Lecture - Pharmacology (Anti-inflammatories) Flashcards

1
Q

Alright, so anti-inflammatory compunds are ‘preventors’

-what is the class of the drug and give me an example of one that is inhaled vs oral

What’s another class that is covered in this lecture?

A

So they are corticosteroids and the inhaled one is called fluticasone and the oral is prednisone

Cromolyns are mentioned but will not be in the exam

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2
Q

Alright, how do steroids work?

A

They need to get into the nucleus and they increase transcription and translation and this will increase the protein it produces so alter the cellular function

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3
Q

What are the two types of corticosteroids and give examples of each type

A

Glucocorticoids eg cortisol

-it is part of the stress response produced by HPA axis and it impacts the renal cortex - it is an anti-inlam on its own and it regulates gene expression and glucose levels and formation. Also impacts phospholipid release and it reduces eosinophilic recruitment etc

Mineralcorticoids eg aldosterone (spironolactone is an aldosterone antagonist)

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4
Q

So glucocorticoids’ primary action is to regulate gene expression. What are they highly effective at suppressing?

A

Inflammatory cytokines and immune cells

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5
Q

What does cortisol control and how?

A

It controls carbohydrates, fat and protein metabolism and is anti-inflammatory

How: It prevents phospholipid release and decreases eosinophil recruitment and action

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6
Q

Glucocorticoid binds to intracellular receptor and then what happens? There are three things that happen - this had a red box around it so you should know this

A

It binds to the intracellular receptor and that complex interacts with DNA. This interaction will:

  1. Up-regulate gene transcription of phospholipase inhibitors: LIPOCORTIN-1
  2. Up-regulates anti-inflammaotry: IL-10, IL-12 and IL-1 receptor antagonist
  3. Down-regulates pro-inflammatory: IL2, 3, 4, 5, 6, 11, 13, 15, TNF-a, GM_CSF, endothelial adhesion molecules, COX, PHOSPHOLIPASE A1, iNOS etc

So note that phospholipase A2 will be downregulated by cortisol itself and also by lipocortin-1

Also note that iNOS is inducible NO synthase: contained by macrophages - in an inflam resp in lungs, they bring out lots of NO and this causes damage. If we can reduce it from an anti-inflam agent eg corticosteroids, it should be good

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7
Q

SO in this pathway, where will the glucocorticoids affect?

A
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8
Q

What are the 4 pertinent effects of glucocorticoids (eg fluticasone/prednisone) in asthma?

A
  1. Reduce the recruitment/number of inflammatory cells
    - consequently reduce damage to airways epithelium
    - because you reduce inflammatory cytokines that reduce other cells
  2. Inhibit macrophages function:
    - reduces antigen response
    * -it reduces iNOS which is in the macrophages*
  3. Reduce vascular permeability
    - decrease histamine release from basophils and mast cells
    - bc reduce the prostaglandins from the pathway too and they vasodilate
  4. No effect on bronchodilation
    - but overtime may decrease airways hyper-responsiveness
    * -imp bc those inflam agents increase the responsiveness to Ach*

NB - cannot reverse airways remodelling in poorly managed asthma

-if airways are damaged, there is no going back so need to manage from the get-go

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9
Q

High dose/ow dose oral/inhaled steroids generally have systemic effects

A

High dose oral steroids - they travel around systemically after getting through the gut and the volume is larger so get everywhere in the body

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10
Q

What are the metabolic actions of the ORAL glucocorticoids?

A
  1. Carbohydrates
    - they decrease uptake and glucose utilisation
    - they increase gluconeogenesis (hepatic)
    - so using corticosteroids on diabetic people can compound the problem because get increased glucose in the plasma

2. Proteins

  • increase catabolism
  • decrease anabolism
  • -so they don’t give you gainz*

3. Fat

  • re-distribution
  • cause fat gain and muscle wastage
  • fat gain and musce wastage isn’t good

NB: glucocortecioids are not anabolic steroids

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11
Q

How do glucocorticoids affect the HPA axis?

Start off by explaining what the HPA axis even is

A

HPA axis: hypothalamus releases CRH on anterior pit and ACTH released and impacts on adrenal cortex to release cortisol. That cortisol is a glutocirodi (endogenous), it has negative feedback so reduces ACTH and on hypothalams so reduce CRH release.

It also has metabolic effects = impact glucose levels like increase glucose production. So we boost metabolic effects and reduce stress response

When we put a glucocorticoid inside system that resembles cortisol - it’s going to have same effect in that it will decrease the production of cortisol. If have acute release then will have a short term effect and reduce the stress response. But if high dose steroids for long time = downregulate the stress response so the body is no longer able to fight inflammation

So high systemic dose of glucocorticoids leads to chronic negative feedback of HPA axis

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12
Q

What are the regulatory actions of glucocorticoids?

