8.0 Inflammation Flashcards

Question 1

Q

What is the triple response of Lewis?

Answer

A

1) Flush Local vasodilation within seconds (due to histamine) 2) Flare Neurogenic imflammation within 30-60 seconds 3) Wheal Increase vascular permeability causes plasma leakage Few minutes

Question 2

Q

What is dermatographic urticaria?

Answer

A

“Exaggerated triple response "”Skin writing”“ May be triggered by drugs (e.g. penicillin) Treatment = antihistamines + Omalizumab”

Question 3

Q

What is the effect of prostaglandins (PGE2 + PGI2)?

Answer

A

Vasodilation

Question 4

Q

What is the effect of histamine?

Answer

A

Vasodilation and ↑ vascular permeability

Question 5

Q

What is the effect of TNF-a/IL-1?

Answer

A

More cytokine release Permeability Express adhesion molecules

Question 6

Q

Role of: 1) C3a 2) C3b 3) C5a 4) C5b-C9

Answer

A

1) C3a Mast cell stimulation 2) C3b Opsonisation 3) C5a Activates mast cells 4) C5b-C9 MAC 1 of each factor apart from C9 (12-18 C9s)

Question 7

Q

What do mast cells release following stimulation?

Answer

A

1) Histamine 2) Heparin 3) Leukotrienes 4) Nerve growth factor 5) Preformed cytokines

Question 8

Q

What cells contain histamine?

Answer

A

1) Mast cells - found in acidic granules with HMW heparin 2) Basophils - found in acidic granules with HMW heparin 3) Enterchromaffin-like cells 4) Histaminergic neurons of the brain

Question 9

Q

What particles cause mast cell degranulation?

Answer

A

“<div><img></img></div>”

Question 10

Q

Role and GPCR for the 4 histamine receptors?

Answer

A

“H1 - Smooth muscle contraction (ileum + bronchioles) - Blood vessel dilation - Itching - Triple response H2 - Increase heart rate - Increase gastric acid secretion<div> </div><div><img></img></div>”

Question 11

Q

What 2 enzymes metabolise histamine?

Answer

A

1) Histaminase - Deaminates histamine → imidazole acetaldehyde 2) Histamine-N-Methyltransferase - Transfers methyl group to nitrogen on imidiazole ring → N-methylhistamine Imidazole acetaldehyde + N-methylhistamine are inactive at H receptors

Question 12

Q

What is mastocytosis?

Answer

A

“<div><img></img></div>”

Question 13

Q

Whats the problem with 1st generation antihistamines?

Answer

A

Crossed BBB → drowsiness

Question 14

Q

Whats the problem with 2nd generation antihistamines?

Answer

A

Had an effect on hERG → long QT syndrome

Question 15

Q

What cells in the stomach secrete HCl?

Answer

A

Parietal cells

Question 16

Q

What is the pathway of HCl secretion?

Answer

A

“<div><img></img></div>”

Question 17

Q

Synthesis pathway for bradykinin:

Answer

A

“<div><img></img></div>”

Question 18

Q

What inhibits kallikrein?

Answer

A

C1 esterase inhibitor Deficiency in this → hereditary angioedema

Question 19

Q

What inactivates bradykinin?

Answer

A

Kinases Kinase 1 → des-Arg-bradykinin Kinase 2 (ACE) → Inactive kinin

Question 20

Q

What are the receptors for bradykinin and what are their agonists?

Answer

A

B1 (↑ in inflammation) : agonist = des-Arg-bradykinin B2 (constitutive) : agonist = bradykinin + Kallidin

Question 21

Q

Structure of arachidonic acid:

Answer

A

(5,8,11,14-eicosatetetroenoic acid) 20 carbon unsaturated fatty acid 4 double bonds

Question 22

Q

Mechanism of COX inhibition for most NSAIDs?

Answer

A

Reversible inhibition - Enter hydrophobic channel in enzyme - Hydrogen bond with Arg120 - This interaction prevents arachidonic acid from entering the catalytic domain

Question 23

Q

Differences between COX1 + COX2 hydrophobic channels?

Answer

A

COX1 = narrow hydrophobic channel COX2 = wide hydrophobic channel

Question 24

Q

How is selective COX-2 inhibition achieved?

