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204: Theme 1 - Immunology > Pharmacological aspects of Immunology > Flashcards

Pharmacological aspects of Immunology Flashcards

1
Q

What are the NSAIDs groups?

(6)

A
  • Aspirin
  • Propionic acid derivatives - e.g. ibuprofen, naproxen
  • Arylalkanoic acids – e. g indometacin, diclofenac
  • Oxicams - e.g. piroxicam
  • Fenamic acids - e.g. mefanamic acid
  • Butazones - e.g. phenylbutazon
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2
Q

Explain the Eicosanoid pathways

  • what are their end products and their clinical relevance? (4)
A
  • Leukotrienes: bronchial constriction
  • Thromboxanes: platelet aggregation, vasoconstriction
  • Prostaglandins: bronchial tone, vascular tone, hyperalgia
  • Prostcyclins: vasodilation
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3
Q

What effect does NSAID’s have on the Eicosanoid pathway

A
  • NSAID’s are non-specific inhibitors of the cyclooxygenase pathway
  • this irreversibly binds the enzymes to prevent prostaglandin synthesis
  • therefore the tissue-specific synthases are not produced
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4
Q

What is the mechanism of action of NSAIDs?

(3)

A
  • All inhibit cyclo-oxygenase
  • Three isoforms
    • COX-1 - Constitutive expression – all tissues
      • Stomach, Kidney, Platelets, Vascular endothelium
      • Inhibition → anti-platelet activity, also side effects
    • COX-2 – Induced in inflammation (IL-1)
      • Injury, infection, neoplasia
      • Inhibition → analgesia and anti-inflammatory actions
    • COX-3 – CNS only?​
      • May be relevant to paracetamol
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5
Q

What are the indications for NSAID therapy?

A
  • Short-term management of pain (and fever)

As mild analgesics (orally and topically)

  • mechanical pain of all types
  • minor trauma
  • headaches, dental pain
  • dysmenorrhoea

As potent analgesics (orally, parenterally, rectally)

  • peri-operative pain
  • ureteric colic
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6
Q

Where is NSAID useful as an anti-inflammatory agent?

A
  • Gout
  • Inflammatory arthriitis: ankylosing spondylitis, rheumatoid arthritis
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7
Q

What are the indications for Aspirin?

  • why might the use be limited?
A
  • Limited in use for pain and inflammation limited by
    • GI toxicity
    • Tinnitus – mechanism obscure, usually reversible
    • Reye’s syndrome (fulminant hepatic failure in children)
  • Mainly used for its Anti-platelet effect
    • Primary and secondary prevention eg stroke and MI
    • Treatment of acute MI and stroke
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8
Q

Explain how NSAID produces GI toxicity (3)

  • what are the presenting effects?
A
  • In the GI tract prostaglandins E2 and I2
    • Decrease acid production
    • Increase mucus production
    • Increase blood supply
    • as NSAID’s inhibit this, all the above is reversed
  • NSAID inhibition in stomach and duodenum
    • Irritation
    • Ulcers (gastric 15-30%, duodenal 10%)
    • Bleeding
  • Similar effect in the colon
    • Colitis – esp with local preps e.g. rectal diclofenac
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9
Q

What is the risk of NSAID GI toxicity

A
  • Upper GI bleeding
    • Relative Risk 4.7 all users
    • Azapropazone = 23.4
    • Piroxicam = 18.0
    • Small differences between others…
  • Biggest risk factor for GI bleed = previous GI bleed
    • Age
    • Chronic disease (e.g.rheumatoid disease)
    • Steroids
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10
Q

Explain how NSAIDs cause nephrotoxicity

  • contraindications to avoid this
A
  • Primarily related to changes in glomerular blood flow
    • Decreased glomerular filtration rate
    • Sodium retention
    • Hyperkalaemia
    • Papillary necrosis
  • Acute renal failure 0.5-1%
  • Avoid or dose adjust in renal failure
  • Avoid in patients likely to develop renal failure
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11
Q

What is the relationship between asthma and Aspirin?

A
  • About 10% of asthmatics experience bronchospasm following NSAID
  • perhaps because of arachidonic acid is shunted down the 5LPO pathway when COX is inhibited so more leukotrienes are produced
    • leukotrienes cause bronchial constriction
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12
Q

How can NSAID toxicity be prevented?

