Anti-Inflammatory Drugs Flashcards
1
Q
Inflammatory Mediators
Cytokines and Chemokines
A
Cytokines and Chemokines
**cell recruitment and activation**
- Can ↑ blood flow & vascular permeability but mainly cause cell recruitment & activation
- Cytokines- peptides that often work medium- long term by inducing cellular changes (druggable)
- Chemokines- chemoattractant cytokines- cause mainly inflammatory cell recruitment e.g. (IL-8 –neutrophils; eotaxins, eosinophils, MCP-1, monocytes)
- Cytokines released–> circulation production of acute phase proteins (which have inflammatory properties) by the liver & ↑ temperature (by causing release of PGE2 in the hypothalamus)
2
Q
Inflammatory Mediators: Stored in Cells
A
- Immediate release
- In the short term it is ineffective to target synthesis
- You need to target receptors or molecule itself
- Histamine
- H1 anti-histamines
- Neuropeptides
3
Q
HIstamine
A
- Stored in mast cells, platelets, basophils
- Produce its effects by activation of cell surface receptors
- H1 receptor is involved in inflammation
- Massive histamine release–> hypersensitivity type I & anaphylactic reaction
- Increases Blood Flow and causes: Vascular Permeability, and Itch
- Causes cell recruitment
- Is druggable!
4
Q
H1 anti- histamines
A
antagonise histamine for the h1 receptor & prevent it binding –> anti-inflammatory
- Use: Primarily to control pruritus (severe skin itching) in allergic disease
- First generation of H1 antagonists- had an anti-pruritic action & a sedative effect (not desirable in man); Also anti-emetic & anti-nausea effect (H1 effects in the CNS)
- Second generation- devoid of these effects (they don’t cross the blood-brain barrier)
5
Q
Neuropeptides
A
(small peptides for neuronal communication)
- Calcitonin gene related peptide (CGRP)
- Vasoactive intestinal polypeptide (VIP)
- Tachykinins:
- Substance P (SP)
- Neurokinins (A and B)
6
Q
INFLAMMATORY MEDIATORS:
SYNTHESIZED BY ACTIVATED CELLS
A
Here we may be able to target: their synthesis, the molecules themselves and their receptor targets
- Lipid Mediators: Prostaglandins and Leukotrienes, PAF - Specific in the way they are made and where they come from
- Cytokines/Chemokines
- Other Molecules
7
Q
Lipid Mediators
A
- Prostaglandins
- Synthesis: Phospholipase A2 converts cell membrane phospholipids –>arachidonic acid
- COX converts arachidonic acid–> prostaglandins (D2, E2, F2a & I2) & thromboxane (TxA2)
- NSAIDs block the formation of prostaglandin by antagonising COX
- This is common to all the lipid mediators. Has enzyme phosph A2 which starts cutting bits of lipid away from membrane
- Leukotrienes
- Synthesis: 5- lipoxygenase (5-LO) converts arachidonic acid –> LTC4, LTD4, LTE4 LTB4
- Leukotriene D4 (LTD4) receptor antagonists prevent 5-LO binding
- E.g. zafirlukast (Accolate)
- monolukast (Singulair)
- Main use:
- *To ↓Bronchoconstriction - Asthma prophylaxis**
8
Q
Cytokines/Chemokines
(activated Cells)
A
- Cytokines include: interleukins (IL-1, IL-6), interferons & tumour necrosis factor (TNF)
- Chemokines (chemotactic cytokines) include: CXCL8 (IL-8) and CCL11 (eotaxin-1)
- Most= newly synthesised; some are also stored in cells (e.g. TNF in mast cells)
- Inhibitors of TNFα are used clinically in humans
9
Q
Other Molecules
(activated Cells)
A
- Cells can also release:
- nitric oxide (NO)
- reactive oxygen species (oxidative burst)
- enzymes that can cause tissue damage (e.g. elastase)
- Cells can form/release more than one type of mediator
- e.g. Mast cells–> Histamine, Serotonin PGD2 , LTC4 , PAF cytokines (e.g. TNF & IL-4)
- Different types of cells produce different mediators
10
Q
INFLAMMATORY MEDIATORS: DERIVED FROM PLASMA PRECURSORS
A
Plasma Derived Mediators-
- Plasma contains the precursors for:
- Bradykinin (BK) (tissue or plasma activation)
- Factors of the complement system (C5a)
- Opsinogens, Chemoattractants, pore-forming complex
11
Q
the 3 Druggable Mediators
A
- Histamine
- PGE2
- LTC4, LTD4
12
Q
Acute mediators of Inflammation
A
- Acute Inflammation is an immediate response to injury
- Incombination they account for the:
- Cardinal signs of inflammation:
-RUbor (redness)
Calor (heat)
- Tumor (swelling)
- Dolor (Pain)
- Functio laesa (loss of function): lose normal tissue function
13
Q
Anti-Inflammatory Drugs
A
- inhibit the formation, release or action of pro-inflammatory mediators of inflammation
- WHen pro-inflammatory mediators are released in excess, there can be damage to the host and anti-inflammatory drugs may be required
14
Q
NSAIDs
A
Prostaglandins–> ↑ blood flow, enhanced swelling, pain & ↑ body temperature- NSAIDs reverse these effects by inhibiting COX
- classical NSAIDs inhibit both COX-1 & COX-2 non- selectively
- COX-1= constitutive- required all the time for normal physiological effects of prostaglandins
- e.g. PGE2/PGI2 gastric cytoprotection &↑ renal blood flow. PGI2/TXA2 haemostasis
- COX-2= inducible- present only where there is inflammation (except normally present in endothelium)
15
Q
Clinical uses of NSAIDs
A
- Control pain in acute & chronic inflammatory conditions
- ↓ swelling after injury/surgery & in acute/ chronic inflammatory conditions (& ↓ vasodilation)
- ↓ fever associated with inflammatory conditions
- Inhibit platelet activation in thromboembolic disease (may be relevant to inflammation)
27
Q
Clinical Uses of Corticosteroids
A
- Allergic diseases, anaphylaxis
- Topical: inflammatory conditions of the skin, eye and ear
- Immunosuppression occurs with ↑ doses/prolonged use of glucocorticoids- can be beneficial as –> ↓circulating lymphocyte numbers & activation- treats auto-immune / chronic inflammatory conditions
- Other uses: hypoadrenocorticism (deficit in mineralocorticoids), Induce parturition in cattle & sheep
