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Unit 11 > W3: Pharmacology of Inflammation > Flashcards

W3: Pharmacology of Inflammation Flashcards

1
Q

What pain killer is normally associated with arthiritis?

A

Steroids

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2
Q

What painkiller is normally associated with injury?

A

NSAIDs

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3
Q

What is the chemical origin of aspirin?

A

Salicylic acid (willow bark)
Is acetylated to form acetylsalicylic acid - this is the aspirin compound.

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4
Q

What are the clinical used of aspirin?

A

Like all NSAIDs it is:
- analgesic
- anti-pyretic
- anti-inflammatory

Unique to aspirin: is an anti-thrombotic

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5
Q

What are the pathological localised responses in inflammation that can be targeted by drugs?

A

Vasodilation - increased blood flow
Increased blood vessel permeability - leakiness
Increased neuronal sensitisation - causes pain

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6
Q

What are the different types of mediators of inflammation?

(aware not memorise)

A

Peptides: bradykinins, neuropeptides (substance P), C3a C5a, thrombin
Cytokines: IFN-alpha, IFNy, TNFalpha
Small molcules: Histamine, seratonon, ATP, adenosine
Free radicals: NO, ROS
Lipids: Eicosanoid, platelet activating factor

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7
Q

What is an eicosanoid?

A

A lipid that mediates inflammation.
Lipid based signalling molecules derived from arachidonic acid that have a role in the innate immune response.

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8
Q

Describe the structure of a lipid membrane bilayer

A

Hydrophobic tails (two fatty acid chains)
Hydrophilic heads (phosphate group potentially with an additional group bound)
Arranged in two layers with tails facing inwards towards each other.
Two groups are joined by binding to glycerol.

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9
Q

What is the structure of arachidonic acid?

A

Consists of 20 carbons and 4 unsaturated bonds (polyunsaturated fatty acid)
C20:49(ω:6)
As when starting from terminal omega carbon first double bond is on carbon six.

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10
Q

How does arachidonic acid link to the structure of the lipid membrane?

A

Can be found on C2 on the phospholipid
Makes up some of the hydrophobic tails.

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11
Q

What is the structure of eicosapentaenoic acid?
What is its useful function clinically?

A

Fatty acid -COOH group
20 carbons
5 unsaturaded bonds
ω3

Reduce cardiovascular deaths**

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12
Q

What enzymes are involved in the degradation of phospholipids?
Phospholipase A2 is the one to memorise

A

Phospholipase A1 - hydrolyse ester bond at sn1 position
IMPORTANT ONE ONLY - Phospholipase A2 - hydrlyse ester bond at sn2 position
Phosphlolipase C -hydrolyse glycerophosphate bond
Phospholipase D - released head group of phospholipid molecule

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13
Q

Describe how active prostaglandins are made via the COX pathway?

A

Arachidonic acid is released from membrane phospholipids by phospholipase A2.
Arachidonic acid is then converted to Prostaglandin G2 by COX enzyme (dioxygenase reaction)
Then converted to prostaglandin H2 by COX enzyme (peroxidation) (commitment step in prostaglandin production)

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14
Q

Why is COX considered a bifunctional enzyme?

A

Catalyses two reactions
1. Dioxygenation of arachidonic acid
2. Peroxidation of PGE2 (this COX action can also be referred to as PGE2 synthase)

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15
Q

What is the pharmacology of aspirin?

A

Targets cyclo-oxygenase enzyme
Acts as an irreversible inhibitor
Acetylates the Ser530 residue in the COX enzyme, this residue is found within the active site of the cox enzyme.
Aspirin is converted to salicylic acid in the process.
Therefore preventing the binding of arachidonic acid to the COX enzyme.

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16
Q

Why does the production of prostaglandins vary between different tissues?

A

Different tissues will produce different enzymes
Different enzymes will be responsible for converting PGH2 to different terminal prostaglandins.

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17
Q

What are the five different types of prostaglandins produces at the end of PG synthesis?

A

PGD2
PGF2alpha
PGE2
TxA2
PGI2

Note the number refers to the number of double bonds

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18
Q

How is PGD2 produced?
What receptor does it act on?

