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Pharmacology Year 2 > Anti-inflammatory and Immunosuppressant Drugs > Flashcards

Anti-inflammatory and Immunosuppressant Drugs Flashcards

1
Q

What are NSAIDs?

A

Non-steroidal anti-inflammatory drugs

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2
Q

What was the first non-steroidal anti-inflammatory drug synthesized in a lab?

A

Aspirin ( acetal salicylic acid)

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3
Q

How many non-steroidal anti-inflammatory drugs (NSAIDs) are there?

A

Over 50.

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4
Q

How do Aspirin, Paracetamol, and Ibuprofen work and what is their outcome?

A

> All of these drugs inhibit production of inflammatory mediators, especially target inflammatory mediators called prostaglandins and thromboxane, by inhibiting cyclooxygenases (COX enzymes).

> Reduces pain and swelling.

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5
Q

What is the function of inflammatory mediators, like prostaglandins and thromboxane, and how is this possible?

A

> They cause a localised inflammatory response

> They are lipid soluble (fat soluble) so can diffuse out of cells to do paracrine signalling.

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6
Q

What are the 3 steps of production for prostaglandins and thromboxane inflammatory mediators?

A
  1. Phospholipase A2 generates pre-curser called arachidonate from phospholipids in cell membrane.
  2. COX enzymes (cyclooxygenases) acts on arachidonate.
  3. The inflammatory mediator is converted into prostaglandins or thromboxane.
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7
Q

What do a)Prostaglandin F2 b)Prostaglandin D2 c)Prostaglandin E2 control?

A

a) Prostaglandin F2 controls myometrial contraction (initiation of labour)

b) Prostaglandin D2, inhibits platelet aggregation, and is a vasodilator

c) Prostaglandin E2, is a vasodilator, and a hyperalgesia (increases pain perception by acting directly on nociceptors)
>It increases signalling by bradykinin and 5-HT (serotonin) to nociceptors.

> They all attract immune cells to damaged areas.

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8
Q

What do Thromboxanes control?

A

They all act as Vasoconstrictors

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9
Q

What are the 3 therapeutic functions of NSAIDs?

A

1) Anti-inflammatory

2) Analgesic (reduce certain sorts of pain

3) Antipyretic (lower raised temperature)

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10
Q

How do NSAIDs have anti-inflammatory effects, and when is this ineffective?

A

> They decrease vasodilation and in turn oedema (swelling).

> Ineffective against mediators causing tissue damage, usually associated with chronic inflammatory conditions.

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11
Q

What symptom does NSAIDs inhibit by increasing vasodilation of vessels to the head?

A

This stops headaches as these are caused by vasoconstriction of blood vessels to the head.

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12
Q

How do NSAIDs have Antipyretic effects?

A

> Thermostat in hypothalamus activated by the chemical mediator called IL-1 (raises temperature of body), this signalling involves COX2 production of Prostaglandin.

> So NSAIDs inhibiting COX2, returns body temperature back to normal.

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13
Q

How do NSAIDs have analgesic effects?

A

> Decrease production of Prostaglandins E2 in damaged and inflamed tissue which sensitizes nociceptors.

> So, nociceptors send out less pain signals to the brain.

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14
Q

How do NSAIDs have antipyretic effects?

A

Thermostat in hypothalamus activated via IL-1 induced COX2 production of PGE, NSAIDs inhibit this.

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15
Q

How many isoforms of COX (cyclooxygenases) enzymes are there?

A

3

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16
Q

Where are the 3 isoforms of COX (cyclooxygenases) enzymes found and what is their function?

A

1) COX-1
>Produced in platelets, Stomach, Kidney, Colon, and most tissues
>For homeostatic effects.

2) COX-2
>An inducible enzyme, made in response to injury and inflammation (only present in injured cells)
>For inflammatory repones

3) COX-3
>Found in brain and kidneys
>Not much known about this enzyme.

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17
Q

How many subunits and catalytic sites do COX enzymes have?

A

2 subunits and 2 catalytic sites.

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18
Q

What intracellular organelle are COX enzymes embedded in?

A

endoplasmic reticulum

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19
Q

How do COX enzymes interact with the endoplasmic reticulum membrane to produce prostaglandins or thromboxane in 3 steps?

A

1) Arachidonic acid floats to ER membrane (produced at plasma membrane) from cytosol of cell

2) Arachidonic acid moves through the ER membrane and into the cyclooxygenase site of an embedded COX enzyme and binds.

