8.0 Inflammation Flashcards
What is the triple response of Lewis?
<b>1) Flush</b><br></br>Local vasodilation within seconds (due to histamine)<br></br><br></br><b>2) Flare</b><br></br>Neurogenic imflammation within 30-60 seconds<br></br><br></br><b>3) Wheal</b><br></br>Increase vascular permeability causes plasma leakage<br></br>Few minutes
What is dermatographic urticaria?
“Exaggerated triple response<br></br>"”Skin writing”“<br></br>May be triggered by drugs (e.g. penicillin)<br></br><br></br>Treatment = antihistamines + <b>Omalizumab</b>”
What is the effect of prostaglandins (PGE2 + PGI2)?
Vasodilation
What is the effect of histamine?
Vasodilation and ↑ vascular permeability
What is the effect of TNF-a/IL-1?
More cytokine release<br></br>Permeability<br></br>Express adhesion molecules
Role of:<br></br>1) C3a<br></br>2) C3b<br></br>3) C5a<br></br>4) C5b-C9
<b>1) C3a</b><br></br>Mast cell stimulation<br></br><br></br><b>2) C3b</b><br></br>Opsonisation<br></br><br></br><b>3) C5a</b><br></br>Activates mast cells<br></br><br></br><b>4) C5b-C9</b><br></br>MAC<br></br>1 of each factor apart from C9 (12-18 C9s)
What do mast cells release following stimulation?
1) Histamine<br></br>2) Heparin<br></br>3) Leukotrienes<br></br>4) Nerve growth factor<br></br>5) Preformed cytokines
What cells contain histamine?
<b>1) Mast cells</b> - found in acidic granules with HMW heparin<br></br><b>2) Basophils</b> - found in acidic granules with HMW heparin<br></br><b>3) Enterchromaffin-like cells</b><br></br><b>4) Histaminergic neurons of the brain</b>
What particles cause mast cell degranulation?
“<div><img></img></div>”
Role and GPCR for the 4 histamine receptors?
“<b>H1</b><br></br>- Smooth muscle contraction (ileum + bronchioles)<br></br>- Blood vessel dilation<br></br>- Itching<br></br>- Triple response<br></br><br></br><b>H2</b><br></br>- Increase heart rate<br></br>- Increase gastric acid secretion<div><br></br></div><div><img></img></div>”
What 2 enzymes metabolise histamine?
<b>1) Histaminase</b><br></br>- Deaminates histamine → imidazole acetaldehyde<br></br><br></br><b>2) Histamine-N-Methyltransferase</b><br></br>- Transfers methyl group to nitrogen on imidiazole ring → N-methylhistamine<br></br><br></br><b>Imidazole acetaldehyde + N-methylhistamine are inactive at H receptors</b>
What is mastocytosis?
“<div><img></img></div>”
Whats the problem with 1st generation antihistamines?
Crossed BBB → drowsiness
Whats the problem with 2nd generation antihistamines?
Had an effect on hERG → long QT syndrome
What cells in the stomach secrete HCl?
Parietal cells
What is the pathway of HCl secretion?
“<div><img></img></div>”
Synthesis pathway for bradykinin:
“<div><img></img></div>”
What inhibits kallikrein?
C1 esterase inhibitor<br></br><br></br>Deficiency in this → hereditary angioedema
What inactivates bradykinin?
Kinases<br></br><br></br>Kinase 1 → des-Arg-bradykinin<br></br><br></br>Kinase 2 (ACE) → Inactive kinin
What are the receptors for bradykinin and what are their agonists?
B1 (↑ in inflammation) : agonist = des-Arg-bradykinin<br></br><br></br>B2 (constitutive) : agonist = bradykinin + Kallidin
Structure of arachidonic acid:
(5,8,11,14-eicosatetetroenoic acid)<br></br><br></br>20 carbon unsaturated fatty acid<br></br>4 double bonds
Mechanism of COX inhibition for most NSAIDs?
<b>Reversible inhibition</b><br></br>- Enter hydrophobic channel in enzyme<br></br>- Hydrogen bond with Arg120<br></br>- This interaction prevents arachidonic acid from entering the catalytic domain
Differences between COX1 + COX2 hydrophobic channels?
COX1 = narrow hydrophobic channel<br></br><br></br>COX2 = wide hydrophobic channel
How is selective COX-2 inhibition achieved?
Drugs contain a <b>bulky sulphur side chain</b> - thus the drug is too big to fit into the narrow hydrophobic channel of COX-1<br></br><br></br>COX-2 selective inhibitors tend to end in <b>-coxib</b>
- Released by platelets during activation and aggregation
- Causes further aggregation of platelets and vasoconstriction
2) Intestinal enterochromaffin cells
3) Serotonergic neurons (ENS + CNS)
o ↑ gluconeogenesis
o ↑ protein catabolism
o ↓ protein anabolism
o Redistribution of fat
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)
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)
- Target = TNF α
- Mechanism = sequesters excess TNFa in rheumatoid arthritis
- Steps:
- Info:
Treatment: Rheumatoid arthritis
- 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
- Target = IL-1 receptor
- Mechanism = Antagonist
- Steps:
Blocks IL1- dependent signalling ⟶ ↓ inflammation in rheumatoid arthritis
- Info:
• ↑ susceptibility to infection
Treatment: Rheumatoid arthritis
- 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)
- 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
- 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
- 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)
- 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
- 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
- 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
- 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
- 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)
- Target = B2 receptor (bradykinin receptor)
- Mechanism = Antagonist
- Steps:
Antagonist ⟶ ↓ vasodilation
- Info:
Treats hereditary angioedema (HAE)
- 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
- 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)
- 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
- 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
- Target = K⁺ / H⁺ pump on parietal cells
- Mechanism = Inhibits pump
- Steps:
Inhibits pump ⟶ ↓ HCl secretion
- Info:
Treatment of: GORD + peptic ulceration (preferred treatment)
- 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)
- 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
- 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
- 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
- Target = H2 receptor
- Mechanism = Antagonist
- Steps:
↓ effect of histamine on parietal cells ⟶ ↓ HCl secretion
- Info:
Treatment of: Peptic ulcers
- 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
- 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
- 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])
- 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
- 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)
- 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
- Target = Phosphodiesterase
- Mechanism = Inhibitor
- Steps:
Inhibits PDE ⟶ ↑ cAMP levels ⟶ bronchodilation + prevention of mast cell degranualtion
- Info:
Prophylactic treatment for asthma
- 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
- Target = 5-Lipoxygenase
- Mechanism = Inhibitor
- Steps:
Inhibition → ↓ leukotrienes
- Info: Used in maintenance treatment of asthma
