Anti-Inflammatory Drugs

Question 1

Inflammatory Mediators

Cytokines and Chemokines

Answer 1

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)

Question 2

Inflammatory Mediators: Stored in Cells

Answer 2

• Immediate release
• In the short term it is ineffective to target synthesis
• You need to target receptors or molecule itself

1. Histamine
2. H1 anti-histamines
3. Neuropeptides

Question 3

HIstamine

Answer 3

• 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!

Question 4

H1 anti- histamines

Answer 4

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)

Question 5

Neuropeptides

Answer 5

(small peptides for neuronal communication)

• Calcitonin gene related peptide (CGRP)
• Vasoactive intestinal polypeptide (VIP)
• Tachykinins:
• Substance P (SP)
• Neurokinins (A and B)

Question 6

INFLAMMATORY MEDIATORS:

SYNTHESIZED BY ACTIVATED CELLS

Answer 6

Here we may be able to target: their synthesis, the molecules themselves and their receptor targets

1. Lipid Mediators: Prostaglandins and Leukotrienes, PAF - Specific in the way they are made and where they come from
2. Cytokines/Chemokines
3. Other Molecules

Question 7

Lipid Mediators

Answer 7

- 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**

Question 8

Cytokines/Chemokines

(activated Cells)

Answer 8

• 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

Question 9

Other Molecules

(activated Cells)

Answer 9

• 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

Question 10

INFLAMMATORY MEDIATORS: DERIVED FROM PLASMA PRECURSORS

Answer 10

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

Question 11

the 3 Druggable Mediators

Answer 11

• Histamine
• PGE2
• LTC4, LTD4

Question 12

Acute mediators of Inflammation

Answer 12

• 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

Question 13

Anti-Inflammatory Drugs

Answer 13

• 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

Question 14

NSAIDs

Answer 14

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)

Question 15

Clinical uses of NSAIDs

Answer 15

• 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)

Question 16

Side Effects of Classical NSAIDs

(non-selective for COX)

Answer 16

• 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

Question 17

Coxibs

(Selective COX-2 Inhibitors)

Answer 17

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

Question 18

NSAIDs mechanism of action

Answer 18

• 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

Question 19

Pharmacokinetic considerations

Answer 19

• 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

Question 20

Contra-indications of NSAIDS

Answer 20

• 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

Question 21

Paracetamol (acetaminophen)

Answer 21

• Not an NSAID but shares some properties: anti-pyretic, analgesic, but not anti-inflammatory)
• Side effects: Hepatotoxicity (NB severe in paracetamol overdose)

Question 22

The Cascade Principle

Answer 22

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

Question 23

Glucocorticoids

Answer 23

• Anti-inflammatory drugs that inhibit the formation & action of pro-inflammatory mediators & induce the formation of anti-Inflammatory mediators

Question 24

Mechanism of anti-inflammatory action

(glucocorticoids)

Answer 24

• 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 ↓

Question 25

Pharmacokinetic Considerations | (Glucocorticoids)

Answer 25

* 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**

Question 26

Duration of effect of corticosteroids

Answer 26

* **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**

Question 27

Clinical Uses of Corticosteroids

Answer 27

* **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**

Question 28

Contra-indications | (one of the most misused class)

Answer 28

* 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**

Question 29

SIde effects of Corticosteroids

Answer 29

**_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.

Question 30

Immunosupressive Agents

Answer 30

**_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

Question 31

Mediator: Serotonin

Answer 31

* Increase BF * Increase Vascular Perm. * Involved in Pain

Question 32

Mediator: Bradykinin

Answer 32

* Increase BF * Vascular Perm. * Involved in Pain

Question 33

Chemokines

Answer 33

* Increase BF * Vascular Perm. * Recruit Cells