(4)

A
  • Is an NSAID the answer (paracetamol, opioids, COX2 inhibitor, non-pharmacological?)
  • Consider risk factors eg age, renal impairment, previous peptic ulcer disease
  • Avoid or dose adjust in renal impairment
  • Consider co-administration of gastroprotection with proton pump inhibitor
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13
Q

How is Paracetamol metabolised?

A
  • Phase 1 oxidation reaction (induced by enzyme inducers e.g alcohol)
    • NAPQI
  • Phase 2 conjugation reaction (following phase 1)
    • NAPQI-glutathione –> excreted
    • these pathways can easily be oversaturated leading to overdose after a few extra pills
  • Direct Phase 2 conjugation
    • paracetamol sulphate and glucuronide –> excreted
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14
Q

What is the treatment for paracetamol overdose?

A
  • N-acetylcysteine (glutathione precursor) used in paracetamol poisoning
    • enables NAPQI to be harmlessly removed
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15
Q

What are Selective COX-2 Inhibitors?

  • what are they used for
  • risk/indication
A
  • Selective inhibition of COX-2 in vitro and in vivo
  • Anti-inflammatory and analgesic in humans
  • Objective evidence of selectivity (GI, platelets) at > anti-inflammatory doses
  • Comparable efficacy (not superior) to non-selective NSAIDs in
    • Acute pain
    • Dysmenorrhoea
    • Inflammatory joint disease
  • Controversy due to apparent increased risk of MI – but may have been a result of an absence of antiplatelet effect
  • Currently only recommended in high-risk patients and after a cardiovascular risk assessment
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16
Q

What are the side effects of COX-2 Inhibitors?

A
  • has GI-side effects but has a relatively lower risk compared to NSAIDs
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17
Q

What are corticosteroids?

  • example
  • action (6)
A

Cortisol (hydrocortisone) – predominant endogenous glucocorticoid

  • Carbohydrate and protein metabolism
  • Fluid and electrolyte balance (mineralocorticoid effects)
  • Lipid metabolism
  • Psychological effects
  • Bone metabolism
  • Profound modulator of immune response
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18
Q

What is the biological effect o corticosteroids?

A
  • Steroids reduce immune activation by altering gene expression in numerous cell types,
    • including T cells, B cells and cells of the innate immune system.
  • Their onset of action is delayed and they must be taken regularly
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19
Q

What are the immunomodulatory effects of steroids?

  • cell trafficking (2)
  • cell function (7)
  • don’t effect (2)
A
  • Cell trafficking
    • Lymphopenia, monocytopenia (redistribution)
    • Neutrophilia and impaired phagocyte migration
  • Cell function
    • T cell hyporesponsiveness
    • Inhibited B cell maturation
    • Decreased IL1, IL6 and TNFa production (monocytes)
    • Widespread inhibition of Th1 and Th2 cytokines
    • Inhibition of COX - prostaglandins
    • Impaired phagocyte killing
    • ↓collagenases, elastases etc
  • Don’t effect
    • Immunoglobulin levels
    • Complement
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20
Q

What is the clinical use/ indication cor corticosteroids?

  • types of preparations
A
  • To suppress inflammation of all kinds, particularly in acute disease but also in maintenance therapy
    • Asthma, Crohn’s / UC, Eczema, Multiple sclerosis, Sarcoid, allergy, rheumatoid arthritis, systemic lupus erythematosus etc etc
  • Replacement therapy in hypoadrenalism
    • _​_hydrocortisone used
  • Myriad preparations, and also routes
    • Systemic (oral and parenteral)
    • Topical (skin, joint injections, inhaled, enteric-coated, rectal)
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21
Q

What are the five key Corticosteroid drugs to remember?

  • what are their potency
  • lipid solubility
  • systemic vs topical use
A
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22
Q

What are the Early side effects of steroid therapy?

(4)

A
  • Weight gain
  • Glucose intolerance
  • Mood change
  • Suppression of ACTH release
23
Q

What are the Late side effects of steroid therapy?

(7)

A
  • Proximal muscle weakness
  • Osteoporosis
  • Skin changes
  • Body shape changes
  • Hypertension
  • Cataracts
  • Adrenal suppression
24
Q

How do corticosteroids affect the adrenal system?

