NSAIDS + Corticosteroids Flashcards
What are the beneficial and adverse effects of the inflammatory response?
Increased blood flow to injured tissue, oedema formation in damaged tissue dilutes noxious stimuli, attraction of leucocytes and macrophages, generation of antibodies, increased supply of nutrients and oxygen. Adverse - significant pain, long lasting hyperalgesia, loss of function, release of mediators may induce a cycle of inflammatory cell attraction and further mediator release.
Name the Mediators of Inflammation
Amines - histamine, 5-hydroxytryptamine, kinins, complement, cytokines - interleukins, eicosanoids - prostaglandin E2, prostacyclin, Platelet activating factor.
What is the function of histamine?
It is released from cells such as mast cells, basophils and eosinophils and causes vascular dilation and increased vascular permeability.
What is the function of 5-HT
It causes increased vasoconstriction and is released from cells such as mast cells and platelets.
What is the function of bradykinin
Formed from kininogen in plasma by factor XII, it causes increased vascular dilation and is a mediator of pain.
What is the Definition of NSAIDS?
Agents which inhibit the formation of eicosanoids from arachidonic acid. Prostaglandins and thromboxanes and luekotrienes.
What is the NSAIDS mechanism of action?
They inhibit the enzyme cyclo-oxygenase (COX) there are two enzymes - COX-1 and COx-2. COX 2 is a constitutive enzyme. COX-2 is an inducible enzyme produced by inflammatory cells. NSAIDS mainly are non selective reversible inhibitors of COX1 and COX2. They have an analgesic and antipyretic effect centrally and peripherally they are anti inflammatory, analgesic, anti thrombotic, anti endotoxic.
What are Endotoxins and how do NSAIDS affect them?
Endotoxins are lipopolysaccharides generated by gram negative bacteria. Endotoxins damage white blood cells and vascular endothelium thus releasing vasoactive mediators. NSAIDS prevent the generation of vasoactive mediators during endotoxaemia.
Describe the Absorption and Distribution of NSAIDS?
They are Given orally or parenterally. They are well absorbed after oral administration as they are weak acids (In gut low PH, non ionised). Food may interfere with absorption. Increases some (mavacoxib) decreases others (Flunixin). It is highly protein bound (approaching 99%) It has a small apparent volume of distribution. It accumulates at sites of inflammation. Often has a short half life – but duration of effect is long due to the binding to COX enzyme.
Describe the Metabolism of the NSAIDS
Hepatic metabolism, some excretion of unaltered drug (alkaline urine enhances this), some metabolites are active, slow metabolism and excretion in young (up to 6 weeks old) Some display zero order kinetics.
What are the Side effects of Nsaids?
Related to the inhibition of Cox-1. GIT ulceration - reduced synthesis of prostaglandins which inhibit gastric acid secretion and promote mucous secretion. Nephrotoxicity - effect of inhibition of prostaglandins on renal blood flow. In face of relative hypovolaemia/hypotension prostaglandins dilate the afferent arteriole and allow activation of RAAS to constrict the efferent arteriole. COX inhibitiion leads to increased apoptosis of medullary interstital cells. Potential to induce hepatic injury. Coagulation affects eg aspirin. COX2 selective agents desirable.
Describe Aspirin
Hydrolysed to an active moiety - salicylate. It irreversibly binds to cyclo-oxygenase - it has a selectivity for Platelet COX. Its side effects are gastrointestinal erosions, haemorrhage, and emesis. It is oxidised and some is conjugated to glucuronide or sulphate. there are massive species variation in half life.
Explain why Aspirin is a more effective antithrombotic agent at low doses.
TXA2 is inhibited at low doses whereas the disaggregatory eicosanoid PGI2 is not. At high doses PGI2 synthesis by endothelial cells inhibited. TXA2 Promotes platelets to stick together and localised vasoconstriction *inhibited at low doses.
Describe the Effects / Metabolism of Paracetamol
- glucuronidation 2.sulphate conjugation 3. N hydroxylation. Pathway 3 yields NABQI. NABQI binds to glutathione. But if glutathione is saturated it binds to hepatic proteins causing necrosis. Paracetamol has an alternative mechanism of action - it is a good antipyretic and analgesic but an inferior anti inflammatory. It interferes with cyclic endoperoxidases rather than cyclo oxygenase enzyme.
