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BSMS 204- Theme 1 > Lecture 16- Pharmacological aspects of Immunology > Flashcards

Lecture 16- Pharmacological aspects of Immunology Flashcards

1
Q

NSAIDS:

A

Large chemically diverse family of drugs

  • Aspirin
  • propionic acid derivates- ibuprofen, naproxen
  • Arylalkanoic acid- piroxicam
  • Oxicams- piroxicams
  • Fenemic acid- mefanamic acid
  • Butazones- phenylbutazones
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2
Q

which pathways does the NSAIDs work on?

A

Eicosanoid pathways

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3
Q

Describe the mechanism of action of NSAIDs?

A

arcachidonic acid—->prostaglandins H2 via Cox enzyme

  • NSAID block this enzyme
  • Preventing the building up of:
  • thromboxanes
  • Prostaglandins
  • Prostacyclins
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4
Q

Explain the function of Thromboxanes, prostaglandins, and prostacyclins?

A 
Thromboxanes: -Platelet aggregation and vasoconstriction
-Prostaglandins: 
Bronchial tone
vascular tone and hyperalgesia
-Prostacyclins:
Vasodilation
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5
Q

Which COX enzymes does the NSAID block and what is the normal function?

A 
COX-1: all tissues express it- stomach, kidney, platelets, vascular endothelium
Inhibition: antiplatelet activity
-COX-2: Induced inflammation (IL-1)
caused by:
injury, infection and neoplasia
Inhibition: Analgesia and anti-inflammatory actions
COX-3: CNS only?
May be relevant to paracetamol only
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6
Q

what are the indication for NSAID therapy?

A

Short-term management of pain (and fever) and anti-inflammation

1) As mild analgesics (orally and topically):
- mechanical pain of all types
- minor trauma
- headaches, dental pain
- dysmenorrhoea
2) As potent analgesics (orally, parenterally, rectally)
- peri-operative pain
- ureteric colic

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7
Q

Why has aspirin is no longer used for pain-relief and inflmmation?

A

Use for pain and inflammation limited by

  • GI toxicity
  • Tinnitus – mechanism obscure, usually reversible
  • Reye’s syndrome (fulminant hepatic failure in children)
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8
Q

What are the current uses of aspirin?

A

Anti-platelet effect:

  • Primary and secondary prevention eg stroke and MI
  • Treatment of acute MI and stroke
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9
Q

How is GI toxicity caused by NSAIDS?

A

In the GI tract prostaglandins E2 and I2:
-Decrease acid production
-Increase mucus production
-Increase blood supply
NSAIDS block the production of prostaglandins

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10
Q

what is the consequences of NSAID use on the stomach and dueodenum and colon?

A
  • Irritation
  • Ulcers (gastric 15-30%, duodenal 10%)
  • Bleeding
  • Colitis: esp with local preps
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11
Q

Which NSAIDs have the highest risk for upper GI bleeds?

A

1) Azapropazone = 23.4
2) Piroxicam = 18.0
Small differences between others…

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12
Q

what is the biggest risk factor for the GI bleeds and what are the other risk factors?

A

1) Biggest risk factor for GI bleed = previous GI bleed
Other risk factors:
-Age
-Chronic disease (e.g.rheumatoid disease)
-Steroids

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13
Q

How does the NSAIDS cause the nephrotoxicity?

A

Primarily related to changes in glomerular blood flow causing:

1) Decreased glomerular filtration rate
2) Sodium retention
3) Hyperkalaemia
4) Papillary necrosis

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14
Q

How does aspirin cause bronchospasm?

A

-Due to increased production of leukotrienes

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15
Q

How can the NSAID toxicity be prevented?

A
  • Use of NSAID esstential? alternatives?
  • Consider other risk factors
  • Give with a PPI (gastroprotection)
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16
Q

Which NSAIDS to use?

A

From least to Most risk of SE:

Ibuprofen>Naproxen>Diclofenac>Indometacin

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17
Q

Describe paracetamol use and mechanism of action?

A

-Not NSAID
-Minimal anti-inflammatory
-Good analgesic/antipyretic
-very well tolerated
-Mechanism of action not well understood:
does not bind to CoX-1 or 2- weak inhibitor
-May Inhibit COX-3
-Dangerous in overuse

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18
Q

Describe the metabolism of paracetamol?

A

Normal metabolism:

Paracetamol………….>Paracetamol sulphate and glucuronide via phase II conjugation reaction and excreted

19
Q

Describe the metabolism of paracetamol in an overdose?

A

Paracetamol converted to N-acetyl–p-benzoquinoneimine
(NAPQI) via phase I oxidation reaction causes hepatic necrosis
NAPQI goes through phase II conjugation reaction to form: NAPQI - glutathione
which is then excreted

20
Q

What is the treatment option in paracetamol poisoning?