  • How is this managed?
A
  • High-dose exogenous corticosteroids suppress endogenous production within 1 week
    • _​_clinical effects not seen until later
  • After prolonged therapy adrenal cortex begins to atrophy and endogenous production takes some time to recover upon cessation
  • Abrupt withdrawal below replacement dose reduces the ability to deal with physiological stress – eg infection – and may precipitate an adrenal crisis
    • Steroid warning card
    • Tail dose slowly
    • Increase dose during acute illness and prior to surgery
25
Q

Link between infection and corticosteroid use

A
  • Risk is related to cumulative dose
  • Phagocytic defects (risk occurs early on)
    • Bacterial infection – S. aureus, enteric bacteria etc
    • Fungal infection – candida, aspergillus
      • candida using inhalers - rinse mouth after use
  • Cell-mediated defects (risk occurs later on)
    • Intracellular pathogens
    • TB
    • Varicella
    • Listeria
    • Pneumocystis
26
Q

What are Disease-modifying anti-rheumatic drugs (DMARDS)?

A
  • diverse group of drugs that target the immune system
  • Derive name from use in rheumatoid arthritis, but also used in
    • transplantation and myriad other autoimmune and inflammatory disorders
      • _​_chronic urticaria, eczma, psoriasis
    • also sometimes (in higher doses) for cancer chemotherapy
27
Q

How are Disease-modifying anti-rheumatic drugs (DMARDS) distinguished from other drug classes

  • NSAID
  • Steroids
  • Biologics
A
  • NSAIDS: despite name, not disease-modifying
  • Steroids: the idea of DMARDS is that they’re ‘steroid-sparing’
  • Biologics: newer class of drugs resembling naturally-occurring molecules
28
Q

Give examples of Disease-modifying anti-rheumatic drugs (DMARDS)

(3)

  • what are their actions, indications
A
  • Methotrexate: competitive inhibitor of dihydrofolate reductase (DHR)
    • anti-folate action which is needed for purine synthesis in DNA
    • reduces T cell activity
    • used in Rheumatoid arthritis, Psoriasis, Chrons disease
  • Azathioprine: Inhibits thiopurine S methyltransferase (TPMT)
    • also inhibits purine synthesis
    • similar indications to methotrexate, more widely used in transplantation
  • Ciclosporin: Inhibits calcineurin which in turn reduce T lymphocyte activity
    • similar indications to aza/metho
    • used in more dermatology and transplantation
29
Q

What is Ciclosporin?

  • action
  • indication
  • toxicity
A
  • Inhibits calcineurin, which in turn reduces T lymphocyte activity

Main indications

  • more widely in dermatology and transplantation
  • Rheumatoid arthritis, Psoriasis, Crohns disease

Main toxicities

  • Hepatotoxicity
  • Nephrotoxicity
  • Gum hyperplasia
  • Hirsutism

NOTE tacrolimus (newer formulation) is easier to take and tolerate, and available for topical use (esp eczema)

30
Q

What is Azathioprine?

  • action
  • indication
  • toxicity
A
  • Inhibits thiopurine S methyltransferase (TPMT), also inhibits purine synthesis
    • Folate needed for purine synthesis in DNA
    • This reduces T cell activity

Main indications

  • more widely in transplantation
  • Rheumatoid arthritis, Psoriasis, Crohn’s disease

Main toxicities

  • GI upset very common when starting
  • Hepatotoxicity
  • Leucopenia
  • Pulmonary fibrosis
  • Teratogenic
31
Q

What is Methotrexate?

  • action (4)
  • indication
  • toxicity
A
  • Competitive inhibitor of dihydrofolate reductase (DHR), therefore anti-folate action
    • Folate needed for purine synthesis in DNA
    • This reduces T cell activity, and also (in higher doses) tumour synthesis
  • Increases adenosine level (anti-inflammatory)
  • Reduces the production of damaging polyamines
  • Induces apoptosis of activated CD4+ and CD8+ T-cells

Main indications

  • Rheumatoid arthritis
  • Psoriasis
  • Crohns disease

Main toxicities

  • Hepatotoxicity
  • Leucopenia
  • Pulmonary fibrosis
  • Teratogenic

NOTE weekly dosing; errors have caused major toxicity

32
Q

What are therapies for rheumatoid arthritis (RA)

