Anti-inflammatory Drugs Flashcards
Inflammatory mediators are targeted by anti-inflammatory drugs.
What are the three classes of inflammatory mediators, based on where they are produced in the body?
- Stored in cells
- Synthesized by activated cells in tissues &/or blood
- Derived from precursors in plasma
Give examples of inflammatory mediators that are stored in cells, such as granulocytes & mast cells
- Vasoactive amines:
Histamine
Serotonin (5-HT; 5-hydroxytryptamine)
2. Neuropeptides:
Vasoactive intestinal polypeptide (VIP)
Calcitonin-gene-related-peptide (CGRP)
Substance P (SP)
4. Neurokinins:
Neurokinin A (NA)
Neurokinin B (NB)
Give examples of inflammatory mediators that are synthesized by cells from lipids in the plasma membrane.
Eicanosoids (peptide hormones) produced arachidonic acid/lipids in plasma membrane, also called Lipid mediators or prostanoids:
Prostanoids catalysed by COX:
Prostaglandins (PG)
PGD2
PGE2
PGF2α
PGI2 (Prostacyclin)
Thromboxanes (Tx), TxA2
Leukotrienes (LT) catalysed by 5- Lipooxygenase 5-LOX:
LTB4
LTC4
LTD4 LTE4
Platelet-activating factor (PAF) derived from cell-membrane phospholipids
Lipoxins derived from lipids (AA metabolites):
Resolvins
Protectins
Maresins
What are some important, pro-inflammatory cytokines (cell-signalling molecules) synthesized or secreted by mast cells or epidermal cells during inflammation?
Interleukins:
IL1 - stored in epidermal cells
IL6
Interferons
Tumour necrosis factor (TNFα) - stored in mast cells
Nitric oxide (NO)
Enzymes & oxygen-derived free radicals:
Elastase
Collagenase
Explain how inhibiting prostaglandin formation will affect an inflammatory response.
Give examples of drugs that act by these mechanisms.
Prostaglandin formation can be reduced by inhibiting the COX enzyme using COX inhibitors.
COX-1 vs COX-2:
The prostaglandins produced by COX-1 catalysis are typically “housekeeping” or “good” PGs that protect the GIT tract by producing mucus & increase blood flow.
PGs produced by COX-2 are pro-inflammatory & can cause pain via swelling, increased blood flow via vasodilation, & in some cases pyrexia. Thromboxane, a PG, causes vasoconstriction & is important for clotting – some PGs like TxA2 are pro-resolution & anti-inflammatory toward the end of an infection.
NSAIDs are COX-inhibitors. Examples of selective COX-2-inhibiting NSAID are carprofen (Rimyadyl) & meloxicam (Metacam)
Aspirin & ibuprofen are non-specific COX inhibitors, whose side effects include stomach ulcers.
The NSAID phenylbutazone (Equipalazone or “bute”) is supposedly a COX-2 inhibitor but has adverse effects for the GIT.
NSAIDs mainly used for treating acute & chronic inflammation: reducing swelling after surgery and in acute & chronic inflammatory conditions, reduce fever, reduce signs of endotoxic (bacterial) shock & inhibit platelet activation in thromboembolic disease.
Explain how inhibiting the actions of histamine will affect an inflammatory response and give examples of drugs that act by these mechanisms.
Histamines cause inflammation, vasodilation (increased blood flow) and pruritus during acute allergic reaction.
Drugs that target histamines at their receptors – ie., anti-histamines, aka inverse agonists – can be older generation, less-specific antihistamines that target not just H1 receptors, but also INHIBIT activity at 5-HT (seratonin, a vasoconstrictor), α-1 (cause constriction in smooth muscle during fight-flight) & M (muscarinic) receptors.
H1 receptors are found throughout the body and especially in vascular smooth muscle, the heart, CNS and vascular endothelial cells.
Diphenhydramine (Benalyn, Nytol) is an older generation antihistamine, which cause drowsiness & have local anaesthetic properties.
Newer generation H1 antihistamines are more selective and don’t inhibit 5-HT or the other adrenergic & muscarinic receptors. These include cetirizine (Zirtek) & desloratidine (Neoclarityn), which don’t cause sedation. H1 antihistamines are also used as anti-emetics, but are mainly used to reduce itching in allergic reactions (pruritus).
Some antihistamines have effects more on H2 receptors, which act more in the GIT and produce gastric acid, thus antihistamines that target H2 receptors REDUCE stomach acid.
Explain how inhibiting the actions of leukotrienes (LT) will affect an inflammatory response and give examples of drugs that act by these mechanisms.
Leukotrienes are like PGs, except they are synthesized by the action of LOX instead of COX enzymes.
Like PGs, they increase blood flow (vasodilation) and vascular permeability, but some of them are also involved in chemotaxis (recruiting other cells to the site of infection) & cell activation, thus escalating the inflammatory response.
