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BM324: Fundamental Pharmacology > Block C Lecture 1 - Pharmacological Modulators > Flashcards

Block C Lecture 1 - Pharmacological Modulators Flashcards

1
Q

What are the 3 criteria a substance needs to meet to be considered a mediator?

A
  1. It is released from local cells in sufficient quantity to mediate biological activity on target cells within an appropriate time frame
  2. Application of an authentic sample of the proposed mediator reproduces the biological effect
  3. Interference with the synthesis/release/actions of the mediator ablates/modifies the original biological response

(Slide 10)

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2
Q

What are eicosanoids?

A

A group of mediators that are generated from the fatty acid precursor arachidonic acids. They are not stored “pre-formed” in the cell

(Slide 11)

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3
Q

What can eicosanoids mediate?

A

Paracrine and autocrine signalling
(Slide 11)

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4
Q

What do eicosanoids not mediate?

A

Autocrine signalling
(Slide 11)

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5
Q

How quickly to eicosanoids degrade and what does this result in?

A

They degrade within about 30s - 5 mins, meaning they cannot travel far in the body
(Slide 11)

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6
Q

What are paracrine, autocrine and endocrine signalling?

A

Paracrine Signalling - cells release hormones that bind to nearby cells in order to communicate with them

Autocrine Signalling - A cell secretes a hormone that binds to receptors on the same cell, causing changes in the cell’s function

Endocrine Signalling - A cell releases hormones which bind to cells far away in order to transmit signals throughout the body

(Slide 12)

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7
Q

How is arachidonic acid freed from the membrane phospholipid bilayer?

A

Inflammatory stimuli paired with phospholipase A2 (PLA2) catalyses the hydrolysis of phospholipids, specifically cleaving phospholipid molecule to release arachidonic acid and a lysophospholipid

(Slide 13)

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8
Q

What does he type (class) of eicosanoid derived from arachidonic acid depend on?

A

The enzymes which are involved
(Slide 13)

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9
Q

What are the 3 pathways in which arachidonic acid can be converted to eicosanoids and what do these pathways produce?

A

Cytochrome P450 epoxygenase pathway - produces Epoxyeicosatrienoic acids

COX pathway - produces prostanoids (Prostaglandins + Thromboxanes)

Lipoxygenase (LOX) pathway - produces HETEs, Leukotrienes and Lipoxins

(Slide 13)

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10
Q

How do COX1 and COX 2 produce prostanoids?

A

Through oxygenation and cyclization of Arachidonic acid to give PGG2 and PGH2 intermediates
(Slide 17)

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11
Q

State 3 properties of COX1 enzyme.

A

Constitutive expression (constantly expressed)
Present in almost all cell types
Low to moderate PG release
Transient (short lived) release of PG
Protective roles in the kidney and stomach

(Slide 17)

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12
Q

State 2 properties of COX 2 enzyme.

A

Induced by inflammatory cytokines
Primarily present in inflammatory cells
Higher levels of PG formation
Sustained (constant) PG release
(Slide 17)

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13
Q

What is a well known inhibitor of both COX1 and COX2?

A

Aspirin
(Slide 17)

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14
Q

What type of receptors are prostanoid receptors?

A

GPCRs
(Slide 18)

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15
Q

What are the 5 types of prostanoid receptors we have identified?

A

Prostaglandin D2 (PGD2) receptors - DP1 and DP2

Prostaglandin E2 receptors - EP1 and EP4

Prostaglandin F Receptor - FP

Prostaglandin I2 (prostacyclin) receptors - IP1 and IP2

Thromboxane receptor (TP) - TPα (TXA2) and TPβ
(Slide 18)

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16
Q

What class of drugs does aspirin belong to?

A

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

(Slide 19)

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17
Q

How does arachidonic acid lead to decreased platelet aggregation and vasodilation in endothelial cells?

A
  1. COX2 metabolises arachidonic acid and promotes synthesis and release of PGI2.

2a. PGI2 acts of IP receptors on platelets and promotes coupling to Gs pathways

2b. PGI2 can also bind to smooth muscle cell IP receptors, causing vasodilation

3.This promotes the rise of adenylate cyclase and cAMP which will reduce platelet aggregation (through activation of PKA)

(Slide 20)

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18
Q

How does arachidonic acid lead thrombosis occurring?

A
  1. COX1 metabolise arachidonic acid, synthesising TXA2.

2a. Upon release, TXA2 binds to TP receptors on platelets and promotes G protein coupling events (Gq, G12/13) which lead to platelet shape changing and secretion leading to increased platelet aggregation

2b. TXA2 also binds to TP receptors on smooth muscle cells and then Gq-coupled events promote vasoconstriction.

  1. The pathways above will promote thrombosis when triggered

(Slide 20)

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19
Q

What do NSAIDs do?

A

They inhibit COX1 and COX 2 enzymes, in the process inhibiting prostaglandin and thromboxane synthesis, reducing inflammation

(Slide 21)

20
Q

NSAIDs have antithrombotic and analgesic effects. What do these mean?

A

Antithrombotic - Prevents formations of blood clots.
Analgesic - Relieves pain.

(Slide 21)

21
Q

What 3 side effects can the inhibition of COX1 be associated with?

A

Ulcers
Prolonged bleeding time
Kidney Problems
(Slide 22)

22
Q

What was the first COX2 selective NSAID developed?