A

PGH2 converted by PGD2 synthase
Binds to DP1 and DP2 receptors
Can be converted to PGF2 by PGF synthase

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19
Q

How is PGF2alpha produced?
What receptor does it act on?

A

PGD2 converted by PGF2alpha synthase
PGE2 convereted by PGE2 9-ketoreductase
Also can be produced from PGH2
Acts of FP receptors

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20
Q

How is PGE2 produced?
What receptor does it act on?

A

PGH2 converted to PGE2 synthase
Acts on EP1,2,3,4 receptors

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21
Q

How is thromboxane produced?
What receptor does it act on?

A

PGH2 converted by thromboxona synthase
Acts of TP receptors

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22
Q

How is PGI2 produced?
What receptor does it act on?

A

PGH2 converted by PGI synthase
Acts on IP receptors

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23
Q

What are the common features of prostanoid receptors?

A

GPCRs
Expressed in different levels in different tissues

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24
Q

How does the naming of drugs relate to their effect on prostaglandins?

A

prost - agonists
piprant - antagonist

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25
Q

What is the role of treprostinil?

A

is a PGI2 analogue
IP receptor agonist
Causes vasodilation
Used to treat hypertension in pulmonary arteries

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26
Q

What is the physiological role of PGD2?

A

Produced by mast cells, CNS, heart and male reproductive organs.
Role in allergic inflammatory response, vasodilatory and a chemoattractant

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27
Q

What is the physiological role of PGF2alpha?

A

Is wideley expressed including by the female reporductive system
Responsible for uterine contractions and luteolysis

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28
Q

What is the physiological role of PGE2?

A

Is widely expressed
Causes inflammation, fever, nerve sensitisation (pain) and vasodilation

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29
Q

What is the physiological role of TxA2?
Thromboxane

A

Produced by platelets, lungs etc
Role in platelet activation and vasoconstriction

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30
Q

What is the physiological effects of PGI2?

A

Is widely expressed, including by the endothelium.
Role in platelet inhibition and vasodilation (feature of inflammation)

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31
Q

Why are prostaglandins only suited to be para/autocrine?

A

Very short half life.

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32
Q

What are the mechanisms underpinning the anti-inflammatory effects of NSAIDs?

A

PGE2/D2 reduced as production inhibited
Do not function - inhibits vasodilation (increased blood supply and fluid extravasation)

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33
Q

How do NSAIDs act as anti-pyretics?

A

Inhibit PGE2 production
Inhibit PGE2 from acting as an endogenous pyrogene on the hypothalamus.

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34
Q

How do NSAIDs act as analgesics?

A

Inhibit PGE2 prodcution
Inhibit action of sensitising free nerve endings

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35
Q

How can the decrease in thromboxane caused by NSAIDs have varying effects in different patients?

A

Less Thromboxane produced by platelets
Some patients is beneficial as an anti-thrombotic to reduce risk of MI
Some patients have side effects as also anti-haemostatic - so increased risk of bleeding.

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36
Q

How do prostaglandins sensitise free nerve endings?

A

Bind to prostanoid receptor
Particularly PGE2 binding to EP1,2,3,4 receptors
Activates Protein Kinase A
Increases the number of active voltage gated sodium ion channels in the cell membrane - leads to increased chance of depolarisation reaching threshold.

37
Q

What are the negative effects of prostaglandins?

A

Sensitise nerve endings
Potentiate action of vasodilators
Mediate thermoregulatory centre response to infection

38
Q

What are the beneficial physiological effects of prostaglandins?

A

Gastro-protective effects (HCO3- production and increased mucosal blood flow)
Regulate renal blood flow.

39
Q

What are the main differences between COX-1 and COX-2?

A

Both are inhibited by NSAIDs
COX-1 is constitutive (e.g platelets, gut, kidney etc) and has physiological effects - therefore its inhibition causes negative side effects.
COX-2 is inducible by macrophages and inflammatory cells so only present in pathological inflammatory conditions - therefore its inhibition by NSAIDs has positive or desired effects.

40
Q

What is the purpose of —-coxib drugs?

A

Are NSAIDs that selectivly inhibit COX-2
THis reduces the adverse events/ side effects of NSAIDS
However, have increased cardiovascular side effects.