-these are the other effects

A
  1. Osteoporosis
    - inhibits Vit D-mediated Ca2+ absorption
    - suppresses osteobalst function
    * -so yeah, this happens with high dose chornic use*

2. HPA axis suppression

-switch off endogenous glucocorticoud production aka adrenal or HPA axis suppression

3. Inflammation and immune reactions

  • decrease chronic inflammation
  • immunosuppression allowing eg pulmonary aspergilllosis
  • decrease wound healing
  • also reduce TH2 response - useful in asthma inflammation but if body is exposed to systemic infection then we will downgrade the response to that (immunosuppression) so it’s a problem giving chronic corticosteroids
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13
Q

Just appreciate this image of the effects chronic oral corticoisterouds have - the ADRs

A
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14
Q

And some more ADRs of chronic oral/systemic glucocorticoids

A
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15
Q

So you’ve seen the ADRs of chronic oral/systemic use of gluocorticoids - how do you minimise them collectively?

A

Inhalation route minimises ADRs

  • Fluticasone propionate is an example of an inhaled glucocorticoid
  • It can also be given as a combination inhaler (Seretide) with salmetereol (a LABA)
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16
Q

Glucocorticids- inhalation PKs

So this had a red box around it and the question he will ask in the exam is

“How would you recommnend she takes the drug - route, time of day, etc”

A

You have lesser dose as inhalers because they have immediate acess to the targets in resp airways and dont need to go through GIT and 1st pass

But if the drug does cross the airways into the circulation then v little of it will survive bc 1st pass breaks it down

17
Q

Deposition of aerosols

  1. Those inhaled drug aerosols are between what sizes and what two things have you been taught?
  2. If you were to instruct to a pateint how to take the inhaler, how would you tell them?
  3. Where does asthma tend to happen?
A

Brownian motion = Small particles in airways bounce around and v little reach site of action

Lower airways = asthma

We need to get the particles down all the way to the bronchioles and they will face turbulence

Anything about 10 micrometer particles - those larger particles are going get stuck almost when they go through the upper larger airwyas bc turning is hard so you’re going to get impaction upon the upper airways, back of esophagus ad trachea but v little get down to lower airyas.

But if you have even smaller particles (these are powder inhalers), they undergo sedimentation and they go with the flow all the way to the bottom of the airways but PATIENT NEEDS TO TAKE A DEEP BREATH IN GENTLY AND NOT BREATH - HOLD IT. This will aloow the partciles to sediment on the airways down there

18
Q

What’s the deposition of inhaled fluticasone like?

A

What if the drugs gets scross the airways?

90% of the drug impacts the upper airways, 10% into lower airways and has an effect (so out of 1 in 100 dose we put in systemically, only 10% needs to get to lung to have an effect)

Some of it through poor technique etc will get into the esophagus and to the stomach - some of it imapcts at the back of the mouth. 90% dwn to the stomach.

What doesnt get broken down by the acid etc will go to the liver and 1% of that survives enough to get into the systemic circulation.

So, we will still get a small % getting into the systemic circulation and if they have really bad technique, more of it will get into the systemic circulation. This builds up tolerance in the liver so more drug gets to the systemic circulation and you’ll start seeing systemic effects of corticoisterods

19
Q

Inhaled glucocorticoids and adrenal crisis

So inhaled drugs:

  1. So with chronic high dose use of inhaled drugs, what tends to happen?
  2. What things does this resilt in?
  3. What is secondary adrenal insufficiency?
A
  1. Suppress endgogenous cortisol production aka reducing the stress response. If you put on chronic corticosteroids - you’ve left them immmunosuppressed and failed to leave any renal reserve
20
Q

So in a table form, what are the major adverse effects and risks associated with them for inhalation glucocorticoid toxicity?

A

Focus on first and thid!

21
Q

Prevention of inhaled glucocortioids ARDs

  1. What two things are you likely to get?
  2. How do you recude these ADRs?
A

Oropharyngeal candidiasis: Invasion of mucosa - it will produce a problem in the apteint so need to correct that eg anti-fungal mouth washes

We would reccomned that the pateint gargles periodically esp aftre inhaling the fluec with salt solution (stop fungal taking hold) but salt hurts so use the anti-fungal mouth wash. Alcohol mouth wash should be avoided

Volume spacer: To prevent the large particles impacting the back of the airways

If the pareitn gets immuosuppression then reduce the frequency Putting them on a high dose steroid will cause problem and taking it off will cause problem so what you do is start slow to effect, track the symptoms with eg PEFR everyday or spiromtery on regular bases or FENO (NO is made by macrophages and if inflam going on in airways then this is released) so if you give them gluco then you will reduce this. SO if the pateint has high NO then increase gluco but if low levels then decrease gluco.

We also will get drug particles imapcting the mucosa in the larynx - it is going to hit the back of the throat and damage that so get hoarseness and yeah

22
Q

Oral glucocorticoids:

  1. What do you take?
  2. When do you use it?
  3. What is SOS?
  4. How long do you use them?
    - what id you need to use them for longer?
  5. What could they result in?
A

Acute asthma exacerbations: dangerous condition so need SOS

23
Q

What is the black box warning in this lecture?

A

Looks at switching chronic systemic steroids to inhalation delivery for the asthmatic pateints. Yes, you will still effect the inflam resp in lungs but have knocked back the HPA axis. It takes a while for that to recover. Even if you are using inhalation, you stil need to reduce the systemic oral steroids slowly

And if stressed then return to systemic eg when undering infection, surgery, tarumatic stress etc - restore prednisone