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Pharm > Anti - Inflammatory And Immunosuppressant Drugs > Flashcards

Anti - Inflammatory And Immunosuppressant Drugs Flashcards

1
Q

What are NSAIDS?

A

Non steroidal anti inflammatory drugs

And example is aspirin

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2
Q

What is the issue with salicylic acid being ingested and how is it made into aspirin?

A

Salicyclic acid causes gastric irritation and diarrohea
Adding an acetyl group to the acid causes it to change synthetically
This can be used for arthritis treatment

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3
Q

Examples of NSAIDs?

A 
Aspirin = this is acetyl salicylic acid 
Ibuprofen = neurophen
Paracetomol = sold as tylenol
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4
Q

What does Aspirin and ibuprofen do?

A

They decrease the production of inflammatory mediators

These mediators encourage an inflammatory response

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5
Q

Examples of pro inflammatory mediators (lipid derived)

A

Eicosanoids / prostaglandins + paracrine mediators

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6
Q

Features of pro inflammatory mediators:

A

They are synthesised in cells
They can be synthesised all the time = constitutively
Or Synthesis of these mediators may also be caused by tissue damage
These mediators diffuse out of cells and act upon surrounding cells. They then exert their actions on receptors on SURROUNDING cells. Their action is stopped when they bind to enzymes

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7
Q

What are the roles of pro-inflammatory mediators?

A

They help the constriction of smooth muscle = this may affect blood vessels which are surrounded by smooth muscles. (This can help cause swelling. Note constriction of smooth muscle can cause the blood vessels to open up and vasodilate!!) (this is good AND bad. Swelling means more blood flow, but also added pressure and oedema = accumulation of fluid)
They also encourage platelet aggregation
They also regulate the contraction of the uterus - involved in labour and birth
They also affect nociceptors = which affect pain receptors. The mediators cause these receptors to have increased sensitivity. (This is good AND bad as it makes you feel pain more)

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8
Q

Note remember prostaglandins are examples of pro inflammatory mediators. How are prostaglandins formed?

A

Phospholipids in the membrane of cells get hydrolysed by phospholipase A2
These creates an intermediate to prostaglandins called arachidonate
This intermediate is then acted upon by cycloxygenase to produce one of the first prostaglandins
Different cells express different types of prostaglandins.

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9
Q

What are NSAIDs roles in terms of prostaglandins?

A

They work to inhibit the synthesis of prostaglandins
Corticosteriods work to control the expression of phospholipase A2. Remember this is what hydrolyses phospholipids in the membrane of cells to form arachidonate which is an intermediate to form prostaglandins by the cyclooxygenase enzyme

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10
Q

What are the roles of prostaglandins and include examples:

A

Prostaglandins PGI2 and PGE2 are hyperalgesic = these increase the sensitisation of nociceptors which are pain receptors. (This is bad as it causes you to feel more pain)
PGI2 and PGD2 are involved in platelet aggregation
PGF2x are involved in bronchoconstriction
These prostaglandins also work as chemoattractants to bring inflammatory cells to areas of damaged
These prostaglandins however also negatively cause vasodilation = this increases swelling. This action can be good to increase blood flow but bad as it causes swelling.

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11
Q

Note why do we want to inhibit prostaglandins?

A

Because these cause vasodilation, which in turn leads to swelling and headaches

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12
Q

What is the difference between COX 1,2 and 3.
(Note COX is short for cyclooxygenase and these are the enymes which break down the intermediate arachidonate into prostaglandins)

A

COX 1

  • these are constitutively active - they are made all the time
  • they have a role in homeostasis
  • unwanted side effects of NSAIDs? They interfere with cox enzymes but this is necessary to stop prostaglandins

Cox 2 - damage initiated

  • These are inflammatory cells
  • These are enzyme induced
  • When the body detects damage remember they release inflammatory mediators like TNF alpha - this causes this cox enzymes transcription

Cox 3 = this is just a spliced variant of cox 1. Its found mainly in the cns

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13
Q

Key note about NSAIDS and COX enzymes?

A

Different NSAIDs have different selectivities for the different COX enzymes. The aim for NSAIDS is to stop these Enzymes so prostaglandins arent formed.

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14
Q

So what do NSAIDs actually do?

A
  • they decrease vasodilation and odema (Abnormal accumulation of fluids) thus they decrease swelling and bruising
  • they dont regulate the production of other inflammatory mediators like cytokines and chemokines
  • however these NSAIDs are no effective in treating chronic inflammatory conditions like arthritis but they are suitable for accidents.
  • decrease in swelling is also good for treating headaches.
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15
Q

NSAIDS are analgesic. What does this mean?

A
  • they reduce certain sorts of pain
  • note they decrease the production of prostaglandin in damaged and inflamed tissues.
  • Remember these sensitise nociceptors to mediators such as bradykinin and 5- HT
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16
Q

NSAIDS are also antipyretic. What does this mean?