41
Q

Suggest why COX-2 selective inhibitors have more cardiovascular side effects than cox-1 inhibitors?

A

Inhibits PGI2 production
Do not inhibit thromboxane production which is associated with cox-1
Overall results in increased platelet aggregation which increases risk of stroke and MI/

42
Q

What type of drug is etoricoxib?

A

A cox-2 selective NSAID

43
Q

What is the chemistry of steroids?

A

All have a shared gonane structure - 17 carbon atoms aranged in a four ringed strcutre with double bonds.
Sterols - contain an additional -OH group at the first ring.
Steroid - indicates a structure similar to a sterol

44
Q

What is the role of cholesterol in the body?

A

Is an endogenous steroid.
1)Present in cell membranes - amphipathic
Decreases membrane fluidity at high temperatures
Increases membrane fluidity at low temperatures.
2) Synthetic precurose - bile, Vitamin D and steroid hormones
3) pathological role in atherosclerosis

45
Q

What are the different types of corticosteroids?
How are they all similar?

A

Synthetic versions of hormones that are all produced in the adrenal cortex and share a similar gonane structure base.
1) Glucorticoids
2) Mineralcorticoids
3)Sex steroids

46
Q

What is the role of glucorticoids?

A

For example cortisol
Have anti-inflammatory or immunsuprresant affects at low doses
Have multiple metabolic effects - (hyperglycemia and insulin resistance)
Mange stress
Maintain homestasis
Wide spread effects

47
Q

What is the role of mineralcorticoids?

A

For example aldosterone
Regulate fluid and electrolyte homeostasis
Role in the RAAS system( increase Na+ and H2O reabsoprtion in the kidney and increase K+ and H+ excretion in the kidney)

48
Q

What is the role of sex steroids?

A

INflucne the development of secondary sec characteristics.
Can be produces in the adrenal gland (more in children) and the gonads (from puberty onwards)

49
Q

What region in the kidney produces what type of hormones?

A

Zona glomerulosa - mineralocorticoids
Zone fasiculata - glucorticoids
Zone reticularis - sex steroids (androgen)
Medulla - adrenaline

50
Q

What are the three different types of oestrogen?

A

Estrone
Estradiol
Estriol

All share an oestrogen-based structure that is common but with unique modifications.

51
Q

What are the main endogenous glucorticoids?

A

Corticosterone
Cortisol.

52
Q

How can the effects of glucorticoids be classified?

A

Metabolic - catabolic, breakdwon of protein and carbohydrate, stimulate glucoenoengensis in the liver (hyperglycemia), increase appetite (obestiy) can increase breakdwon and deposition of lipids
Cardiovascular - increase blood pressure
Immune - streee protective response, decrease inflammation/wound healing and increase risk of infection
Other: osteoporosis, pro-apototic, can affect CNS function (mood, temp, neurodengeration)

53
Q

Where in the body can steroids act?
Why?

A

Can distribute throughout the body as are lipid soluble so can cross cell membranes.

54
Q

What is the pharmacology of steroids?

A

Bind to cytoplasmic steroid hormone receptors.
Cause dissociation from heat shock (chaperone) proteins and heterodimerisation
Active recetor translocates to the nucleus and acts as a transcription factor
Binds to glucorticoid respose element specific sequences on DNA.
Brings about physiological effects by modifying gene expression

55
Q

What are the different receptors of steroids?

A

Are NR3 class receptors
GR for glucorticoids - wide anatomical distribution
MR for mineralcorticoids - limited to mostly the kidney
Sex steroids - PR (progesterone), AR (androgen) ERalpha and beta for oestrogen.

56
Q

What is the relationship between cortisone, cortisol and corticosterone?**

A

Cortisone (oxidized) is a precursor for cortisol (reduced) and aldosterone, a dominant stress hormone in mice. Is inactive at MR and GR receptors.
Corticosterone - manufactured cortisol
Cortisol - manufactured drug that mimics the effects of endogenous cortisone, also endogenous dominant stress hormone in humans.

57
Q

What are the alternative names for cortisone, cortisol and corticosterone?

A

Cortisone = compound E
Cortisol = hydrocortisone
Corticosterone = 17-deoxy-cortisol.