  • most effective?
A
  • Anti-inflammatory drugs: Symptoms relief
    • Non-steroidal anti-inflammatory drugs (NSAIDs)
    • Steroidal anti-inflammatory drugs (glucocorticoids)
  • Disease-modifying anti-rheumatic drugs (DMARDs): Slow the clinical and radiographic progression of RA
    • Synthetic DMARDs: MTX, sulfasalazine, hydroxychloroquine, leflunomide
    • Targeted synthetic DMARDs: JAK inhibitors- tofacitinib, baricitinib
    • Biologic agents (biologicals): TNF-blockers (most effective)
      • Drugs targeting IL-1, IL-6 , B-cells and T-cells
33
Q

Give more detail on the clinical use and action of Methotrexate

A
  • “Anchor drug” in combination therapies
  • Reduces inflammation quickly and keeps it under tight control
  • Reduces the risk of death from cardiovascular disease in people with RA
  • Taking supplements of folic acid reduces side-effects caused by folic acid depletion
34
Q

What are the adverse effects of synthetic DMARDs

  • what is a synthetic DMARD
A
    • Methotrexate, Hydroxychloroquine, Leflunomide are synthetic DMARDs
      • Hydroxychloroquine: accumulation of a drug in the eye –> retinopathy
      • Leflunomide- hypertension
  • Nausea, Loss of appetite
  • Diarrhoea
  • Rash, allergic reactions
  • Headache
  • Hair loss
  • Risk of infections (pneumonia)
  • Hepatotoxicity (metabolism), Nephrotoxicity (route of elimination)
35
Q

Give examples of targeted synthetic DMARDs (2)

  • action
  • indication
A

used in moderate-to-severe active RA in patients who have had an inadequate response to, or are intolerant to one or more DMARDs (as monotherapy or in combination with MTX): more effective

  • Tofacitinib
    • selectively inhibits the JAK1 and JAK3
    • also used in psoriatic arthritis and UC
  • Baricitinib
    • selectively and reversibly inhibits JAK1 and JAK2
36
Q

What are adverse effects of targeted synthetic DMARDs?

A
  • Tofacitinib
    • Anaemia, cough,
    • diarrhoea,
    • fatigue, fever,
    • gastrointestinal discomfort, increased risk of infection
  • Baricitinib
    • Dyslipidaemia, herpes zoster,
    • increased risk of infection,
    • nausea,
    • oropharyngeal pain,
    • thrombocytosis
37
Q

What are biologics?

  • give an example of biologics treatment
A
  • therapeutic treatment derived or synthesised from biological sources
  • Anti-TNF-alpha antibody: in treating Rheumatoid Arthritis
38
Q

What is the role of TNF in the inflammatory cascade of Rheumatoid Arthritis?

A
  • TNF hyperactivity
    • results in high-levels IL-1
  • TNF blockers reduces these effects
39
Q

What are the targets of biologic agents in RA?

40
Q

When are biological therapies indicated?

A
  • Patient has failed to respond to treatment with at least two standard (synthetic) DMARDs,
    • one of which must be MTX (unless the patient cannot take MTX for medical reason)
  • Patient’s RA _disease activity score (DAS 28) is measured as 5.1 o_r over, on two occasions, one month apart
41
Q

What are the currently licensed biologics for the treatment of RA in the UK?

(4)

A
  • TNF-blockers: infliximab, etanercept, adalimumab, golimumab, certolizumab pegol
  • Monoclonal antibody against B cells: rituximab
  • T cell co-stimulation inhibitor: abatacept
  • Monoclonal antibodies against IL-6R: tocilizumab, sarilumab
42
Q

What are the TNF-blockers? (5)

  • how are they best applied
A
  • Infliximab – partially humanized mouse monoclonal anti-hTNF-a antibody
  • Etanercept – soluble TNF receptor dimer
  • Adalimumab – human IgG1 monoclonal anti-TNF-a antibody
  • Golimumab – human IgG1 monoclonal anti-TNF-a antibody
  • Certolizumab pegol – PEGylated anti-TNF-a monoclonal antibody fragment
  • combined with MTX, they give excellent joint protection
43
Q

What is Infliximab

  • mechanism
  • used in?
  • NICE
A
  • Partially humanized mouse monoclonal anti-human TNF-a antibody
    • chimeric antibody
  • Neutralizes free, membrane and receptor-bound TNF-a → antibody-dependent cell-mediated cytotoxicity (ADCC)
  • Treats RA and
  • Also used for the treatment of Crohn’s disease, ulcerative colitis, plaque psoriasis, ankylosing spondylitis
  • NICE only approves infliximab, if combined with MTX
44
Q

What is Etanercept

  • mechanism
  • used in?
A
  • Extracellular domain of the hu p75 TNFR fused with the Fc domain of hu IgG1
    • Binds free and membrane-bound TNF, reducing the accessible TNF in Rheumatoid Arthritis → ADCC
    • it’s a soluble TNF receptor dimer
  • Used in RA
  • Also used for the treatment of juvenile idiopathic arthritis, plaque psoriasis, psoriatic arthritis, ankylosing spondylitis
45
Q

What are the two fully human anti-TNF-alpha mAbs?