A
  • they lower a raised body temperature
17
Q

Example of a mediator that activates prostaglandins?

A
  • a cytokine IL-1 mediator
    This induces the production of Cox2
    This then induces the production of PGE
18
Q

Paracetamol features which make them good?

A
  • they have good analgesic (reducing sensisitivty to pain) and antipyretic (reducing body temperature)
  • paracetomol particularly works on the CNS
    This is where COX 3 is
19
Q

Describe what a COX enzyme looks like:

A
  • it has two identical sub units = two identical dimers . Each have two catalytic sites
  • it is a lipid
  • it is generated from phospholipids in the plasma membrane
  • ## the COX enzyme is anchored into the membrane of the endoplasmic reticulum
20
Q

Specifically, how does arachidonate (arachidonic acid) enter the endoplasmic reticulum (Where the cox enzyme is found) in order to form prostaglandins?

Remember arachidonate is the intermediate for prostaglandin formation

A

Phospholipase A2 acts on the plasma membrane (phospholipids from here) to make arachidonic acid. This is fat solube
This diffuses through the endoplasmic reticulums membrane via diffusion through the cox enzyme
The cox enzyme has a channel, arachidonic acid enters, and is transformed to make prostaglandins.
The cox enzyme also has a peroxide site. This contains a haem group which is required for the reaction to convert the arachidonic acid into prostaglandins.

21
Q

Cox 1 and 2 difference?

A

They have a Similar structure
Remember Arachidonic acid enters through the cox enzymes
Cox 1 s channel is restricted by an isoleucine
Cox 2 channel is restricted by a valene. This is slightly wider in cox 2 than cox 1.
We can create drugs which have restricted access to certain cox enzymes. So we can keep one on and one off.
E.g. keep cox 1 off but cox 2 (which comes on when there is damage) could be kept on

22
Q

What do the NSAIDS do to cox channels?

A

Enters them and stops reactions from occuring

23
Q

Examples of drugs which are cox 1 or 2 selective.

Note NSAIDS make up lots of different drugs, like aspirin for example

A

Note - most NSAID drugs are cox 1 specific. Likely because they are always on and can cause issues like arthritis!
Note - NSAIDs have many varieties. But also note Nsaids dont treat arthritis, just an example of why cox 1 is bad
- aspirin and ibuprofen are more specific for cox1
- diclofenac is cox 2 selective
Rofecoxib = cox 2 selective

24
Q

What are the problems with NSAIDS?

A
  • they can cause cardiovascular issues
    The risk for this is quite low though
    These drugs can vasoconstrict
    If you have hypertension - this makes it worse
25
Q

Why are smaller NSAIDS prescribed for cox 1?

A
  • because cox 1 has a small tunnel
26
Q

Common side effects of NSAIDS

A

Issues with the gut:

  • stopping prostaglandins (this does reduce swelling and pain) affects the secretion of acid in the gut. Prostaglandins usually inhibit acid secretion and protect mucosa
  • thus if you take NSAIDS for a ling time this can cause damaged to the gut - gastric bleeding and ulcers.

Renal function issues?
- prostaglandins do have a homeoestatic role in controlling blood flow in the kidneys,such seen with cox 2 too

Liver damage issues?

  • linked to paracetamol overuse
  • appropriate levels of paracetomol causes toxic component to disappear quickly but too much affects the liver.

Skin rashes

Bronchospasm = asthma

27
Q

How to overcome the issue of NSAIDS in the gut?

A

An angonist like misoprostol can be used which stops the loss of production of prostaglandins in the gut
These stop NSAIDS in the gut.

28
Q

What is the advantages / disadvantages of taking NSAIDS to stop COX 1 and COX 2:

A
  • major disavantage of inhibiting cox 1 = it causes gastrotoxicity
  • however NSAIDs working on cox 1 act as a antithrombotic - this reduces the formation of blood clots

On cox 2
- cox 2 increases blood pressure thus NSAIDS reduce this, treating cox 2 can reduce inflammation.

29
Q

How does aspirin inhibit cox?

A
  • suicide inhibtior
  • its acetyl group forms a covalent bond with the cox channel tunnel
    There stops arachionic acid from reaching the cylooxygenase site
    Neurophen doesnt have this effect of making a covalent bond. Instead it control pharmacokinetic actions
30
Q

Paracetamol benefits?>

A 
Good analgesic drug (reduces pain)
Good antipyretic
Works on cox 3
Interacts with cox enzyme inbrain
Has minimal effect on gut
Not anti inflammatory
31
Q

Aspirin?

A
  • Anti - platelet action
  • reduces risk of colonic and rectal cancer
  • reduces risk of Alzheimers
32
Q

NSAIDS Are …?

A 
Antithrombotic
Analgesic
(Paracetomol and ibuprofen enable this in the short term)
Anti inflammatory
Antipyretic

Pharm (13 decks)

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