Answer

A

Drugs contain a bulky sulphur side chain - thus the drug is too big to fit into the narrow hydrophobic channel of COX-1 COX-2 selective inhibitors tend to end in -coxib

Question 25

Q

Where is serotonin found?

Answer

A

1) Serum - Released by platelets during activation and aggregation - Causes further aggregation of platelets and vasoconstriction 2) Intestinal enterochromaffin cells 3) Serotonergic neurons (ENS + CNS)

Question 26

Q

What are the metabolic actions of steroids?

Answer

A

o ↓ uptake of glucose by muscles/fat o ↑ gluconeogenesis o ↑ protein catabolism o ↓ protein anabolism o Redistribution of fat

Question 27

Q

What are the anti-inflammatory actions of steroids?

Answer

A

• Anti-inflammatory actions: o ↓ influx/activity of leukocytes o ↓ activity of monocytes o ↓ clonal expansion of T and B cells o Switch from Th1 to Th2 response o ↓ pro-inflammatory cytokine production/action (e.g. IL-1, IL-2, IL-5, TNF-α) o ↓ eicosanoid production o ↑ release of anti-inflammatory factors (IL-10, IL-1ra, lipocortin 1, secretory leukocyte inhibitory protein and IkB) • Overall → ↓ activity of innate and acquired immune system (beneficial in some conditions)

Question 28

Q

What are the side effects of steroids?

Answer

A

“•Side effects (seen with large + prolonged doses): o Opportunistic infection (∵ ↓ immune system) o Impaired wound healing o Oral thrush (candidiasis) o Osteoporosis o Hyperglycaemia (∵ glucose metabolism effects) o Muscle wasting o Cushing’s syndrome (see diagram)<div> </div><div><img></img></div>”

Question 29

Q

Adalimumab

Answer

A

Class = Human monoclonal antibody - Target = TNF α - Mechanism = sequesters excess TNFa in rheumatoid arthritis - Steps: - Info: Treatment: Rheumatoid arthritis

Question 30

Q

Alemtuzumab

Answer

A

Class = Monoclonal antibody - Target = CD52, an antigen on mature (but not precursor) lymphocytes - Mechanism = Targets T lymphocytes for destruction - Steps: - Info: • Administered several times a week • Few off target side effects, as with all monoclonal antibodies • Used for treating CLL + T cell lymphomas

Question 31

Q

Anakinra

Answer

A

Class = Recombinant IL-1 receptor antagonist - Target = IL-1 receptor - Mechanism = Antagonist - Steps: Blocks IL1- dependent signalling ⟶ ↓ inflammation in rheumatoid arthritis - Info: • ↑ susceptibility to infection Treatment: Rheumatoid arthritis

Question 32

Q

Arthrotec

Answer

A

Class = Combined NSAID + synthetic PGE₁ - Target = COX + PGE₁ receptors - Mechanism = Diclofenac + misoprostol - Steps: Misoprostol → GI protective because ↑ bicarbonate secretion and ↓ HCl secretion - Info: Used in chronic treatment of RA (to prevent peptic ulceration)

Question 33

Q

Aspirin

Answer

A

Class = NSAID - Target = COX-1 + COX-2 (weakly COX-1 selective) - Mechanism = Irreversible inhibition - Steps: • Acetylation of serine 530 in active sites of COX-1 and COX-2 - Info: • Permanently blocks TXA2 production in platelets, but only temporarily blocks PG production in endothelial cells (because they are replaced quicker) ∴ overall effect is ↓ platelet aggregation • Inhibition of COX-2 → producing 15R-HETE (instead of intermediates for PG and TXA2) • 15R-HETE is converted by 5-LO → aspirin-triggered lipoxin (ATL) which has anti-inflammatory functions Treatment of: Pain/flu/cold/prophylaxis Side effects: Gastric bleeding, renal insufficiency, Reye’s syndrome, Salicylism