Note that TC4 & LTD4 are NOT involved in chemotaxis or cell activation.
Zafirlukast (Accolate) is an anti-leukotriene that targets LTD4, so it can reverse or reduce the vasodilation and vascular permeability.
Mainly these are used to reduce bronchoconstriction and asthma prophylaxis.
Outline the key pharmacokinetic considerations when using non-steroidal anti-inflammatory drugs (NSAIDs) to inhibit prostaglandin formation.
NSAID use must balance maintaining the beneficial, “housekeeping” effects of prostaglandin production, such as gastric cytoproduction, renal blood flow (PGE2 & PGI2) and blood-clotting (TxA2) against the reduction of “bad” pro-inflammatory prostaglandins.
Ie., While PGE2 & PGI2 both help the GIT produce protective mucus and maintain renal blood flow, they are also vasodilatory & cause swelling. PGE2 in particular causes pyrexia & pain.
Also, the prostaglandins thromboxane (TxA2) and PGI2 are both important factors in vascular constriction after injury (first step in clotting) & platelet activation
Describe the main side- and toxic effects associated with use of NSAIDs.
Due to COX-1 inhibition:
- increases risk of renal toxicity (nephrotoxicity) because vasodilation of the afferent artery into kidney is suppressed
- damage to GIT via suppression of protective PG formation (PGE2 & PGI2); results in increased acid, decreased bicarbonate & decreased mucosal
blood flow - liver toxicity (hepatotoxicity) is SEVERE in paracetamol OD
- bone-marrow disturbances at toxic doses
Explain how glucocorticoids affect the inflammatory response and name examples of this class of drug.
Glucocorticoids work at the cellular/DNA level, disrupting & reducing protein synthesis of pro-inflammatory mediators and inducing the formation of anti-inflammatory mediators.
Mainly used for treatment of allergic diseases, anaphylaxis, inflammatory conditions of the eye and ear when applied topically, and if given in high doses, early and via IV, it can be used to treat shock (but this is controversial).
Since glucocorticoids are immunosuppressive over the long term, reducing the amount of circulating lymphocytes & lymphocyte activation, the effect can be used as an advantage in conditions where there’s too much inflammation (eg., autoimmune).
They are also used to treat hypoadrenocorticism (deficiency in mineral corticoids) & to induce parturition in sheep & cattle.
- Outline the key pharmacokinetic considerations when using glucocorticoids.
1. Routes of administration:
Oral
Para-enteral
Topical
Inhaled Intra-articular
2. Long (depot) vs Short-acting preparations:
- Solutions of salts or soluble esters given IM: fast onset, duration 8-24 hrs
- Intermediary soluble esters given SQ: slow onset, duration 4-14 days
- Depot or long-acting insoluble esters given SQ or intra-articular: very slow onset, duration 3 to 6 weeks.
3. Duration of action vs plasma clearance time
Duration of anti-inflammatory effect could be longer than predicted from plasma clearance; ie., the drug might not be detected in blood anymore but the effects still linger.
Describe the main side- and toxic effects associated with use of glucocorticoids.
- Induces parturition in pregnant animals
- Don’t use immediately after surgery because it prevents clotting by reducing production of clotting factors thromboxane, COX and PAF by inhibiting
PLA2 (phospholipase A2 that liberates AA from cell membrane) - Should be used with antibacterial drugs over long term because it is immunosuppressive
- suppression of wound-healing
- inhibition of osteoclast & osteoblast activity
- can predispose horses to laminitis
- can induce Cushing syndrome by suppressing endogenous steroid production: glucocorticoids inhibit cortotropin-releasing hormone CRH by central
nervous system and ACTH adrenocorticotropic hormone from hypothalamus, thus reducing the adrenal glands’ production of endogenous hormone. - Rapid withdrawal of glucocorticoids could lead to Addisonian crisis (ie., insufficient corticosteroid production, resulting in low BP & possibly coma
Outline the mechanism of action and uses of cyclosporin.
Cyclosporin/ciclosporin (Atopica), an immunosuppressive drug, inhibits an enzyme called CALCINEURIN.
This prevents the activation of Nuclear Factor, NF, a transcription factor in the clonal proliferation of activated T-cells (so the NF is called NF-ATc), thus T-cell cytokine production is decreased.
It also decreases the release of histamine from mast cells and basophils.
It is used for atopic dermatitis in dogs (Atopica).
Another calcineurin inhibitor is Tacrolimus (Protopic), a cyclosporin analogue, for immune-mediated kerato-conjunctivitis.
Outline the mechanism of action and use of cromoglycates.
Sodium cromoglycate is an anti-inflammatory that reduces the release of inflammatory mediators by antagonising tachykinin action & decreases leucocyte activation.
Thus it indirectly decreases bronchoconstriction. It’s used clinically to PREVENT bronchoconstriction.
