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BIOL21351 > Lecture 6 - Therapeutics for inflammation > Flashcards

Lecture 6 - Therapeutics for inflammation Flashcards

1
Q

H1 receptor antagonists: what is the difference between H1 and H2, what do they do, how many generations are there, what side effects, and what happens when it is injected intradermally?

A

H1 - inflammation
H2 - homeostatic

  • Inflammation
  • release of proinflammatory mediators
  • activation of eosinophils
  • expression of adhesion molecules

first, second and third-generation

Sedation, peripheral antimuscarinic

We observe the triple response (red, wheal flare), including vasodilation of the small arterioles and precapillary sphincters and an increase in vascular permeability. We know that histamine has a role in other areas too – release of proinflammatory mediators, eosinophil activation and expression of adhesion molecules

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2
Q

NSAIDs - prostaglandins: what are they and what do they do?

A

Non-steroidal anti-inflammatory drugs - Don’t have a direct effect on the inflammatory process - they suppress the signs and symptoms by inhibiting the binding of arachidonate to COX enzymes

  • Anti-inflammatory: decrease in PGE2 and PGI2. Indirect inhibition of oedema
  • Analgesic: decreased PG synthesis results in less sensitisation of nociceptors to bradykinin and 5-HT
  • Anti-pyretic: IL-1 releases PGEs in the CNS > elevate hypothalamic set point.
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3
Q

COX: what forms are there, what do they do, and what do the drugs against them do?

A

COX-1 - constitutively (always) produced and expressed in most cells including platelets, role in homeostasis, GI protection, renal blood flow, and platelet aggregation

COX-2 induced in inflammatory cells

Drugs against COX-1 result in increased acid secretion and decreased blood flow to the stomach & kidneys

Drugs against COX-2 result in decreased vasodilation and oedema

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4
Q

Classification of NSAIDs

A

COX-1 inhibitors are specific for COX-1 (low-dose aspirin)

COX-2 inhibitors are specific for COX-2 (meloxicam)

Highly selective COX-2 inhibitors are specific for COX-2 (celecoxib, etoricoxib)

Non-selective COX inhibitors, (ibuprofen, indometacin, and high-dose aspirin)

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5
Q

How do COX-enzymes bind with arachidonate?

A

Both COX-1 and COX-2 have a hydrophobic channel which allows arachidonate binding, causing the typical cascade of reactions

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6
Q

How do COX inhibitors inhibit COX enzymes?

A

COX inhibitors bind to COX-1, inhibiting its binding with arachidonate

COX-2 inhibitors can also bind to its ‘side pocket’, inducing a conformational change, preventing arachidonate binding

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7
Q

Gastrointestinal adverse effects of NSAID use and their mechanism

A
  • Gastric ulceration - due to inhibited gastric mucosa blood flow
  • Discomfort
  • Nausea
  • Diarrhoea
  • Ulceration
  • Bleeding

Chemical irritancy, gastric acid reflux, loss of homeostatic PGs, ischaemia, and gastric mucosa breakdown

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8
Q

Renal adverse effects of NSAID use and their mechanism

A
  • Fluid retention
  • Electrolyte disturbance
  • Renal failure

Loss of homeostatic PGs

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9
Q

Cardiovascular adverse effects of NSAID use and their mechanism

A
  • Exacerbation of hypertension
  • Exacerbation of congestive heart failure

Secondary to renal disturbances

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10
Q

Pulmonary adverse effects of NSAID use and their mechanism

A
  • Exacerbation of asthma

Loss of homeostatic PGs, increase in leukotriene production

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11
Q

Haematological adverse effects of NSAID use and their mechanism

A
  • Hemorrhage

Decreased TXA₂ production

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12
Q

What does aspirin do?

A

Irreversibly inhibits COX enzymes for the lifetime of platelet (~10 days)

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13
Q

Glucocorticoids: what are they and what do they do?

A

Inhibit phospholipase A2 and induction of cyclo-oxygenase

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14
Q

5-lipoxygenase inhibitors: what are they and what do they do?

A
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15
Q

TXA2 synthase inhibitors: what are they and what do they do?

A
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16
Q

PG antagonists: what are they and what do they do?

A
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17
Q

Leukotriene receptor antagonists: what are they and what do they do?

A

Inhibits LTD4

Montelukast - used to treat asthma

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18
Q

PAF agonists: what are they and what do they do?

A

Platelet-activating factor antagonists

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19
Q

Adrenal cortex: what are the three layers and what do each produce?

