What are Eicosanoids?
A precursor generated from phospholipids in the CNS
What are the 3 key groups of Eicosanoids?
- prostaglandins (PGs)
- thromboxanes (TXA)
Which enzyme produces Eicosanoids from the phospholipids in the plasma membrane?
What activates phospholipase A2 to produce Eicosanoids (5)?
- antigen-antibody binding on mast cells
- complement C5a
- cell damage
What is the precursor of Eicosanoids?
What other chemical mediator is produced from plasma membrane?
Platelet activating factor
Which two Eicosanoids can also be called prostanoids?
What is the nomenclature of prostaglandins?
PG = prostaglandin
Letter = basic structure it comes from
Number = the no of C=C
Most often (arachidonic acid is the precursor)
- how many C=C does PG have?
Which cells release prostaglandins?
ANY injured cell
Which process is Prostaglandin a key mediator in?
What are the effects of prostaglandin in blood vessels?
Vasodilation (PGE1&2, PGI1)
What are the effects of prostaglandin in healing?
Inhibit platelet aggregation (PGI2 & PGE)
n.b. TXA2 = increased platelet aggregation
What are the effects of prostaglandin in the respiratory system?
N.b. varies with prostaglandin
Bronchodilation = PGI2 & PGE2
Bronchoconstriction = PGF2 & TXA2
How do prostaglandins affect pain?
Sensitise nociceptive neurones to the action of mediators (bradykinin & serotonin) = activate pain fibres
How do prostaglandins affect fever?
Act on the hypothalamus = increase body temperatureInflammation = macrophages release IL-1 = AA-> PGE2 = acts on neurones in pre optic area (sets our internal core temp) = increase thermostatic set point = heat generation (shivering, skin vasoconstriction = destroy infection)
When PG production stops (immediately broken down) = decrease set point = heat dissipating (sweating and vasodilation)
Which enzyme converts arachidonic acid (AA) to PG H2 = prostanoid precursor?
How many active sites does COX have?
What are the actions of the two COX active sites?
- Cycloxegynase site = AA -> PGG2
- Heme with peroxidase activity = reduces PGG2 to PGH2
How many COX isoenzymes exist?
COX-3 (not really understood = splice variant of COX-1)
n.b. different tissues express varying levels of COX-1 & 2= SELECTIVE INHIBITION POSSIBLE
Where is COX-1 found?
Consitutive (always there) in most cells
What does COX-1 do?
Maintains tissue homeostasis
Housekeeping: gastric protection, blood clotting, renal blood regulation
n.b. inflammation is NOT the main role
What is the key difference between COX-1 & COX-2?
COX-1 binding pocket is NARROW
COX-2 binding picket is WIDE
What induces COX-2?
Inflammation (abundant in activated macrophages)
When is COX-2 unregulated?
In various carcinomas
What does COX-2 produce?
Prostanoids = mediate inflammation
What are the two main types of anti-inflammatory agents?
- non steroidal anti-inflammatory drugs (NSAIDs)
Which 3 other drugs act as anti- inflammatory agents?
- H1 receptor antagonists
- chondroprotective drugs
What does NSAIDs stand for?
Non steroidal anti-inflammatory drugs
How do NSAIDS target inflammation?
inhibit cyclo-oxygenase (COX) = reduced prostaglandin & thromboxane synthesis
When are NSAIDs most commonly used in treatment?
- non-infectious/non-allergenic inflammation (e.g. headache, sprained ankle)
- control inflammation and pain (e.g. trauma, post-surgery & osteoarthritis)
Which action of cyclo-oxygenase do most NSAIDs inhibit?
Endoperoxidase synthase (no PGG2 produced)
n.b. PGG2 & PGH2 = unstable = produced on demand & broken down very quickly
What are the 3 different effects that NSAIDs have?
- Anti-inflammatory (reduce vasodilation, oedema, pain & fever)
- Analgesic (reduce PG synthesis -> pain from inflammation & tissue damage)
- Anti-pyretic = anti-fever
NSAIDSs differ in their selectivity for COX isoenzymes...Which NSAID (1) is COX-1 preferring?
NSAIDSs differ in their selectivity for COX isoenzymes...Which NSAID (1) has an equal effect on both isoenzymes?
NSAIDSs differ in their selectivity for COX isoenzymes...Which NSAID (1) is COX-2 preferring?
List these 4 drugs in order of strength of their anti-inflammatory effects?
Aspirin & ibuprofen
Strongest = Indomethacin
Moderate = Aspirin & Ibuprofen
Essentially none = Paracetamol
What are the 2 additional effects of salicylates (aspirin)?
- reduce platelet aggregation (prophylaxis of strokes & thromboembolism)
- analgesic- antipyretic (partial)
What are the pharmacokinetics of salicylates (aspirin)?
Weak acid = absorbed in stomach
Hydrolysed to salicylic acid in plasma & at low therapeutic doses most is bound to serum albumin
What % of salicylates (aspirin) is excreted unchanged?
What % of salicylates (aspirin) is oxidised?
The effects of aspirin are DOSE DEPENDANT!! What are the effects of aspirin at the following doses?
0.5-1 mg/kg = anti-platelet
5-10 mg/kg = analgesic/antipyretic
>30 mg/kg = anti-inflammatory
What is the main side effects of salicylates?
- Gastric bleeding(loss of mucosal protection by PGs & inhibition of platelet aggregation)
What is salicylism?
What can cause salicylism?
- viral infection (liver/CNS disturbances)
- repeated ingestion of high doses = chronic toxicity (20-40% fatal)
- altered acid/base balance (uncouples oxidative phosphorylation
What are the effects of overdose?
Respiratory & metabolic acidosis (tinnitus, dizziness, hearing loss & nausea;
reye's syndrome = serious liver & brain damage)
What is the name drug that Aspirin interacts with?
