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pharmacology > anti-inflammatories > Flashcards

anti-inflammatories Flashcards

1
Q

what is an early NSAID (non-steroidal anti-inflammatory)?

A

From white willow, aspirin has for a long time been known to be an anti-inflammatory, analgesic and antipyretic (brings down fever)
Issues at the time with the salicylic acid was how harsh it was on the stomach
In 1897 dude called Hoffman tinkered with the structure of salicylic acid to form acetyl-salicylic acid, which had much fewer gastric side effects

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2
Q

what is the pathway the COX enzymes are involved in?

an overview of the molecules involved

A

release of arachidonic acid - derived from cell membrane phospholipids by phospholipase A2, in response to some kind of cell injury

this acid acts as substrate/second mediator for COX enzymes and lipoxygenases, resulting in production of lipid soluble mediators

the COX enzymes convert arachidonic acid into prostaglandins and thromboxane

(lipoxygenases convert the acid to leukotrienes)

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3
Q

what do the prostaglandins (PG-I2, PG-E2, PG-F2) and thromboxane, from the COX pathway, do?

A

PG I2 = is a vasodilator, is a hyperalgesic (inc. sensitivity to pain), decreases platelet aggregation ( i.e reduces clotting)
Thromboxanes - thrombotic (increase clots)

PGE2 - vasodilator (to allow immune cells to reach site of inflammation) and hyperalgesic

PG F2 = bronchoconstrictor (makes it harder to breathe), and involved in myometrial contraction in birth

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4
Q

briefly/generally, how do PGs work as hyperalgesics?

A

sensitises nociceptors, by increasing ion-channel activity, to inflammatory mediators like bradykinin and serotonin
Reducing PG production therefore reduces pain

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5
Q

briefly, how do NSAIDs work as analgesics?

A

they inhibit cyclo-oxygenase enzymes (COX enzymes)

COX1 and COX2 inhibitors inhibit Cyclooxygenation reaction of Arachidonic Acid to prevent production of PGs

reducing production of PGs prevents them from increasing pain sensitivity and cause inflammation and vasodilation
(and thromboxane which can cause clotting)

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6
Q

how do NSAIDs work as anti-inflammatories to reduce swelling?

A

by decreasing vasodilation usually caused by prostaglandins (only really effective in acute injuries, not chronic)

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7
Q

how are NSAIDs antipyretic?

A

inhibition of COX 2 prevents the production of PG-E which would normally cause the hypothalamus to raise the temperature

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8
Q

COX enzymes - general structure and location in the cell?

A

found at the ER membrane

The cyclooxygenase active site is buried deep within the protein, and is reachable by a tunnel that opens out in the middle of the knob. This acts like a funnel, guiding arachidonic acid out of the membrane and into the enzyme for processing

has two active sites, a peroxidase sight and a cyclooxygenase site

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9
Q

how do COX 1 and 2 differ in their structure and how can this be exploited?

A

COX 2 has a smaller A.a. (valine) at the bend in the structure where COX 1 has an isoleucine. this means COX 2 has a wider channel and gives rise to a gap, which can act as a selectivity filter for certain drugs (so you could get COX 1 or COX 2 selective drugs)

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10
Q

genetically, how do the three COX enzymes differ?

A

COX 1 and 2 are encoded by different genes

COX 3 is a spliced variant of COX 1, meaning overall there are actually only two COX genes

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11
Q

what is different about paracetamol’s method of inhibition?

A

it binds to the peroxidase site of the COX enzyme, not the cyclooxygenase site

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12
Q

how might a drug be COX 2 specific?

A

it could block the COX 2 channel but be too bulky to enter and then block the COX 1 channel, due to COX 2 channel being wider (has a valine, not an isoleucine)

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13
Q

how does aspirin work?

A

covalently bonds to Ser in COX, so arachadonic acid is prevented from reaching the cyclooxygenase site

This is permanent inhibition, so the enzyme must be re-synthesisedarachidonic

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14
Q

what is rofecoxib (Vioxx)?

A

a COX 2 selective NSAID withdrawn a year after production due to cardiovascular complications as a result of the drug’s pro-thrombotic actions

possibly exaggerated by underlying medical conditions

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15
Q

aspirin - what effects does it have and is it selective?

not just as an NSAID, + absorption?