A

zona glomerulosa (outermost) - produces mineralocorticoids, main hormone is aldosterone which regulates water and electrolyte balance

zona fasciculata (middle) - glucocorticoids, main hormone is hydrocortisone/cortisol (corticosterone in rodents)

zona reticularis produces androgens

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20
Q

Glucocorticoid production

A
  • Hypothalamus reacts to stress
  • Corticotropin-releasing hormone (CRH) is released
  • CRH acts on the anterior pituitary and produces adrenocorticotropic hormone (ACTH)
  • ACTH acts on the adrenal cortex (zona fasciculata) to produce cortisol
  • Cortisol does negative feedback on the hypothalamus and anterior pituitary gland as well as activating various physiological effects
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21
Q

What does cortisol do?

A
  • Gluconeogenesis
  • Fat metabolism
  • Protein metabolism
  • Anti-inflammatory actions
22
Q

Exogenous glucocorticoids: what do they do and what are the examples?

A

Modify expression of many genes > approx. 1% of the total genome is affected, resulting in:
* Suppress immune system (innate & adaptive)

Increased blood glucose levels, stimulate CHO, fat and protein metabolism, and decreased bone formation

  • hydrocortisone (topical)
  • prednisolone
  • prednisone (pro-drug)
  • methylprednisolone
  • betamethasone
  • dexamethasone
23
Q

Why is cortisol highly prevalent when you wake up?

A

Blood-glucose level relations: your body has fasted so energy is moved around the body

24
Q

Fludrocortisone: how potent is it?

A

Some of the glucocorticoids have such high mineralocorticoid activity that their anti-inflammatory glucocorticoid effects are of no benefit

For example, the mineralocorticoid activity of fludrocortisone is so high that its anti-inflammatory activity is of no clinical benefit

25
Q

Lipophilic

A

Can passively diffuse into the membrane

26
Q

How do steroids cause an effect on the genome?

A

Steroids diffuse into the membrane, dimerise with a receptor (SR dimer) then enter the nucleus and bind to a hormone response element (HRE) region and affect the genome, either upregulating or downregulation protein production

27
Q

Steroids: their anti-inflammatory effect on cells

A

Decreased transcription of genes for adhesion proteins and cytokines:
* Reduced migration of leukocytes (neutrophils) from blood vessels into the epithelial cells
* reduced activation of neutrophils, macrophages & mast cells & T-helper cells
* reduced T cell proliferation
* reduced fibroblast action: decrease collagen & glycosaminoglycans production and decrease healing and repair

28
Q

How do steroids affect mediators in inflammation?

A

Reduces the production of the following mediators:
* Eicosanoids (via inhibition of PLA2 & COX-2)
* Cytokines: IL-1-6, IL-8, TNFα, cell adhesion factors & GM-CSF (granulocyte-macrophage colony-stimulating factor - important in leukocyte growth factor)
* Plasma complement proteins
* NO by induced NO synthase (iNOS)
* Histamine release
* IgG

pro-anti-inflammatory actions:
* Increased synthesis of IL-10 and annexin-1 - two mediators that have anti-inflammatory actions

29
Q

Exogenous corticoids: adverse effects

A
  • Euphoria
  • Osteoporosis
  • Tendency to hyperglycaemia
  • Negative nitrogen balance
  • Increased appetite
  • Increased susceptibility to infection
  • Obesity

Inhaled steroids:
* oral candidiasis
* Local immunosuppression

oral steroids:
* Bruising
* Weight changes
* Osteoporosis
* Adrenal suppression

30
Q

Long-term issues of taking exogenous glucocorticoids

A

Adrenal suppression

steroid treatment supplements replace endogenous cortisol and steroid treatment leads to decreased CRH and ACTH release

patients on course of steroid therapy >3 weeks must not suddenly stop treatment: Addisonian crisis

31
Q

DMARDs: what are they, when are they used, what do they do, and what examples of them are there?

A

Disease-modifying antirheumatic drugs

One of the first drugs somebody takes as they modify the disease itself

immunosuppressants:
* methotrexate
* azathioprine
* cyclosporin

Antimalarials:
* chloroquine

gold salts:
* sodium aurothiomalate
* auranofin

Miscellaneous:
* penicillamine
* sulphasalazine
* levamisole
* tacrolimus

32
Q

Methotrexate: what is it and what is its process?

