, ***Adalimumab, golimumab, certolizumab
  2. IL-1 receptor antagonist
    - Anakinra
  3. IL-6 receptor antagonist
    - ***Tocilizumab
    - Sarilumab
  4. T-cell co-stimulation modulator
    - ***Abatacept (contain CTLA-4)
  5. B-cell cytotoxic agent
    - ***Rituximab (Anti-CD20) —> Complement activation (MAC) + ADCC

Indication:
- moderate to severe RA not responded adequately to >=1 traditional DMARDs

Precaution:
1. T-cell co-stimulation modulator / B-cell cytotoxic agent / IL-1 receptor antagonists
—> NOT recommended to use in combination with TNF inhibitors
—> ↑ risk of infection
2. Increase risk of ***TB infection

23
Q

T-cell co-stimulation modulators

A

Abatacept:
contains endogenous ligand CTLA-4
—> **binds to CD80 and CD86 of APC
—> compete with CD28 on T-cell
—> **inhibit T-cell binding to APC via CD28
—> prevent activation of T-cell

Administration:
***IV infusion over 30 mins (once every 2 weeks x3, followed by monthly infusions, t1/2 = 13 days)

Adverse effects:
1. Infusion and **hypersensitivity reactions
2. Modest ↑ risk for **infection (greater risk with TNF inhibitors and with Anakinra —> combination not recommended)

24
Q

TNF-α blocking agents and IL-1 receptor antagonist

A

Block actions of **TNF-α and **IL-1

***Prevent:
1. Vasodilatation
2. ↑ Vascular permeability
3. Expression of adhesion molecules

25
Q

Adverse effects of biological DMARDs

A
  1. ***↑ Susceptibility to infections (esp. TB infection)
  2. ***Bone marrow suppression / haematologic toxicity (leukopenia, anaemia, thrombocytopenia, neutropenia)
  3. GI disturbance
  4. Allergic / Hypersensitivity reactions
  5. Injection site irritation
26
Q

Targeted Synthetic DMARDs (tsDMARDs)

A

Janus-activated Kinase / JAK Inhibitors (***Tofacitinib, Baricitinib)

Mechanism:
Binds to ATP binding site of catalytic domain of JAK
—> inhibit Janus-activated kinase (JAK)
—> ↓ signaling by **IFN and **IL-6

Characteristics:
- Orally bioavailable
- Indicated for patients with inadequate responses to 1 or more DMARDs

Precaution:
- Drug interactions
—> Tofacitinib: metabolised by CYP3A4
—> Baricitinib: metabolised by organic anion transporter 3

Adverse effects:
1. ↑ risk of **infection (esp. Herpes virus due to inhibition of Type 1 interferons —> consider zoster vaccination prior to treatment)
2. ↑ risk of **non-melanoma skin cancer
3. ↑ plasma level of **liver enzymes (liver function monitoring)
4. ↑ plasma level of **lipoprotein (LDL and HDL)
5. GI perforation
6. Potential risk of ***anaemia, leukopenia, neutropenia, lymphopenia, thrombocytopenia (due to many haematopoietic growth factors including erythropoietin and granulocyte macrophage-colony stimulating factor signaling through JAK phosphorylation)

27
Q

General therapeutic strategies against arthritis

A
  1. ↓ Pain (analgesia)
    - Paracetamol, NSAIDs
  2. ↓ Inflammation
    - NSAIDs, Glucocorticoids
  3. ↓ Progression of joint problem
    - DMARDs, Glucocorticoids

MSS (32 decks)

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