Anti-inflammatory drugs (Concepts) Flashcards
What is the process of bradykinin synthesis?
What are the 2 types of kininogens and what are their derivatives?
- High molecular weight (HMW) kininogen → Bradykinin
- Low molecular weight (LMW) kininogen → Kallidin
How is Hageman factor/factor VII activated?
Contact with -ve surface when leaking out of blood vessels (e.g. collagen, basement membrane)
What is the main functions of plasma/tissue kallikreins?
- Plasma kallikreins: Bradykinin production
- Tissue kallikreins: Kallidin production
How is bradykinin inactivated?
Cleavage by kininses
What are the kininases and their mechanisms of action?
- Kininase I: Removes C-terminus Arg to form des-Arg-Bradykinin, a ligand for bradykinin B1 receptors.
- Kininase II: Removes 2 C-terminus amino acids to inactivate badykinin.
What is another name for kininase II?
Angiotensin converting enzyme (ACE)
What are the bradykinin receptors?
- B1 (Gq-coupled)
- B2 (Gq-coupled)
When are B1 receptors expressed and what are its ligands?
- Expression: Induction by pro-inflammatory cytokines such as IL-1
- Ligand: des-Arg-Bradkinin
When are B2 receptors expressed and what are its ligands?
- Expression: Constitiutive
- Ligands:
1. Bradykinin
2. Kallidin
What are the effects of bradykinin receptor stimulation?
- Vasodilation
- Pain
How do bradykinin receptors mediate vasodilation?
- B1 →(endothelium)→ ↑[Ca2+]i → eNOS → ↑[NO] →(VSM)→ ↑[cGMP] → PKG → Vasodilation
- B2 →(endothelium)→ ↑[Ca2+]i → PLA2 → ↑[PGI2] →(VSM)→ ↑[cAMP] → PKA → Vasodilation
How do bradykinin receptors mediate pain?
- Bradykinin receptors on nociceptors (Aδ/C neurones) cause stimulation and pain
- Bradykinin receptors on nociceptors also cause sensitisation to pain through phosphorylation of ion channels and decreasing threshold of stimulation
How is kallikrein inhibited?
C1-esterase inhibitor
What are the causes of hereditary angioedema (HAE)?
- Type I HAE: Mutations compromising C1-inhibitor synthesis/secretion
- Type II HAE: Mutations causing production of inactive C1-inhibitor
What are the 4 groups of cytokines?
- Interleukins
- Chemokines
- Interferons
- Colony-stimulating factors
What is the nomenclature of chemokines?
- C = 1 N-terminus Cys residue
- CC = 2 adjacent N-terminus Cys residue
- CXC = 2 N-terminus Cys residue separated by an amino acid
- CX3X = 2 N-terminus Cys residues separated by 3 amino acids
What is unusual about chemokine receptors compared to other cytokine receptors?
Chemokine receptors are GPCRs while most cytokine receptors are RTKs
What are the functions of interleukins?
- Pro-inflammatory effects
- Anti-inflammatory effects
What are the function of chemokines?
Chemoattraction (mainly), but not restricted to.
What are the functions of interferons?
- INFα & INFβ: Anti-viral function
- INFγ: Stimulation of TH1 response
What are the functions of colony-stimulating factors?
Stimulates formation of mature colonies of leukocytes
What cell are NGF secreted from on what is its function?
- Mast cells and macrophages
- Sensitisation of nociceptors
What receptors mediate pain sesnitisation effects of NGF?
Tropomyosin-related kinase A (TrkA)
What are the functions of tachykinins?
- Mast cell degranulation
- Smooth muscle contraction
- Vasodilation
- Pain sensitisation
What are examples of tachykinins?
- Neurokinin A
- Substance P
What are the receptors associated with the tachykinins?
- Substance P = NK1R
- Neurokinin A = NK2R
All NK receptors (NK1-3R) are Gq-coupled GPCRs
What is the difference between bradykinin and tachykinins?