Describe Phenylbutazone
More potent anti inflammatory than analgesic. Activity is associated with cyclo oxygenase inhibition. It concentrates in inflammatory exudate. Its absorption is reduced by food. There are very large interspecies differences in kinetics. The active metabolite is oxyphenbutazone. Zero order kinetics - half life varies with dose.
What is Carprofen?
A poor cyclo-oxygenase inhibitor yet potent anti inflammatory. It is a racemic mix and is COX-1 sparing. It is generally well tolerated, has a good safety profile in dogs. Can be used as a perioperative analgesic with reduced risk of nephropathy.
Describe the ‘Coxib’ NSAIDS
Developed to increase GI safety. Once daily administration they have hepatic metabolism and biliary excretion. e.g Robenacoxib. Mavacoxib is a preferential COX-2 inhibitor given orally as food increases bioavailability. It is highly bound to plasma protein and has an extended half life giving therapeutic levels for one month. Mainly eliminated unchanged in the bile.
Describe the uses of Hyaluronan
A ubiquitous molecule. A non sulphated proteoglycan which is naturally occurring and imparts important structural characteristics to synovial fluid ad cartilage. It is classed as a chondroprotective agent. It can be given intra articular and intravenous administration. Used in dogs and horses. It scavenges free radicals and induces PGE2 synthesis and proteoglycan synthesis.
What are Polysulphated Glycosaminoglycan & pentosan polysulphate??
They have a structure similar to heparin. They are for intra articular and intra muscular use in horses and subcut in dogs. They stimulate matrix metalloproteinase production. the drug is not contained in the ccartilage but is excreted by the kidney.
Describe Matrix Metalloproteinases
A family of proteolytic enzymes, which play a role in matrix degradation. They are endogenous inhibitors called TIMPs. MMPS play a role in joint disease. There is a potential role of MMP inhibitors in management of inflammatory joint disease. Tetracyclines are weak inhibitors.
Where are corticosteroids synthesised?
The adrenal cortex produces corticosteroids;
- mineralocorticoids - aldosterone (Zona glomerulosa)
- Glucocorticoids - cortisol (hydrocortisone) and cortisone (zona fasciculata and reticularis). They are synthesised and released as required. Synthesised from cholesterol obtained from plasma and stored in the adrenal gland.
Describe the Structure of Glucocorticoids.
They have a four ring , 21 carbon basic structure. They are all biologically active steroids so have a double bond at C4-5 and a ketone at C3. Substitutions can increase the gluconeogenic potency and decrease the mineralocorticoid activity.
What are the pharmacokinetics of Glucocorticoids
They are highly protein bound. They bind to albumin and corticotrophin binding globulin. CBG has a high affinity but low capacity and binds only to endogenous corticosteroids apart from prednisolone. Albumin binds to endogenous and synthetic. Hydrocortisone has a short half life (90 minutes). Metabolism occurs in the liver. There is reduction of the C4-5 double bond and conjugation with sulphate or glucuronic acid. It is excreted in the urine.
What is the mechanism of action of glucocorticoids?
They cross the cell membrane by diffusion and bind to steroid specific cytoplasmic receptors. Receptor steroid complex translocates to the nucleus and increases or decreases the transcription of specific mRNAs and up or down regulates gene expression. Some effects linked to interaction of the steroid receptor complex with transcription activator protein which acts as an enhancer of gene transcription. They inhibit cytokines, cyclo oxygenase and collagenase.
Describe the Metabolic Effects of Glucocorticoids.
They increase gluconeogenesis, inhibit utilisation of glucose, increase glycogen storage in response (insulin release), cause protein breakdown and reduced synthesis, redistribution of fat, and negative calcium balance.
Describe the Systemic effects of Glucocorticoids
Elevation of Liver enzymes, induction of parturition/abortion, alteration of CNS function, Mineralocorticoids activity.
What are the Anti-inflammatory effects of corticosteroids?
Have an effect on blood vessels by decreasing vasodilation and fluid exudation, inflammatory cells by decreasing action of T helper cells, decreasing accumulation of leucocytes, decreasing macrophage activity, decreasing fibroblast function, decreasing function of osteoblasts and increasing osteoclasts, and inflammatory mediators by decreasing production of prostanoids, inhibiting PLA2, decreasing generation of inflammatory cytokines and decreasing histamine release.
Describe the Immune suppressive effects of Glucocorticoids at low and high doses?
Low doses - cellular response inhibited lymphocytes, eosinophils, monocytes and basophils. Increase in neutrophils.
High doses - humoral response inhibited.