A

An immunosuppressant DMARD

  • Folate analogue
  • Reversible inhibitor of dihydrofolate reductase - used in cancer treatments (affects cell proliferation): reversible inhibitor of dihydrofolate reductase - a crucial enzyme in synthesising purine and pyrimidine in many organisms, including bacterial and protozoa, causing Mammalian cells to be arrested in the S phase of the cell cycle
  • anti-inflammatory effects: Methotrexate inhibits AICAR transformylase, resulting in an increase in intracellular AICAR (5-aminoimidazole-4-carboxamide ribonucleotide) levels which in turn inhibits the enzymes responsible for the catabolism of adenosine and AMP - as a result, the levels of extracellular adenosine increases

SUMMARY: Methotrexate inhibits AICAR transformylase which, through enzymes, causes an increase in AMP, causing more adenosine to be formed - adenosine increases IL-10 (anti-inflammatory.), inhibits the production of ROS, LTB4, TNFα, IL-6 & 8, reduced expression of E-selectin

33
Q

azathioprine: what is it, what does it do, and what are the possible side effects?

A

An immunosuppressant DMARD

  • Used to treat inflammatory bowel disease, autoimmune diseases, e.g. RA; tissue rejection
  • Metabolised to mercaptopurine, a purine antagonist that inhibits DNA synthesis.

Side effects include liver toxicity and bone marrow suppression

34
Q

cyclosporin: what is it, what does it do, and what are the possible side effects??

A

An immunosuppressant DMARD

  • Used to treat ulcerative colitis, tissue rejection, RA
  • T-cell selective immunosuppressant
  • Inhibits IL-2 gene transcription

The most significant side-effect is kidney toxicity

35
Q

chloroquine: what is it, what does it do, and what are the side effects?

A

Anti-malarial DMARD (aka hydrochloroquine)

  • Down-regulate T-cell activity
  • Used to treat RA plus systemic lupus
  • Anti-inflammatory action is slow. Usually used with NSAIDs

Side-effects: irreversible retinopathy, ototoxicity, myopathy with long-term use

36
Q

sodium aurothiomalate: what is it and what does it do?

A

Gold salt DMARD

Intra-muscular injection with a slow onset of action (months)

37
Q

auranofin: what is it and what does it do?

A

Gold salt DMARD

Inhibits induction of IL-1 and TNF-α with slow onset of action (months)

38
Q

penicillamine: what is it and what does it do?

A

Miscellaneous DMARD

Reduces numbers of T-lymphocytes, inhibits macrophage function, decreases IL-1 and rheumatoid factor, and prevents collagen from cross-linking.

39
Q

sulphasalazine: what is it and what does it do?

A

Miscellaneous DMARD

Scavenges toxic free radicals produced by neutrophils.

40
Q

levamisole: what is it and what does it do?

A

(google ig?)

41
Q

tacrolimus: what is it and what does it do?

A

Miscellaneous DMARD

An antibiotic which inhibits T-lymphocyte signal transduction and IL-2 transcription.

42
Q

Adenosine: what does it do in regards to inflammation?

A

Increase IL-10 (anti-inflammatory interleukin)

inhibits production of ROS, LTB4, TNFα, IL-6 & 8

reduced expression of E-selectin

43
Q

Anticytokine drugs: what are they, what are the targets, when are they administered, how are they administered, what results do they achieve, and what side effects are present?

A

Anti-inflammatory drugs

  • TNF-α
  • IL-1, -6, -12 and -23
  • T and B cells

Later on - they are quite expensive

Plant-based - lack of oral bioavailability - injection required

DAS28 (disease activity score from assessment of 28 joints) score is reduced significantly after the first 3 months of treatment - lower the score, the less painful the joints

long-term risk of infection & malignancy with TNF-α antagonists? TB, hep. B reactivation, septicaemia, lymphoma

44
Q

Anticytokine drugs: examples of them

A
  • Adalimumab
  • Infliximab
  • Etanercept
  • Golimumab
  • Anakinra
  • Tocilizumab
45
Q

Adalimumab: what do they target and when is it used?

A

TNF (neutralises)

Inflammatory arthritis; Crohn’s

46
Q

Infliximab: what do they target and when is it used?

A

TNF (neutralises)

Inflammatory arthritis; Crohn’s; colitis

47
Q

Etanercept: what do they target and when is it used?

A

TNF (decoy receptor)

Inflammatory arthritis

48
Q

Golimumab: what do they target and when is it used?

A

TNF (neutralises)

Inflammatory arthritis; colitis

49
Q

Anakinra: what do they target and when is it used?

A

IL-1 (R antagonist)

Inflammatory arthritis

50
Q

Tocilizumab: what do they target and when is it used?

A

IL-6 (R antagonist)

Inflammatory arthritis

51
Q

Drugs ending in mab: what is the meaning?

A

Monoclonal antibody

BIOL21351 (17 decks)

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