Bradykinins cause slow contraction of smooth muscles while tachykins cause fast contraction of smooth muscles, at least in guinea pig ileum.
What are examples of anti-inflammatory peptides?
- IL-10
- TGFβ
- Annexin-A1
What are the lipid mediators of inflammation (eicosanoids)?
- Leukotrienes
- Lipoxins
- Platelet-activating factor (PAF)
- Prostanoids
What is the common precursor for lipid mediators?
Arachidonic acid (aside from PAF)
What is the precursor for PAF synthesis?
Lysoglyceryl-phosphorylcholine
What is the rate-limiting step in synthesis of all lipid mediators?
PLA2 mediated breakdown of phospholipids (Phospholipid → Arachidonic acid + Lysoglyceryl-phosphocholine)
What induces synthesis of lipid mediators?
Any pro-inflammatory cytokine that causes ↑[Ca2+]i
What are the leukotrienes and what are their functions?
- 12-HETE: Chemotaxis
- LTB4:
1. Chemotaxis
2. Activation of neutrophils (↑ expression of adhesion molecules)
3. Activation of macrophages (↑ expression of pro-inflammatory cytokines) - LT(C-E)4 (cysteinyl leukotrienes, CysLT):
1. Bronchoconstriction
2. Increased vascular permeability
3. Increased mucous secretion
How is 12-HETE synthesised?
Arachidonic acid →(12-Lypoxygenase)→ 12-HETE
How is LTB4 synthesised?
Arachidonic acid →(5-Lipoxygenase)→ 5-HETE → LTA4 →(LTA4 hydrolase)→ LTB4
How are the CysLTs synthesised?
LTB4 →(LTC4 synthase)→ LTC4 →(Peptidases)→ LTD4 + LTE4
What receptors do leukotrienes act on?
LTB4 → BLT1 + BLT2 (Gq or Gi)
CysLTs → CysLT1 + CysLT2 (Gq)
What are the efficacies of CysLTs at CysLT receptors?
- CysLT1: LTD4 > LTC4 > LTE4
- CysLT2: LTD4 = LTC4 > LTE4
Which cells are CysLTs produced by?
- Mast cells
- Eosinophils
How are lipoxins synthesised?
- LTA4 →(12-Lipoxygenase)→ LTX4
- Arachidonic acid →(15-lipoxygenase)→ 15S-HETE →(5-lipoxygenase)→ LXA4 + LXB4
What are the functions of lipoxins?
Binds to FRP2 receptors (Gi-coupled) and has anti-inflammatory effects and antagonises action of CysLT1 receptors
What are the functions of PAF?
- Vasidilation (through PLA2 activation)
- ↑TXA2 production in platelets (promotes platelet aggregation)
- Chemotaxis (neutrophils)
What are the prostanoids?
- TXA2
- PGD2
- PGE2
- PGF2
- PGI2
What does the number in the name of prostanoids represent?
- Number of C=C double bonds
- (No. of C=C bonds in precursor) - 2
What are the other numbers of C=C bonds possessed by prostanoids?
1 and 3 (e.g. PGI1 & PGI3)
What is the reaction catalysed by COX?
Arachidonic acid →(cyclisation + oxygenation)→ PGG2 →(reduction)→ PGH2
What is responsible for the production of different prostanoids from PGH2 in different cells?
Expression of different synthase enzymes
What types of prostanoids are produced by different types of tissues?
- Tissues/vascular endothelium: PGE2 + PGI2
- Mast cells: PGD2
- Macrophages: PGE2 +TXA2
- Platelets: TXA2
What are the receptors acted on by PGD2 and what are the effects?
- DP1 (Gs):
- Vasodilation
- Inhibition of platelet aggregation
- Smooth muscle relaxation (GI/uterine) - TP (Gq): Bronchoconstriction
What are the receptors acted on by PGE2 and what are the effects?
