Anti-Inflammatory Drugs Flashcards
Inflammatory Mediators
Cytokines and Chemokines
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)
Inflammatory Mediators: Stored in Cells
- 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
HIstamine
- 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!
H1 anti- histamines
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)
Neuropeptides
(small peptides for neuronal communication)
- Calcitonin gene related peptide (CGRP)
- Vasoactive intestinal polypeptide (VIP)
- Tachykinins:
- Substance P (SP)
- Neurokinins (A and B)
INFLAMMATORY MEDIATORS:
SYNTHESIZED BY ACTIVATED CELLS
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
Lipid Mediators
- 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**
Cytokines/Chemokines
(activated Cells)
- 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
Other Molecules
(activated Cells)
- 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
INFLAMMATORY MEDIATORS: DERIVED FROM PLASMA PRECURSORS
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
the 3 Druggable Mediators
- Histamine
- PGE2
- LTC4, LTD4
Acute mediators of Inflammation
- 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
Anti-Inflammatory Drugs
- 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
NSAIDs
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)
Clinical uses of NSAIDs
- 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)
Side Effects of Classical NSAIDs
(non-selective for COX)
- Damage to GIT via suppression of gastro protective PG formation–> ↑ acid and ↓ bicarbonate & mucus production –> gastric ulcers & bleeding (COX-1 inhibition)
- Nephrotoxicity when dehydrated (suppression of protective afferent artery vasodilatation)-renal dilation bty COX-1
Coxibs
(Selective COX-2 Inhibitors)
E.g. firocoxib, mavacoxib, robenacoxib
- Have improved safety profile as they don’t inhibit COX-1
- Renal toxicity is still possible (kidney is unusual & normally contains COX-2)
- In man: small ↑ risk of thrombotic events (due to disrupted balance between TXA2 & PGI2)
- recommended use is only to patients prone to gastric problems & only used after assessment of CV risk
NSAIDs mechanism of action
- Aspirin: competitive (salicylic acid) & irreversible inhibitor (acetyl part, only active for 15mins)
- Carprofen: reversible competitive inhibitor of COX
- Indomethacin: slowly reversible/ irreversible inhibitor- stronger action
- Inhibitory activity= variable- between different NSAIDs in same species & same drug in different species
- Can come in the form of injection, tablets, in feed granules or as a paste
Pharmacokinetic considerations
- Oral & parenteral (non-GI) routes of administration have different licensing for different species
- NSAIDs are often highly plasma protein bound
- Plasma clearance times vary considerably with species
- Dose requirements vary between species; you cannot extrapolate from one species to another
Contra-indications of NSAIDS
- Do not use an NSAID with/ within 24h of another NSAID – (avoids confusion and potential overdose)
- Avoid use of NSAIDs in dehydrated, hypovolaemic or hypotensive animals (↑ risk of renal toxicity)- need COX-1 and 2 for function
Paracetamol (acetaminophen)
- Not an NSAID but shares some properties: anti-pyretic, analgesic, but not anti-inflammatory)
- Side effects: Hepatotoxicity (NB severe in paracetamol overdose)
The Cascade Principle
1) Licensed veterinary drug for same species and indication<– first choice
2) Licensed veterinary drug but different species or indication
3) Licensed human drug or imported veterinary drug
4) Extemporaneous preparation for veterinary use
Glucocorticoids
- Anti-inflammatory drugs that inhibit the formation & action of pro-inflammatory mediators & induce the formation of anti-Inflammatory mediators
Mechanism of anti-inflammatory action
(glucocorticoids)
- Effects on protein synthesis: ↓ production of pro-inflammatory mediators
- Inhibit pro-inflammatory signalling molecules inside cells; cytokine & chemokine synthesis is ↓
- ↓ PLA2 action by inducing lipocortin (annexin1)–> ↓ synthesis of pro-inflammatory lipid mediators
- Inhibit the induction of COX-2 by cytokines/bacterial products
- ↓ release of some inflammatory mediators e.g. release of stored cytokines
- ↓ production of inflammatory cells by the bone marrow
- ↓ circulating complement components
- ↓ vasodilation, ↓ vascular permeability (and thus swelling) & ↓ leukocyte accumulation & activation
∴ ↓ tissue damage & inflammation as release of mediators, enzymes & free radicals by activated cells is ↓
Pharmacokinetic Considerations
(Glucocorticoids)
- Many routes of administration: Oral, parenteral, topical, inhalation & intra-articular routes
- Range of preparations available: Short- (not acute) and long-acting, as well as depot
- The duration of anti-inflammatory effect is longer than would be predicted from plasma clearance
Duration of effect of corticosteroids
- Solutions of salts/ soluble esters: given IV, fast onset, last 8-24hours
- Intermediary soluble esters: given SC, slow onset, last 4-14days
- Depot/ long acting (insoluble esters): given SC or intraarticular, slow onset, last 3-6weeks
Clinical Uses of Corticosteroids
- 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
Contra-indications
(one of the most misused class)
- Renal disease & Diabetes mellitus (antagonise the effects of insulin)
- Avoid use in: Pregnant animals & immediately after major surgery
- Don’t use glucocorticoids without antibacterial drugs in animals with bacterial infections
SIde effects of Corticosteroids
Side effects of Corticosteroids
- Suppression of wound healing & response to infection. Inhibition of osteoblast & ↑ osteoclast activity
- Can predispose horses to laminitis & induce iatrogenic Cushing syndrome (long term use)
- Hypothalamic-pituitary-adrenal axis is suppressed–> endogenous steroid production suppressed
- Too rapid withdrawal can precipitate an addisonian crisis (insufficient cortisocosteroid production)
Prevention of side effects: Progress to lowest effective dose & alternate day therapy
-Progressive weaning after long term therapy.
Immunosupressive Agents
Cyclosporine:
- Mech. of Action : - Inhibition of enzyme calcineurin; prevents activation of a TF (NFAT-c) –>↓ T lymphocyte activation & ↓ histamine release from mast cells & basophils
- Main side effect: renotoxicity (in man but not in dogs)
- Clinical uses: Atopic dermatitis in dogs (Atopica®) Topically for some eye conditions
Tacrolimus: cyclosporine analog, also inhibits activation of NFAT-c
Azathioprine (also cytotoxic drug): DNA synthesis inhibitor- inhibits proliferation of cells, especially lymphocytes. Used for autoimmune diseases & organ transplantation.
- *Oclacitinib** (Apoquel, Zoetis): Immunomodulator blocking Janus kinases- treat pruritus (itching)
- *Sodium cromoglycate & nedocromil sodium**- not fully understood but indirectly ↓ bronchoconstriction
Mediator: Serotonin
- Increase BF
- Increase Vascular Perm.
- Involved in Pain
Mediator: Bradykinin
- Increase BF
- Vascular Perm.
- Involved in Pain
Chemokines
- Increase BF
- Vascular Perm.
- Recruit Cells