58
Q

Why is there very little cross-reactivity between glucocorticoid and mineral corticoid receptors?

A

In order to react at receptors cortisone must be converted to cortisol.
GR are associated with location with higher 11Beta-HSD type 1 (reductase) that catalyses to cortisol so active and able to interact
MR and associated with 11Beta HSD type 2 receptors (dehydrogenase) whic convenrtes active cortisol back to cortisone so unable to bind to receptor.

59
Q

What is the role of 11beta-HSD type 1 in glucorticoid metabolism?

A

Is widely distributed across the body
Amplifies the effect of glucocorticoids on GR.
Is a reductase, converts cortisone (inactive) to cortisol (active) hence allows binding to receptor

60
Q

What is the role of 11beta-HSD type 2 in glucorticoid metabolism?

A

Has a restricted distribution mainly in the renal tubules.
Is a dehydrogenase, converts cortisol (active) to cortisone (inactive)
Prevents cortisol (a glucorticoid) from reacting at MR receptors despite having a high IC50.

61
Q

What is the role of liquirice in hypertension?

A

Glycrrhizin inhibts 11beta-HSD type 2 - leads to increased activated cortisol in renal tubules - bind to MR receptors and cause hypertension by mimciking the effects of aldosterone.

62
Q

What is the cross reactivity between glucorticoids and mineralcorticoids?

A

Glucorticoids in theory could react with MR receptors
Mineral corticoids have very little activity at GR receptors

63
Q

What is meant by transactivation and transrepssion?

A

Transactivation - increased gene transcription
Transrepression - decreased gene transcription

64
Q

How do glucorticoids cause basic transactivation?

A

Activates glucroticoid receptor binds to glucorticoid response element on DNA and activates transcription machinery
Acts as a transcription factor

65
Q

How do glucocorticoids cause basic transrepression?

A

Normally - trascription factor causes activation of transcription machinery
Activated glucorticoid receptor binds to negative glucorticoid response element
Causes dissociation of transcription factor, hence the transcription machinery is not activated.

66
Q

What are the glucorticoid response elements?

A

Specific sequences of DNA where glucocorticoid receptors can bind to bring about their effects
Contain Zn fingers that coordinate with 4 cysteine residues on the DNA molecule, consisting of two symmetrical subunits that sit within the major groove of the DNA helix.
Binds to a palindromic sequence of DNA.

67
Q

How do glucocorticoids influence mediated transrepression?

A

1) In absence of glucocorticoid Fos and Jun subunits dimerise to form an AP-1 transcription factor that binds to a promotor region and activates transcription machinery. GLucorticoids interfere with and suprress this so transcription machinery is not turned on.
2) Also interfere with the action of NFkappaB transcription factors - inhibits them from activting trasncription machinery.
This reduces the expression of genes such as pro-inflammatory cytokines, COX and growth factors.

68
Q

What are glucocorticoid-regulated proteins?

A

Approximately 10% of genes are modulated by GCs (not all of which are related to inflammation)
A glucorticoid regulated protein just means its level of transcription can be altered by glucorticoids.

69
Q

What proteins are up-regulated by glucorticoids?

A

1)Annexin A1 - this inhibits phospholipase A2 - leading to lower arachidonic acid - leads to lower prostaglandins, platelet-activating factor and leukotrienes.
2) Anti-inflammatory cytokines such as IL-1 receptor antagonist and IL-10.

70
Q

What proteins are downregulated by glucorticoids?

A

COX-2
iNOS
Phospholipase A2
Pro-inflammatory cytokines such as TNFalpha and IL-1

71
Q

What are the humeral affects of glucocorticoids on the immune and inflammatory responses?

A

Decreased mediators of inflammation
Decrease PG synthesis, decrease H2 release, decrease NO generation and decreased complement activation

72
Q

What are the cellular effects of glucorticoids on inflammation and immune responses?

A

Decreased neutrophil migration into tissues
Decreased T cell activation/proliferation
Decreased B cell activation/proliferation hence less IgG production

73
Q

What is the use of dexamethasone in covid-19?

A

Clinical trials showed a slight decrease in mortality compared to usual treatment.

74
Q

What are the side effects of corticosteroids?