- EP1 (Gq): Smooth muscle contraction (bronchial/GI)
- EP2 (Gs):
- Bronchodilation
- Vasodilation
- Smooth muscle relaxation (GI) - EP3 (Gi):
- Smooth muscle contraction (GI)
- Fever
- Inhibition of gastric acid secretion
- Promotion of gastric mucous secretion - EP4 (Gs): Sensitisation of nociceptors
What are the receptors acted on by PGI2 and what are the effects?
IP (Gs):
- Vasodilaton
- Inhibition of platelet aggregation
What are the receptors acted on by PGF2α and what are the effects?
FP (Gq): Uterine contraction
What are the receptors acted on by TXA2 and what are the effects?
TP (Gq):
- Vasoconstriction
- Bronchoconstriction
- Platelet aggregation
What is the general rules regarding prostanoid receptors?
- Gs-coupled receptors mediate smooth muscle relaxation and inhibition of platelet aggregation.
- Gq-coupled receptors mediate smooth muscle contraction and promotion of platelet aggregation.
- Gi-coupled receptors mediate fever and protection of gastric mucosa.
How is platelet aggregation controlled by prostanoids?
Balance between pro-aggregation TXA2 produced by platelets and anti-aggregation PGI2 produced by endothelium.
What is the mechanism of action of most NSAIDs?
Enters hydrophobic tunnel and forms H-bond with Arg120 to prevent entry of arachidonic acid (reversible inhibition)
What is the mechanism of action of aspirin?
Acetylates Ser530 in active site (irreversible inhibition)
What are the types of COX enzymes?
- COX 1 is constitutively expressed in tissues
- COX 2 is only expressed during inflammation
What property of COX 2 allow it to be selectively targeted?
Side pocket in hydrophonic channel of COX 2 accommodates bulky side-groups on COX 2 selective drugs
What are the side effects of COX 2 selective NSAIDs and the mechanism?
- Side effects:
1. Renal insufficiency
2. Increased risk of myocardial infarction - Mechanism: COX 2 is constitutively expressed in renal and cardiac tissue. It produces PGI2 that protects against thrombosis by causing vasodilation and inhibiting platelet aggregation.
What is the mechanism behind the anti-inflammatory effects of aspirin?
- Inhibition of prostaglandin production and the contributions of prostaglandins to inflammation.
- Production of 5L-HETE by COX 2 and then aspirin-triggered lipoxin (ATL) by 5-lipogygenase. This has similar anti-inflammatory effects as LXA4
What are the side effects of NSAIDs?
- GI bleeding
- Renal insufficiency
- Increased risk of myocardial infarction
- Bronchospasms
What is the consequence of aspirin overdose?
- Uncoupling of Kreb’s cycle
- Increased O2 demand and CO2 production
- Reflex increase in ventilation rate (low doses) or: Suppressed by the drug (high doses)
- Respiratory acidosis
- Fever & vomiting
- Dehydration
- Coma & death
How can an aspirin overdose be treated?
- Fluids to prevent dehydration
- Bicarbonate to counter acidosis
- Charcoal to absorb aspirin in the GI tract
- Haemodialysis to remove aspirin from blood
What is unusual about paracetamol compared to other NSAIDs?
- Does not have good anti-inflammatory effect
- Better anti-pyretic and analgesic than many NSAIDs
What is the mechanism of action of paracetamol?
Reduction of amino acids in active site responsible for conversion of PGG2 to PGH2
How is paracetamol eliminated from the body?
- Paracetamol is eliminated in liver by conjugation
- When liver enzymes saturated, it is converted to NAPQI by oxidases
- NAPQI is toxic, but is conjugated with glutathione in the liver
What is the minimum toxic dose of paracetamol?
150mg/Kg
What are the consequences of paracetamol overdose?
- Nausea
- Vomiting
- Liver failure and death
What activities can affect metabolism of paracetamol?
- Alcohol consumption causes increased expression of liver enzyme Cyp2E1 and increased production of NAPQI
- Fasting decreases amount of available glutathione