A

Celebrex
(Slide 22)

23
Q

What are 2 examples of COX2 selective inhibitors that had to be taken off the marker or were rejected by the FDA (Food and Drug Administration)?

A

Vioxx
Bextra
(both withdrawn due to side effects)

Arcoxia
Prexige
(both rejected by the FDA due to liver complications)

(Slide 23)

24
Q

COX1 produces PGE2 - what is PGE2 responsible for in the GI mucosa and how does it do this?

A

It’s responsible for gastric protection, and it does this by increasing mucus secretion, bicarbonate concentration and mucosal blood flow

(Slide 23)

25
Q

What is bicarbonate and what is it responsible for?

A

It’s also known as hydrogen carbonate and has the chemical formula HCO3- it’s a negatively charged ion responsible for maintaining the bodies acid-base balance and helps maintain a stable pH
(Slide 23)

26
Q

How does increasing mucosal blow flow help promote gastric protection?

A

By supporting the physiological processes that maintain the integrity of the stomach lining, preventing damage from gastric acid, digestive enzymes, and harmful substances
(Slide 23)

27
Q

What are PGE2 (produced by COX1) and PGI2 (produced by COX2) responsible for in the kidney?

A

Afferent arteriolar vasodilation - resulting in an increase in glomerular filtration rate (GFR)

Increase NA and water excretion

(Slide 23)

28
Q

What are the side effect of inhibiting COX1 and 2 enzymes in the context of the kidneys?

A

Na and Water retention
Hypertension
Hemodynamic acute kidney injury (kidney dysfunction that occurs due to impaired blood flow)

(Slide 23)

29
Q

What is PG12 (produced by COX2) responsible for in the cardiovascular system?

A

Vascular vasodilation and inhibition of platelet aggregation

(Slide 23)

30
Q

What is TXA2 (produced by COX1) responsible for in the cardiovascular system?

A

Platelet aggregation and Vasoconstriction

(Slide 23)

31
Q

What are the context of COX2 -> COX1 inhibition in the cardiovascular system and why is this the case?

A

As COX2 is inhibited more than COX1, PGI2 is inhibited more than TXA2 is. As a result the risk of a stroke or myocardial infarction (heart attack) increases

(Slide 23)

32
Q

Why do NSAIDs cause damage to the GI tract?

A

As they are acidic
(Slide 24)

33
Q

How can we naturally inhibit the COX enzyme?

A

By introducing fish oils to our diet; fish oils provide alternative fatty acids to arachidonic acid and are metabolised into anti-inflammatory prostacyclins rather than pro-inflammatory prostaglandins

(Slide 24)

34
Q

What is a specific example of a lipoxygenase enzyme (LOX enzyme)?

A

5 lipoxygenase (5-LO)

(Slide 31)

35
Q

What 3 products does peroxidation of arachidonic acid by 5 lipoxygenase (5-LO) produce?

A

Leukotrienes (LTA4)
Hydroxyeicosatetraenoic acid (5-HETE)
Lipoxins

(Slide 31)

36
Q

What is peroxidation?

A

Peroxidation refers to the oxidative degradation of molecules, particularly lipids, in which, typically, reactive oxygen species (ROS) or oxygen itself interact with the molecules, leading to the formation of peroxides (5-LO isnt an ROS though)

(Slide 31)

37
Q

What is 5-HETE converted into?

A

LTA4
(Slide 32)

38
Q

What is LTA4 converted into?

A

LTB4 and cysteine leukotrienes LTC4, LTD4 and LTE4
(Slide 32)

39
Q

What 3 types of cells produce leukotrines?

A

White blood cells, mast cells and platelets
(Slide 32)

40
Q

What are the functions of the BLT1 and BLT2 receptors?

A

BLT1 - Primarily involved in chemotaxis and immune cell recruitment

BLT2 - Immune regulation and chronic inflammation

(Slide 33)

41
Q

What are the functions of CysLT1 and CysLT2 receptors?

A

CysLT1 - Causes bronchoconstriction, increased vascular permeability and immune cell activation

CysLT2 - Modulate inflammation and are thought to have an anti-inflammatory response, reducing bronchoconstriction and vascular permeability

(Slide 33)

42
Q

What are 4 examples of inflammatory diseases the LTB4 leukotriene can contribute to?

A

Answers Include:

Atherosclerosis (the build-up of fats, cholesterol and other substances in and on the artery walls)

Rheumatoid arthritis

Inflammatory bowel disease

Cancer

Inflammatory pathways in obesity

Insulin resistance

(Slide 34)

43
Q

What are 2 examples of inflammatory disease that Cys-LTs (LTC4, LTD4 and LTE4) contribute to?

A

Asthma

Atherosclerosis

Inflammatory Bowel Disease

(Slide 34)

44
Q

What is an example of a 5-LO inhibitor and what condition is it used to treat?

A

Zileuton - used in clinical treatment of asthma

(Slide 35)

45
Q

What is an example of a CysLT1 antagonist and what is it used to treat?

A

Montelukast and Zafirlukast - used for treatment asthma and seasonal allergy

(Slide 35)

46
Q

What are 2 methods other than inhibiting COX that can be used to block arachidonic acid inflammation?

A
  1. Inhibiting PLA2 - blocking mediated arachidonic acids release from the membrane. This is done via steroids promoting the synthesis of lipocortin, which inhibits PLA2
  2. Promoting synthesis of anti-inflammatory lipoxins over prostanoids - aspirin does this

(Slide 35)

BM324: Fundamental Pharmacology (12 decks)

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