Question 34

Q

Azathioprine

Answer

A

Class = Immunosuppressant - Target = De novo purine synthesis and nucleotide and protein synthesis - Mechanism = Inhibits B cell and T cell proliferation - Steps: • Prodrug for 6-mercaptopurine (6-MP), which is converted by hypoxanthine prosphoribosyl transferase (HPRT) to thioinosic monophosphate (TIMP), which is then converted to produce two products that have inhibitory effects upon DNA function - MeTIMP, which inhibits de novo purine synthesis, and 6-thioguanosine nucleotides (6-TGN) which are incorporated into cellular nucleic acids to inhibit nucleotide and protein synthesis. Collectively, the result is impaired cellular proliferation, particularly of B and T cells - Info: Treatment: preventing transplant rejection, IBS and rheumatoid arthritis Side Effects: Bone marrow suppression

Question 35

Q

Basiliximab

Answer

A

Class = Monoclonal antibody - Target = CD25 alpha subunit of the IL2 receptor on T cells - Mechanism = Blocking antibody - IL2 receptor antagonist - Steps: IL-2 receptors are upregulated on T cells and B cells following activation, and are required for clonal expansion. By blocking this receptor to prevent autocrine signalling via IL2 following antigen recognition, basiliximab can prevent T and B cell proliferation - Info: Treatment: Used to decrease the incidence and severity of acute transplant rejection (immunosuppressant)

Question 36

Q

Ciclosporin A

Answer

A

Class = Immunosuppressant - Target = Cylophilin (a Th cell cytoplasmic protein) - Mechanism = Prevents T cell proliferation via suppression of IL-2 synthesis - Steps: Usually an interaction of an antigen with a Th cell causes an increase in cytosolic Ca²⁺ that stimulates the activity of calcineurin, a phosphatase. Calcineurin dephosphorylates the transcription factor NFAT to promote its nuclear localisation, where it acts to promote IL-2 gene expression to induce proliferation. Ciclosporin A binds to a cytosolic protein, cylophilin. The ciclosporin-cyclophilin complex binds and inhibits calcineurin, thereby preventing IL-2 expression and T cell proliferation - Info: Cyclic 11 amino acid peptide Treatment: immunosuppressant in preventing transplant rejection

Question 37

Q

Dexamethasone

Answer

A

Class = Corticosteroid - Target = Glucocorticoid receptor - Mechanism = Agonist - Steps: • Binds to glucocorticoid receptor (GRα) in cytoplasm • This promotes its dissociation from HSP90, dimerization and translocation to the nucleus • In the nucleus the homodimer activates/represses glucocorticoid gene expression in 4 ways to mimic the action of endogenous glucocorticoids - Info: • Long acting (t1/2 = >48hrs) Treatment of: Inflammatory conditions Side effects: CUSHINGOID

Question 38

Q

Etanercept

Answer

A

Class = Anti-rheumatoid arthritis drug - Target = TNF α - Mechanism = Sequestration - Steps: Sequesters the high levels of TNFa that occur in rheumatoid arthritis - Info: •A fusion protein of the soluble TNFa receptor and the Fc portion of IgG1 Treatment: Rheumatoid arthritis

Question 39

Q

Etoricoxib

Answer

A

Class = NSAID - Target = COX-2 selective - Mechanism = Inhibition - Steps: • Bulky sulphur side group molecule ∴ too big to enter channel of COX-1 • Forms hydrogen bond with Arg 120 - Info: Treatment: Inflammation (useful in non-selective NSAID poses GI risk) Side effects: May pose a CVS risk by ↓ basal COX-2 in tissues with constitutive expression

Question 40

Q

Ibuprofen

Answer

A

Class = NSAID - Target = COX (non-selective) - Mechanism = Inhibition - Steps: • Small molecule ∴ enters the hydrophobic channel of both COX-1 and COX-2 • Forms hydrogen bond with Arg 120 - Info: Treatment: Inflammation Side effects: Main one is GI bleeding (∵ ↓ PG)

Question 41

Q

Icatibant

Answer

A

Class = Selective B2 receptor antagonist - Target = B2 receptor (bradykinin receptor) - Mechanism = Antagonist - Steps: Antagonist ⟶ ↓ vasodilation - Info: Treats hereditary angioedema (HAE)