A

-N-acetylcysteine (glutathione precursor) used in paracetamol poisoning

21
Q

Describe the use of selective COX-2 inhibitors?

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
22
Q

Are the selective COX-2 inhibitors better than NSAIDs?

A
  • COX-2 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 absence of anti-platelet effect
23
Q

Why is the COX-2 superior than NSAIDS?

A

-Rates of GI SE and peptic ulceration low

24
Q

Describe the functions of cortisol?

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

25
Q

Describe the mechanism of action for cortiscosteriods?

A
  • Steroid receptors are bound to heat shock protein HSP90
  • Steroid crosses the cell membrane and bind to the steroid receptor releasing HSP90
  • The steroid receptor complex can now leave the cross the nuclear membrane
  • In the nucleus, steroid receptor binds to specific gene regulatory sequence and activates transcription
26
Q

Describe immunomodulation caused by steroids?

A

1) Cell trafficking
-Lymphopenia, monocytopenia (redistribution)
-Neutrophilia and impaired phagocyte migration
2) Cell function
-T cell hyporesponsiveness
-Inhibited B cell maturation
-Decreased IL1, IL6 and TNFa production (monocytes)
-Widespread inhibition of Th1 and Th2 cytokines
I-nhibition of COX - prostaglandins
-Impaired phagocyte killing
-↓collagenases, elastases etc

27
Q

What does the steroid not affect?

A
  • Immunoglobulin levels

- Complement

28
Q

what are the clinical uses for the steroid use?

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 erythematosis etc etc
-Replacement therapy in hypoadrenalism

29
Q

Describe the preparation and routes for the steroid use?

A
  • Systemic (oral and parenteral)

- Topical (skin, joint injections, inhaled, enteric coated, rectal)

30
Q

What are the early SE of steroid therapy?

A

Early:

  • Weight gain
  • Glucose intolerance
  • Mood change
  • Suppression of ACTH release
31
Q

What are the late SE of steroid use?

A

Later:

  • Proximal muscle weakness
  • Osteoporosis
  • Skin changes
  • Body shape changes
  • Hypertension
  • Cataracts
  • Adrenal suppression
32
Q

Describe the adrenal suppression during corticosteroid therapy?

A
  • High dose exogenous steroids suppress endogenous production within 1 week
  • After prolonged therapy, the adrenal cortex begins to atrophy and endogenous production takes some time to recover upon cessation
33
Q

What are the consequences of abrupt withdrawal of steroids after prolonged use?

A

-Abrupt withdrawal below replacement dose reduces ability to deal with physiological stress – eg infection – and may precipitate an adrenal crisis

34
Q

How can the adrenal crisis be prevented?

A

-Steroid warning card
Tail dose slowly
Increase dose during acute illness and prior to surgery

35
Q

Explain the risk of infection due to steroid use?

A

-Risk is related to cumulative dose
-Phagocytic defects
Bacterial infection – S. aureus, enteric bacteria etc
Fungal infection – candida, aspergillus
These are risk factors in early use of steroids

36
Q

Explain the infection risk of prolonged use steroid which occurs later?

A 
-Cell mediated defects
Intracellular pathogens 
TB
Varicella
Listeria
Pneumocystis
37
Q

Explain what DMARDs are?

A
  • A diverse group of drugs that target the immune system
  • Derive name from use in rheumatoid arthritis,
  • Also used in transplantation and other autoimmune and inflammatory disorders;
  • for cancer chemotherapy (higher doses)
38
Q

Describe the mechanism of action of methotrexate?

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
39
Q

What are the main indications for the methotrexate use?

A
  • Rheumatoid arthritis
  • Psoriasis
  • Crohns disease
40
Q

Describe main toxicities caused by methotrexate?

A
  • Hepatotoxicity
  • Leucopenia
  • Pulmonary fibrosis
  • Teratogenic
41
Q

Describe the mechanism of action of azathioprine and uses?

A
  • Inhibits thiopurine S methyltransferase (TPMT): inhibits purine synthesis
  • Similar indications to methotrexate;
  • more widely used in transplantation compared to methotrexate
42
Q

Describe the toxicities caused by azathioprine use?

A

Toxicities similar to methotrexate; GI upset very common when starting

43
Q

Describe the mechanism of ciclosporin and its uses?

A
  • Inhibits calcineurin, which in turn reduces T lymphocyte activity
  • Similar indications to aza/ metho, but used more in Dermatology and transplantation
44
Q

What are the main toxicities of ciclosporin?

A
  • Nephrotoxic
  • Hepatotoxic
  • Gum hyperplasia
  • Hirsuitism

BSMS 204- Theme 1 (21 decks)

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