A

aspirin is anti-platelet/reduces clotting (so cannot be taken with warfarin as blood gets too thin/risk of blood loss)

reduces risk of certain cancers

rapidly absorbed as it is a weak acid

reduced risk of Alzheimer’s

suicide/irreversible inhibitor

slightly COX -1 selective

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16
Q

ibuprofen is the same as aspirin but…

A

ibuprofen is a competitive inhibitor

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17
Q

paracetamol - what properties/effects does it have?

A

Analgesic, the most effective antipyretic due to stronger CNS effects

only a very weak anti-inflammatory

potentially Cox3/1 selective? - method of action not entirely known

Well absorbed, metabolized in liver

Less side-effects than aspirin with long term use, but large doses may increase kidney damage

metabolised into the intermediate NAPQI (N-acetyl-p-benzoquinone imine) is hepatotoxic in unconjugated form

Competitive Inhibitor

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18
Q

aspirin is also used as a …

A

antithrombotic

COX 1 inhibition does also reduce platelet aggregation, so can be used as a prophylactic (at very low doses) for people at risk of stroke

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19
Q

why are COX 2 selective inhibitors desirable?

A

COX 1 important in homeostatic mechanisms you’re not wanting to effect

NSAIDs inhibiting COX 1 can cause stomach ulcers as PGs are responsible for inhibition of stomach acid production to protect mucosa

COX 2 also linked to alzheimers

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20
Q

how can the stomach be protected during prolonged NSAID use?

A

also prescribe a PG analog like misoprostol that can do the job of PGs in the stomach and prevent ulcers, while allowing NSAIDs to do what they need to

21
Q

what are some drawbacks of COX 2 selective inhibitors?

A

may impact cardiovascular safety, though the mechanism is not known. Possibilities include increased arterial blood pressure, or even thrombosis
COX 2 also important in regulating blood flow in the kidney, don’t want to interfere with this and cause renal failure in the elderly

22
Q

aspirin has also been seen to work by inhibiting what?

A

appears to inhibit expression of transcription factor NF-kappaB which has a key role in triggering gene transcription of inflammatory mediators

23
Q

what is rheumatoid arthritis?

A

Inflammation causes swelling of the joints, typically symmetrical
morning stiffness
Inflamed synovium produces inflammatory mediators, bringing in the immune system, degrading the joints, losing synovial fluid, you lose the cushioning and activate sensory nerves in the area, causing pain

24
Q

rheumatoid arthritis - who does it affect? what is the general aim of treatment?

A

genetic component (3x more likely in women)
smoking is a risk factor

typically 40-60yrs old but can affect children

treatment is to limit inflammatory response to prevent further degradation of the joints

25
Q

what cells/mediators are involved in the immune response that occurs in rheumatoid arthritis?

A

initiated by activation of Th1 cells
these then activate macrophages, fibroblasts and osteoclasts

chemical mediators that these cells use to communicate/activate one another are cytokines, mainly IL-2 (and 1???) and TNF-a (tumour necrosis factor), and chemokines

26
Q

what is the difference between chemokines and cytokines?

A

Cytokines activate immune cells
Chemokines bring more immune cells into the area

27
Q

what are the two methods of attack when trying to treat rheumatoid arthritis?

A

apart from treating the symptoms, further inflammation and joint degradation need to be reduced by

  1. targeting the Th1 cells and the beginning of the immune response
  2. targeting the chemokines and cytokines that act as chemical mediators to amplify the immune response
28
Q

what is a DMARD and what are the three examples currently in use?

A

DMARD = disease-modifying antirheumatic drug, typically have been identified by chance and work in different ways

  1. methotrexate is the main example
  2. sulfasalazine - method of action under research
  3. cyclosporin
29
Q

how are methotrexate and sulfasalazine theorised to work?

A

methotrexate - targets Th1 cells, unrelated to its function in RA, but its a folic acid antagonist (folic acid is an essential cofactor) so a supplement must be taken alongside

sulfasalazine - not known for sure, believed to be a free-radical scavenger, to mop up things released by your immune system by e.g. neutrophils to kill pathogens

30
Q

how does cyclosporin work to treat rheumatoid arthritis?

A

targets cyclophilin, a cytosolic protein that regulates a phosphatase known as calcineurin

Calcineurin normally removes phosphate from a transcription factor known as NF kappa B
When dephosphorylated in immune cells this TF goes into the nucleus and normally causes transcription of inflammatory mediators like these cytokines and chemokines.

So this is prevented by cyclosporin

31
Q

why doesn’t cyclosporin completely stop all inflammatory mediators?