Question 42

Q

Loratidine

Answer

A

”- Class = H1 antagonist (3rd generation) - Target = H1 receptor - Mechanism = Antagonist - Steps: • H1 receptors are Gq coupled ⟶ PLCβ ⟶ PKC activation + Ca2+ influx •Antagonism of H1 receptors → 1) Smooth muscle relaxation in the ileum, bronchioles and uterus 2) ↓ endothelial release of NO and consequential vasodilatation 3) ↓ triple response in inflammation - Info: 3rd gen drugs are non-drowsy and lack cardiac side effects Treatment of hay fever and urticaria<div> </div><div><img></img></div>”

Question 43

Q

Methotrexate

Answer

A

Class = Folic acid antagonist (DMARD) - Target = DHFR (dihydrofolate reductase) - Mechanism = Inhibition - Steps: Disruption of nucleotide synthesis ⟶ disruption of DNA replication Helps with Rheumatoid arthritis because prevents leukocyte proliferationpe - Info: ↑↑ use of methotrexate ⟶ toxicity to normal cells (leucovorin can help with this)

Question 44

Q

Naproxcinod

Answer

A

Class = Naproxen (Non-selective COX inhibitor) + NO - Target = COX / soluble guanylyl cyclase - Mechanism = Combination drug of naproxen and NO donor - Steps: - Info: Inflammatory conditions - prevent gastric bleeding. Phase III trials did not show any improvement of side-effects ∴ not used

Question 45

Q

Omalizumab

Answer

A

Class = Humanised monoclonal antibody - Target = IgE - Mechanism = Blocks IgE → prevents mast cell degranulation - Steps: Binds Cε3 region of IgE to prevent is binding to FcεRI on mast cells ∴ causes reduction of FcεRI expression and prevents degranulation - Info: Treatment of: • Dermatographic urticaria • Severe asthma (with no response to β2 agonists and corticosteroids) Built on IgG framework and therefore does not activate FcεRI itself

Question 46

Q

Omeprazole

Answer

A

Class = Proton pump inhibitor - Target = K⁺ / H⁺ pump on parietal cells - Mechanism = Inhibits pump - Steps: Inhibits pump ⟶ ↓ HCl secretion - Info: Treatment of: GORD + peptic ulceration (preferred treatment)

Question 47

Q

Ondansetron

Answer

A

Class = Anti-emetic - Target = 5-HT3 in CTZ - Mechanism = Inhibition - Steps: • 5-HT3 receptors are found on visceral afferents and on CTZ • Circulating chemicals activate CTZ. Signals then activate vomiting centre • Ondansetron blocks these receptors → ↓ emesis - Info: Treatment: Nausea and vomiting (e.g. post chemotherapy)

Question 48

Q

Paracetamol

Answer

A

Class = NSAID (technically not an NSAID ∵ poor anti-inflammatory) - Target = COX-1 + COX-2 (COX-2 selective) - Mechanism = Inhibition - Steps: Inhibition by ↓ site in COX required for PGH₂ and PGG₂ production - Info: Treatment: Pain, pyrexia Side effects: Toxicity • Hepatic conjugation enzymes are saturated → ↑ NAPQI • NAPQI is conjugated to glutathione • Insufficient glutathione → major hepatic and renal toxicity

Question 49

Q

Penicillamine

Answer

A

Class = Disease modifying anti-rheumatic drug (DMARD) - Target = - - Mechanism = Disease modifying - Steps: Decreases IL-1 synthesis and inhibits collagen maturation and generation - Info: Hydrolysis product of penicillin Highly reactive thiol group - chelator properties means that it can be used following heavy metal poisoning and in Wilson’s disease (copper accumulation) Side effects: Rashes, proteinuria and taste disturbance Treatment: D-isomer can be used to treat rheumatoid arthritis

Question 50

Q

Proglumide

Answer

A

”- Class = CCK2 receptor antagonist - Target = Cholecystokinin 2 receptor (CCK2) - Mechanism = Antagonism - Steps: Antagonism ⟶ ↓ action of gastrin (released from G cells) ⟶ ↓ histamine release (ECL cells) ⟶ ↓ HCl release (parietal cells) - Info: Treatment of: GORD + peptic ulceration<div> </div><div><img></img></div>”

Question 51

Q

Ranitidine

Answer

A

Class = H2 receptor antagonist - Target = H2 receptor - Mechanism = Antagonist - Steps: ↓ effect of histamine on parietal cells ⟶ ↓ HCl secretion - Info: Treatment of: Peptic ulcers