Displaces warfarin from plasma proteins = increases the effects of warfarin
What are the 3 effects of paracetamol?
Weak/no anti-inflammatory activity
What is the mechanism of action of paracetamol?
- often appears to be COX-2 selective
- now thought to inhibit COX-1 & 2 by peroxidase function = inhibits PG synthesis of PGs when low levels of arachidonic acid & peroxides are available but little activity at substantial levels of these!
= doesn't suppress inflammation of rheumatoid arthritis & gout but does inhibit the lesser inflammation from tooth extraction
What is the toxic dose of paracetamol?
2-3 X normal dose
What happens when the toxic dose of paracetamol is taken?
= potentially liver toxicity due to saturation of normal liver enzymes
How is paracetamol normally metabolised in the liver?
When the toxic dose of paracetamol is take how is it metabolised in the liver?
Glucuronidation & sulfination is saturated= mixed function oxidases instead (CYP450) = producs NAPQ (toxic metabolite) -> if not inactivated by conjugation with glutathionine it reacts with cell proteins = cell death
Where are ibuprofens derived from?
Which COX enzyme does ibuprofen inhibit?
All of them! = non selective (COX1 & COX2)
What are the 5 effects of ibuprofen?
Mild anti platelet effect
What property of ibuprofen means it can be administered as a topical gel?
It is stable in solution (used for sports injuries - absorbed through skin = less risk of digestive problems)
What are the common side effects of Ibuprofen (11)?
Raised liver enzymes
Epistaxis (nose bleeds)
Salt & fluid retention
What are the infrequent adverse effects of ibuprofen?
Which condition can be exacerbated by ibuprofen?
Asthma -> sometimes fatally!
How does COX-1 inhibition cause gastric ulceration?
inhibition of PGE2 & PGI2 synthesis
Which drugs can cause direct damage to the gastric mucosa?
aspirin can precipitate in cells lining the stomach
Which two drugs irreversibly inhibit platelet COX-1?
What other things (4) can increase GI damage?
- concurrent glucocorticoid administration
- hypovolemic shock
- disruption to gastric blood flow
Why are selective COX-2 inhibitors beneficial in theory?
Target inflammation and reduces the risk of peptic ulceration
Why are selective COX-2 inhibitors not used?
In clinical trials they caused a significant increase in heart attacks and strokes
Which (4) cells produce leukotrienes?
What are the two different leukotriene receptor classes?
BLT (LTB) -> LTB4
= important mediator in all inflammation (activate & targeting of leukocytes & cytokine production)
CysLT (LTC3, LTD4, LTE4)
= mediate bronchoconstriction, vasodilation in most vessels (coronary vasoconstriction), plasma extravasation, role in hayfever & astha treatment
Name two CysLT receptor antagonists:
Where are corticosteroids secreted from?
Which area of the adrenal gland secretes mineralocorticoids (e.g. aldosterone)?
Outer layer of cortex = zona glomerulosa
What action do mineralocorticoids have?
regulate water and electrolyte balance
Which area of the adrenal gland secretes glucocorticoids (e.g. hydrocortisone & corticosterone)?
Middle layer of cortex = zone fascilculata
What action do glucocorticoids have?
Affect carbohydrate and protein metabolism
Which is the most important human glucocorticoid?
In which fashion are glucocorticoids released?
Pulsitile circadian rythmn (highest in morning = declines in evening/night)
What are glucocorticoids produced from?
Which hormone regulates the initial step of glucocorticoid production?
What happens in a loss of corticosteroids (4)?
Which disease causes destruction of the adrenal gland?
Addison's disease (autoimmune or due to chronic inflammation)
How do glucocorticoids have an anti-inflammatory action?
They are part of the immune systems feedback system:
= stimulate Annexin1 (lipocortin) production = blocks phospholipase A2 = blocks parts of inflammatory responseBind to glucocorticoid receptor= up regulates expression of nuclear anti-inflammatory proteins= represses expression of systolic pro-inflammatory proteins (less complement in plasma, less induce NO production, less histamine release from basophils & reduced IgG production)
What are the clinical uses of glucocorticoids (8)?
- Eczema, Rhinitis & allergic conjunctivitis
- hypersensitivity states (severe allergic reactions)
- miscellaneous diseases with autoimmune & inflammatory components (e.g. IBD & rheumatoid arthritis)
- replacement therapy for glucocorticoid deficiency- stop graft rejection
- cancer treatment
- acute spinal injury
Through which routes can glucocorticoids be administered (4)?
What are the pharmacokinetics of glucocorticoids (3)?
- bound to corticosteroid binding globulin in blood
- diffuses into cells
- metabolised by liver
What are the unwanted side effects of glucocorticoid use?
- Suppress response to infection
- suppress endogenous glucocorticoid synthesis
- metabolic actions
- cushings syndrome (m. wasting)
Which glucocorticoid drug is used to treat asmtha?
Which glucocorticoid drug is used to treat eczema?
Which glucocorticoid drug is used to treat rhinitis & allergy?
Which glucocorticoid drug is used to treat Rheumatoid arthritis?
Which glucocorticoid drug is used to treat IBS & crohns disease?
What is Flutricansone proprionate used to treat?
What is Hydrocoritsone, Prednisolone and Dexamethasone used to treat?
What is Beclometasone dipropionate used to treat?
rhinitis & allergy
What is Prednisone used to treat?
What is Budesonide and Dexamethasone used to treat?
IBS & crohns disease
When should use of anti-inflammatory drugs be avoided?
- patients with congestive heart failure or renal insufficiency
-patients taking ACE inhibitors, methotrexate, blood thinners (warfarin) & some oral hypoglycaemic agents= increased risk of bleeding = possible complications during dental surgery