A

there are lots of other transcription factors involved

32
Q

what other class of drugs are used to treat rheumatoid arthritis? include an example and how they work

A

glucocorticoids.
prednisolone
Bind to nuclear receptors that control transcription of certain cytokines

33
Q

why are DMARDs preferred to glucocorticoids (not inc. cyclosporin)?

A

Unwanted side effect - these drugs are immunosuppressants, resulting in increased susceptibility to infections

DMARDs currently preffered as they dont cause the patient to become immunocompromised

34
Q

NSAIDs - why are they used alongside glucocorticoids?

why are they used for osteoarthritis?

A

glucocorticoids aren’t 100% effective - there are still cytokines being produced. therefore pain still needs to be addressed

DMARDs and glucocorticoids are not effective in osteoarthritis

35
Q

what is another way of treating rheumatoid arthritis? (not small molecules)

give two examples

A

biopharmaceuticals

adalimumab - new and upcoming monoclonal antibody, which binds to the key cytokine TNF-a

etanercept - a cytosolic protein mimicking the TNF binding site to act as a decoy

36
Q

what are some pros and cons of biopharmaceuticals for RA?

A

Their specificity reduces immunocompromised side effects
but they are super expensive and not easily administered (injection to joints)
They do last for a few months tho

37
Q

what is asthma?

A

usually an immune response triggered by an allergy, causing a reversible airway obstruction due to hyperresponsive airways

38
Q

why are B2 receptor agonists not the same for everyone?

A

polymorphisms in population mean they are more/less effective from person to person

39
Q

immune response involved in an asthma attack - what immune cells and cytokines are involved and what do they do?

A

Th2 cells are the initially activated cells

cytokines IL-4 and 5 and 13 are key

these cytokines interact with B-cells, causing ‘class-switch recombination’

This means the cell makes IgE antibodies to the allergen causing the attack. IgE bind with very high affinity to receptors on mast cells and eosinophils…

40
Q

mast cells in asthma - how do they ensure a quick response to the ‘allergen’

what substances do they release/produce?

A

found anywhere a pathogen could enter. They have bound IgE antibodies, they are ready as soon as the antigen, like grass pollen, is present again. Super quick
Mast cells response, upon IgE activation, causes degranulation, their vesicles fuse with membrane and release histamines

Also produce PGs, which cause smooth muscle contraction and effect sensory nerve endings

41
Q

what are the physical effects of mast cell inflammatory mediators?

A

SM contraction, mucous secretion from goblet cells. Increased vascular permeability to get more immune cells to the area, recruitment of eosinophils

42
Q

in asthma, what do eosinophils do?

A

Secrete substances designed to kill so they do damage to your tissues

43
Q

what are the steps of an asthma attack? hay fever?

A

Lungs are exposed to the allergen

Early phase response - immediate, coughing and difficulty breathing for about an hour

Delay, and then in severe asthma there is a late phase second attack of increased length and severity

Allergen activates mast cells lining lungs, nose, eyes, which secrete mediators that cause the symptoms

In hay fever it’s just mast cells in upper airways

44
Q

why is there a delay between phase 1 and 2 in an asthma attack?

A

its mediated by cytokines and chemokines that must be synthesised

45
Q

how are the two phases of an asthma attack treated?

A

Phase 1 (immediate, short, less severe) reversed by inhalers and over the counter medication - B2 adrenoceptor agonists. also antihistamines

phase 2 treated with glucocorticoids to control the production of the cytokines (again, the whole immunocompromised issue, so only provided when absolutely needed

46
Q

what permanent damage can occur as a result of asthma attacks?

A

Loss of elasticity
Clogged with mucus

Glucocorticoids are steroids - so using them as a treatment option can cause Cushing’s syndrome effects

47
Q

PG-D2 is a key prostaglandin in asthma. what cells produce it?

A

mast cells, by PG-D synthase

48
Q

what does PG-D2 act on (asthma)

A

DP1 receptors on blood vessels to mediate vasodilation

Dendritic cells to enhance their activation

via DP2 receptors expressed in lung epithelium and immune cells (also known as CRTH2) to attract more Th2 cells and eosinophils (so is responsible for massively increasing immune response/presence)

Thromboxane (TP) receptors to cause bronchoconstriction

note - antagonists of DP1 and 2 receptors, as well as inhibitors, are in development

49
Q

COPD - what kind of immune response is involved?

A

Th1 immune driven response, recruits lots of macrophages that result in stiffening of the lungs

pharmacology (9 decks)

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