Question 52

Q

Salbutamol

Answer

A

Class = β₂ receptor agonist - Target = β₂ receptor - Mechanism = Agonist - Steps: (β₂ = Gs coupled) • β₂ agonism ⟶ ↑cAMP ⟶ PKA activation ⟶ smooth muscle relaxation • ↑ cAMP also inhibits mast cell degranulation - Info: Short acting (max. effect in 30 mins, duration = 3-5hrs) Treatment of Asthma

Question 53

Q

Salmeterol

Answer

A

Class = β₂ receptor agonist - Target = β₂ receptor - Mechanism = Agonist - Steps: (β₂ = Gs coupled) • β2 agonism ⟶ ↑cAMP ⟶ PKA activation ⟶ smooth muscle relaxation • ↑ cAMP also inhibits mast cell degranulation - Info: • Long acting (8-12hr duration) • Long acting ∵ lipophilic tail allows it to encorporate into cell plasma membrane ∴ acts as drug reservoir Treatment of Asthma

Question 54

Q

Sodium aurothiomalate

Answer

A

Class = DMARD (Gold compound) - Target = Unknown - Mechanism = Unknown - Steps: Unknown - Info: - DMARD for rheumatoid arthritis - Half-life increases with time due to accumulation in tissues - Side effects (rash/mouth ulcers/ Chrysiasis [grey/blue skin colour])

Question 55

Q

Sodium cromoglycate

Answer

A

Class = Mast cell stabiliser - Target = ? - Mechanism = Inhibits degranulation - Steps: • Exact mechanism is unclear • Inhibits inward Cl⁻ conductance into mast cells that is required to maintain a negative membrane potential relative to the ECM • In the absence of the electrostatic gradient, Ca²⁺ influx into the cell is diminished with mast cell stimulation, and so histamine release is reduced - Info: Treatment of: • Mastocytosis • Eye-drop for treatment of hayfever • Sometimes as prophylatic treatment of asthma induced by mast cell degranulation

Question 56

Q

Sumatriptan

Answer

A

Class = Sumatriptan - Target = 5-HT1B/D/F - Mechanism = Agonist - Steps: • 5-HT1B → vasoconstriction • 5-HT1D/F → inhibits nociceptor activity - Info: Treatment: Acute migraine attack Interest: • Poor oral absorption • Does not cross BBB Side-effect: Vasoconstriction in peripheral vascular beds (do not Rx in CVS disease)

Question 57

Q

Tacrolimus

Answer

A

Class = Macrolide antibiotic - Target = FK-binding protein - Mechanism = Inhibits calcineurin - Steps: • Tacrolimus binds FK-binding protein • This complex with tacrolimus, inhibit calcineurin in T cells to prevent T cell proliferation • Ordinarily, antigen recognition by a T cell leads to a Ca2+ influx and activation of a phosphatase, calcineurin. Calcineurin dephosphorylates NFAT to promote its nuclear translocation, where it acts as a transcription factor to promote expression of IL-2, and consequential T cell proliferation. By inhibiting calcineurin following FK-binding protein binding, tacrolimus prevents T cell proliferation. - Info: Treatment: Used as an immunosuppressant to prevent transplant rejection

Question 58

Q

Theophylline

Answer

A

Class = PDE inhibor - Target = Phosphodiesterase - Mechanism = Inhibitor - Steps: Inhibits PDE ⟶ ↑ cAMP levels ⟶ bronchodilation + prevention of mast cell degranualtion - Info: Prophylactic treatment for asthma

Question 59

Q

Zafirlukast

Answer

A

Class = CystLT1 receptor antagonist - Target = CystLT1 receptor (leukotriene receptor) - Mechanism = Antagonist - Steps: Inihbits effect of leukotrienes (Bronchoconstriction + increase permeability and mucus secretion) - Info: Used in maintenance treatment of asthma

Question 60

Q

Zileuton

Answer

A

Class = 5-Lipoxygenase inhibitor - Target = 5-Lipoxygenase - Mechanism = Inhibitor - Steps: Inhibition → ↓ leukotrienes - Info: Used in maintenance treatment of asthma

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8.0 Inflammation Flashcards

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