A

Are diverse and substantial on all body systems.
Cushing syndrome:
Menstraul cycle changes and moon facies
Osteopenia/osteoporosis
Obesity
Neurosis - depression
Faces - acne, plethora
Altered muscl physiology (muscle weakness)
Supra-clavicular and dorso-cerivcal fat fats
Infection risk
Elelvated blood pressure
Skin - easy bruising
Adrenal suppression

75
Q

What is the moa of prednisone?

A

Chemistry: Synthetic glucorticoid - converted to active prednisolone
Pharamocology: primary target is GR, secondary target with minimal activity in MR, is an agonist at both.
Physiology: Alters genes expression, increase anti-inflammatory cytokines such as IL-10and Annexin A1 (which inhibits PLA2), decreases inflammatory molecules such as COX and TNFalpha
Desired effects: anti-inflammatory and anti-allergy
Adverse effects: Cushing syndrome and hypertension

76
Q

Compare and contrast the use on NSAIDs and steroids.

A

Steroids - very potent, severe and predictable side effects, non-selective action (affect many genes), are the best drug available for many conditions

NSAIDs - limited but real effects and adverse events, targeted action, first line drug for many conditions. Less potent that NSAIDs as mainly focused on the vascular phase.

77
Q

What other less common drugs can also be used as anti-inflammatories?

A

EP4 receptor antagonist - gapiprant
Leukotriene receptor antagonist - montelukast
Lipoxygenase inhibits - zileuton
Anti-TNFalpha - infliximab
Anti-ILs - Tocilizumab
DMARDs - methotrexate etc
H1 receptor antagonists - fexofenadine

78
Q

What is the pathophysiology of gout?

A

Nucleic acids are broken down into xanthine
Xanthine is converted to uric acid by xanthine oxidase.
An accumulate of uric acid due to increased production or decreased excretion results in an increased deposition of urate crystals particularly in the joint bone or cartilage, which present as tophi (large urate crytsals)
This triggers inflammation

79
Q

Can NSAIDs and steroids be used in gout?

A

Yes, but not aspirin.

80
Q

What is the use of allopurinol in gout?

A

Is a purine analgoue
Targets xanthine oxidase - inhibits it.
Leads to decreased uric acid prodcution.
This treats hyperureiceamia and is a prophylaxis for gout

81
Q

What is the use of febuxostat in gout?

A

Is a non purine
Inhibits xanthine oxidase
Decreases ric acid production leads to lover uric acid levels
Treats chronic hyerpuricaemia and gout

82
Q

What is the role of colchicine in gout treatment?

A

Is a natural alkaloid
Inhibits beta tubulin
This decreases mitotic spindle formation - this disrupts leukocyte function
Treats hyperuricaemia and gout

83
Q

What is the role of probenecid in gout treatment?

A

Is a small molecules
Inhibits OAT1 transporter in renal tubules
Leads to less urate uptake in the renal tubules
This increases urci acid excretion hence treats hyperuricaemia and gout.

84
Q

What is the role of rasburicase in gout treatment?

A

Is a recombinant enzyme
Targets urate and acts as urate oxidase.
Results in conversion of urate to allantione
This decreases uric acid levels
Used to treat hyperuricaemia and tumour lysis syndrome

85
Q

What is the function of canakinumab in gout treatment?

A

Is a recombinant IgG
Binds to and neutralisis IL-1beta
This reduces the amount of IL-1beta that is able to bind to its receptor, therefore decreases IL-1 mediated inflammation
Acts as an anti-inflammatory and treatment for gouty arthiritis.

86
Q

What is the therapeutic anlagesic ladder?

A

Start with non-opiods such as NSAIDs and paracetamol
Weak opiods - such as tramadol, codeine and low dose morphine
Stong opiods - fentanyl and morphine
May also add adjuvants to help the drug work.

87
Q

How does the mechanism of asprin vary from other NSAIDs?

A

Aspirin is a irreversible inhibitor
Other NSAIDs are a competitive inhibitor
Of cox enzymes

88
Q

What are the undesired clinical effects of NSAIDs?

A

GIt ulceration and bleeding
Adverse renal effects - reduce renal blood flow and decrease GFR.

Unit 11 (21 decks)

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