3) COX enzyme activates ad produces prostaglandins or thromboxane.

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20
Q

What are the 2 catalytic sites of a COX enzyme called?

A

1) Cyclooxygenase site

2) Peroxidase site

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21
Q

What is different between COX1 and COX2 and what advantage does this have?

A

> COX1 has smaller cyclooxygenase pore as isoleucine is a larger amino acid blocking it

> COX2 cyclooxygenase pore is wider due to smaller amino acid Valine blocking it; so larger drugs can enter

> Allows us to make selective drugs for both (useful as both enzymes have different function).

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22
Q

Why do we want to have NSAIDs which are selective in inhibiting COX2 enzymes and not COX1?

A

As COX1 prostaglandins have important homeostatic effects so we want to be able to inhibit COX2 without the side-effects of inhibiting COX1.

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23
Q

What are 3 homeostatic mechanisms for COX1 enzymes?

A

The Prostaglandins produced by COX1 play key role in maintaining mucus layer surrounding stomach and GI (protecting lining from acid), Controlling blood loss (through platelet aggregation), maintaining blood flow to kidneys

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24
Q

What are 3 unwanted side effect of NSAIDs that are selective to just COX1 enzymes (like aspirin) and why?

A

1)Ulcers in stomach
>Because COX1 prostaglandins produce mucus layer surrounding stomach and GI tract.

2)Prolonged bleeding
>As platelet aggregation is mediated by COX1.

3) Kidneys don’t receive sufficient blood flow
>As COX1 maintains blood flow to kidneys.