  • used in?
A

Adalimumab

  • treating RA
  • Also used in juvenile idiopathic arthritis, plaque psoriasis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease

Golimumab

  • treating RA
  • In combination with MTX
  • Also used in psoriatic arthritis, ankylosing spondylitis
  • Longer half-life
46
Q

What is Certolizumab pegol?

  • mechanism
  • used in?
  • what is peg?
A
  • PEGylated Fab’ fragment of humanized anti-TNF-a mAb – no Fc portion
  • used to treat RA
  • Also used for the treatment of Chron’s disease

Polyethylene glycol: When covalently attached to drugs, it reduces antigenicity/ immunogenicity prolongs the circulatory time of the drug

47
Q

What is considerations made before anti-TNF therapy?

  • what are the side effects?
  • course of treatment
A
  • Patients screened before starting treatment to exclude an increased risk of side effects, in particular for
    • a past history of tuberculosis (TB),
    • multiple sclerosis,
    • recurrent infection,
    • leg ulcers
    • and a past history of cancer
  • Chest X-ray to be taken to exclude signs of previous TB and to exclude signs of heart failure
  • Increased risk of infections, reactivation of TB
  • cancer can be worsened
  • Live vaccines, against e.g. yellow fever or polio, should be avoided
  • Anti-TNF therapy can be administered for as long as 10 years.
  • Patients can stay on the drug for as long as they continue to respond well to it
48
Q

What is Rituximab

  • mechanism
  • used in
A
  • partially humanized anti-CD20 mAb
  • Rituximab opsonized B-cells are attacked and killed by three mechanisms:
  • 1)Complement mediated cytotoxicity
  • 2-3) Antibody-dependent cell-mediated cytotoxicity (ADCC) – FcgR or CR mediated opsonic phagocytosis
  • 4) Apoptosis of B cell
  • used to treat RA and in the treatment of SLE
49
Q

What is Abatacept

  • mechanism
  • used in?
A
  • CTLA-4/ hu IgG1 soluble receptor fusion protein
    • acts as a T-cell co-stimulation inhibitor
  • Competitive inhibitor of CD28
  • Increases threshold for T-cell activation
  • Suppresses the proliferation of synovial recirculating T cells
  • Reduces the level of inflammatory mediators
  • used in treating RA
50
Q

What are two IL-6R inhibitors?

  • mechanism
  • used in?
A
  • Tocilizumab: humanized anti-IL-6 receptor monoclonal antibody
    • Also used in systemic juvenile idiopathic arthritis
    • Intravenous infusion 8 mg/kg of body weight
  • Sarilumab: fully human monoclonal antibody against IL-6Ra
    • 200 mg once every two weeks, administered as a subcutaneous injection
  • used in patients with critical covid-19 infection
51
Q

What is Anakinra?

  • mechanism
  • used in
A
  • Recombinant IL-1ra- acts an IL-1R antagonist
  • Differs from native human IL-1ra: it has the addition of a single methionine residue at its amino terminus
  • In RA:
    • Reduces bone erosion
    • Decreases osteoclast production
    • Blocks IL-1-induced MMP release from synovial cells
  • Not used in the UK to treat RA, but licensed in the US
52
Q

What are the adverse effects of biological therapies?

  • contraindications?
A
  • Increased risk of infections:
    • Upper respiratory tract infections (nasopharyngitis)
    • Pneumonia
    • Urinary tract infections
    • It is recommended to receive influenza and pneumococcal vaccines before embarking on biological therapy
      • Avoid live vaccines
  • Nausea
  • Headache
  • Hypertension
  • Allergic reactions

​Contraindicated in pregnancy and while breastfeeding (rituximab, tocilizumab, sarilumab, abatacept, anakinra)

53
Q

Review the biologics used in Rheumatoid Arthritis

204: Theme 1 - Immunology (13 decks)

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