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25
What is a suicide inhibitor and an example?
>Suicide inhibitor= drug that covalently binds to target to cause permanent inactivation of target >E.g. Aspirin
26
How does aspirin work?
>Aspirin is a suicide inhibitor binding covalently to an Acetyl group in the cyclooxygenase pore of a COX enzyme. > Arachidonic acid can't enter cyclooxygenase pore so Prostaglandins and Thromboxane cannot be synthesized.
27
How long does Aspirin last and why?
>Lasts 3 hours >As Aspirin needs to be excreted and new COX1 enzymes have to be synthesized (as aspirin is a suicide inhibitor it binds strongly with covalent bonds) till normal levels have been reached.
28
What COX enzyme are a)Aspirin b)Ibuprofen c)Coxibs d) Paracetamol selective to?
a) COX1 selective b)COX1 selective c)COX2 selective d) COX1 and COX3 selective
29
What are 5 side effects of NSAIDs and why are they caused?
1) In the Gut >Ulcers, Diarrhoea, vomiting, gastric bleeding >Prostaglandins produce mucous layer protecting stomach and GI tract from acid. 2) Renal Function failure >Prostaglandins maintain renal blood flow. 3) Liver damage >Paracetamol overdose, first phase metabolism generates very reactive chemical that kills cells. 4) Bronchospasm asthma attacks >due to allergies from aspirin 5) Skin Rashes
30
What risk varies with different NSAIDs?
Risk of GI complications.
31
How high a risk of GI complications does aspirin have?
Aspirin in moderate doses is safe/ low risk of GI complications (can be taken daily)
32
Why do people at risk of stroke take COX1 inhibitors (anti-thrombosis) but what is an unwanted side-effect?
>COX1 controls blood clot formation, people at risk with strokes take daily low levels of COX1 inhibitor to decrease blood clots. >Causes Undesirable gastrotoxicity
33
What is advantageous about taking COX2 selective inhibitors and what is disadvantageous?
>Are good anti inflamatory, good analgesics, and don't effect gut >Issue is as COX2 plays an important role in kidneys, inhibition in COX2 increases blood pressure and increased Na+ conc in body.
34
What is an issue with Rofecoxib being taken?
>It is a Coxib so is very COX2 selective. >Taking it lead to an increase in Na+ and blood pressure leading to heart attacks.
35
What are 3 positive effects of taking Aspirin?
1) Anti-platelet action (stops blood clots) 2) Reduced risk of colonic and rectal cancer 3) Reduced risk of Alzheimer’s / speed of progression
36
Why is Aspirin efficiently absorbed into the ileum?
As it's a weak acid.
37
What 2 symptoms does Paracetamol treat and why?
>Headache or high temperature >Paracetamol is a Analgesic-antipyretic so gives pain relief and reduces body temperature back to normal.
38
What are 2 advantages and 2 disadvantages to Paracetamol?
1)Advantage >Less side-effects than aspirin with long term use >Well absorbed, metabolized in liver 2)Disadvantage >Weak anti-inflammatory effects > large doses may increase kidney and liver damage
39
How does Paracetamol work?
Competitive inhibitor for COX1 and COX3 enzymes
40
What NSAIDs are 1)Antithrombotic 2)Analgesia 3)Anti-inflammatory 4)Antipyretic
1) Aspirin for patients at high risk of arterial thrombosis 2) short term aspirin, paracetamol, ibuprofen >For chronic pain, longer lasting more potent drug eg. Naproxen (+codeine) 3) Ibuprofen, naproxen 4) paracetamol
41
What are 2 examples of chronic inflammatory diseases?
Rheumatoid Arthritis and Asthma
42
What 3 symptoms of Rheumatoid arthritis?
1)Pain >leading to poor sleep 2)Morning stiffness 3)Swelling in effective joints
43
Is there a cure for Rheumatoid arthritis?
No, just can treat symptoms
44
What is a major risk factor for Rheumatoid arthritis?
Smoking
45
What type of condition is Rheumatoid arthritis?
Autoimmune Disease
46
How is an inflammatory response caused in Rheumatoid arthritis patients?
T-cells activate macrophages which release cytokines (IL1 and TNF alpha) driving an inflammatory response.
47
What 2 cytokine mediators drive the inflammatory response in Rheumatoid arthritis?
IL1 and TNF alpha
48
What 2 drug groups can treat symptoms of Rheumatoid arthritis?
Methotrexate and DMOD (Disease Modifying Drugs)
49
What type of drug is Methotrexate and what does is a side-effect?
>It is an antagonist for folic acid that causes immunosuppressant and cytotoxic effects. >It has a side effect of decreasing folic acid
50
How do Methotrexate drugs help treat the inflammatory response caused in Rheumatoid arthritis?
Through methods we don't know this drug causes a cytotoxic and immunosuppressant activity
51
What does Methotrexate treat at a) Low concentrations b) High concentrations and which has more side-effects?
a) Useful for cancer treatments (cytotoxic effect for this) >But has bad side-effects b)Can treat symptoms of arthritis (immunosuppressant effect for this) >Has low side effects
52
What is an example of DMOD (Disease Modifying Drugs)
Sulfasalazine
53
What is Sulfasalazine used to treat?
>Chronic inflammatory bowel disease
54
What are 2 examples of steroid drugs that inhibit the induction phase of the inflammatory response?
Cyclosporin & Glucocorticoids
55
How does Cyclosporin decrease the inflammatory response in 3 steps?
1) Cyclosporin binds to calcineurin (phosphatase enzyme). 2) Calcineurin can no longer activate the transcription factor NFΚB (K=Kappa) 3) NFΚB can no longer drive increase the in production and secretion of cytokines including IL-2 and IL-1 that drive the inflammatory response.
56
How do Glucocorticoids decrease the inflammatory response in 3 steps?
1) Bind to DNA on nuclear receptors (steroids are lipids soluble) 2) Inhibits transcription of genes that make cytokines 3) Less cytokines being produced and secreted leads to a lower immune inflammatory response.
57
What is IL-2 and what does it cause?
IL-2 is a cytokine which drives the inflammatory response, causing T-cells to proliferate which causes swelling
58
If a drug name ends in MAB, what does it contain?
Monoclonal Antibodies
59
What is an example of a Glucocorticoid that inhibits the inflammatory response?
Prednisolone
60
How are monoclonal antibodies used to treat inflammation?
The antibodies bind to TNF-alpha cytokines so it can no longer bind to receptors and drive the inflammatory response.
61
How are monoclonal antibodies administered as a drug?
Injection into blood.
62
How long can one injection of monoclonal antibodies treat inflammation for and does it have side-effects and why?
>3 months due to long half life >Low side effects due to very specific nature.
63
How can injecting soluble receptors be used to treat an inflammatory response?
>Cytokines bind specifically to receptors to change function of immune cells. >So an engineered protein which mimics this receptor with no effect would cause no inflammatory response after cytokines bind.
64
What does it mean that there a limited pattern time on drugs?
When a drug is made after a certain amount of time other companies can copy it and sell it for cheaper.
65
What are COPD (Chronic Obstructive Pulmonary disease) and Asthma examples of?
2 common inflammatory respiratory diseases.
66
What are the symptoms of COPD (Chronic Obstructive Pulmonary disease)?
Breathlessness , Emphysema and eventually respiratory failure as disease progresses.
67
What are 3 treatments for COPD (Chronic Obstructive Pulmonary disease) and what do they help with?
>B2 antagonists, muscarinic antagonists, corticosteroids >Treats symptoms and can slow down progression but doesn't stop the issue all together (like Rheumatoid arthritis)
68
What type of respiratory disease is Asthma?
Reversible Obstructive
69
What are 3 treatments for Asthma and what class of treatment are they in?
1) Bronchodilators >Salbutamol in inhalers 2) Anti-inflammatory agents >Prednisolone (steroid drug through inhaler) >Omalizumab (monoclonal antibody injected).
70
How does Salbutamol in inhalers act as a bronchodilator?
Agonist for B2 adrenoreceptors in airway smooth muscle, when activated cause relaxation of smooth muscle opening the airways up.
71
What type of receptor is B-adrenoreceptors and how do they work?
This is a GPCR that works by a Gs protein (adenyl cyclase)
72
Why would someone with Asthma have to use Anti-inflammatory agents (prednisolone & omalizumab) instead of Bronchodilators (salbutamol in inhalers)?
Some people have polymorphisms in b2-adrenoceptors associated with reduced efficacy of bronchodilators like salbutamol
73
At which stage is volume of air entering lungs at its lowest for asthma and in allergies and why?
>During the secondary response of the immune system less air can enter lungs >After an hour of the early response to an allergen, constriction progressively gets worse.
74
What is Allergic rhinitis and an example?
>inflammation of the inside of the nose (upper airways) caused by an allergen causing mast cell activation. >Hayfever
75
What area is restricted with allergic asthma?
Lower airways as well as upper airways.
76
What occurs during the early phase of Allergic Asthma?
Mast cells lining the airways bind with the allergen and secrete histamine and prostaglandins (inflammatory mediator) causing inflammation of airways by contraction/dilation of airways.
77
How is the early phase of allergic Asthma treated?
With Anti-histamines
78
What occurs during the late phase of Allergic Asthma?
Mast cells secrete cytokines (not histamine) leading to leukocyte infiltration (especially eosinophils) causing inflammation
79
What can Allergic Asthma lead to?
Chronic asthma where inflammation results in tissue damage and airway remodelling.
80
Why is the late phase of allergic asthma 4-5 hours after contact with the allergen?
2nd response is delayed as mast cells have to make cytokines and secrete them driving second late inflammatory response (4-5hours)
81
What is present on mast cells allowing allergens to bind?
IgE antibodies
82
What is the natural role of IgE antibody?
To stop parasite infection
83
What does it mean if someone is ATOPIC?
They are susceptible to allergies
84
How does salbutamol counteract the early phase of allergic asthma?
Salbutamol is an anatgonist for B2-adrenergic receptors counteracts histamine by dilating airways
85
What are 2 treatments we can use for late phase of allergic asthma?
> limited treatments, have to use glucocorticoids >If glucocorticoids are not working a biological drug is needed.
86
What occurs during Chronic Asthma?
>Thickening of airways (growth of smooth muscle cells) makes less stretchy and if exposed to allergens the responses come worse. >More mucus secreting cells too.
87
What class of drug is needed to treat Chronic asthma?
Biopharmaceuticals
88
Why do we need to limit the length of the late phase of allergic asthma?
The longer it lasts, the more damage to tissue caused and the more likely to have chronic asthma.
89
What is an unwanted side-effect over use of steroids?
Cushing Syndrome
90
How does Omalizumab treat asthma?
A monoclonal antibody which binds to IgE antibodies and preventing it from binding mast cells to trigger inflammation response in airways.
91
What are 2 issues for biopharmaceuticals in treating asthma?
>It is very expensive >It does not work for everyone
92
What are PGD2-R and how does it treat asthma?
>Small molecule drugs that work at the level of receptors. >PGD2-R is an antagonist for prostaglandins, decreasing the inflammatory response in airways.
93
What is an advantage to using PGD2-R over biopharmaceuticals?
PGD2-R are small molecule drugs which are cheaper

Pharmacology Year 2 (8 decks)

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