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What are eicosanoids?
- 20 carbon molecule (essential fatty acid) derived from plasma membrane
- Main EFA is Arachadonic Acid
- Lead to production of leukotrienes and prostanoids
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Name the 3 prostanoids and how their formed
Prostaglandins (E and D), Prostacyclin (PGI2), Thromboxane (TXA2)
- Formation
- - Common step: Breaking off phospholipid to make Arachadonic acid (by phospholipase C)
- - Formation of PGH2 by COX 1 or 2
- PGD2: is formed from PGD synthase
- PGE2: from PGE synthase
- PGF2: from PGE2
- PGI2: from prostacyclin synthase
- TXA2: from thromboxane synthase
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What are leokotriense?
- Act on G-protein linked receptors
- Involved in:
- - allergic reactions and athma
- - sustain inflamatory reactions
- Function:
- - chemotaxis
- - vaso- and broncho constriction
- - vascular permeabillity
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Name 2 leokotriene receptor antagonists
- Montelukast
- Zafirlukast
- Used to treat asthma
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State the functions of the following prostanoids:
- PGD2: in mast cells. vasodilation, inhibit platelet aggregation
- PGF2: in smooth muscle and corpus luteum. Uterin contraction, vasoconstriction
- PGI2: in endothelium. Vasodilation, Inhibits platelet aggregation, maintains renal bloodflow and glomerular filtration
- PGE2: mediates fever, contraction of GIT smooth muscle, relaxation of bronchial, vascular and GIT smooth muscle, maintanance of renal bloodflow and glomerular filtration. Gastric mucosal protection
- TXA2: vasocontrictor. Platelet aggregation.
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describe two active sites in COX
- COX site: converts AA to PGG2
- POX site: converts PGG2 to PGH2
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True or False? The conversion of AA to PGH2 is the rate limiting step in prostaglandin production.
True
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State 3 types of Cyclo-oxygenase
- COX 1: constitutive
- COX 2: induced
- COX 3: splice variant of COX 1 gene
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Name three properties of NSAIDS
- Analgesic
- Antipyretic
- Anti-inflammatory
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Discuss classification of NSAIDS by Mode of Action and give examples of each
- Class I: simple, competetive
- - i.e. ibuprofen, naproxen
- Class II: competetive, time-dependent, reversible
- - i.e Diclofenac, indomethacin
- Class II: competetive, time-dependent, irreversible
- - i.e. Aspirin
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Describe drug interaction of Aspirin:
- Mainly Warfarin:
- - displaces warfarin from plasma proteins
- - risk of hemmorage
- Decreases effects of:
- - ACE inhibitors, B-blockers, Diuretics
- Increase effects of:
- - Lithium, methotrexate, phenytoin
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Side effects of NSAIDS
- GI disturbance:
- - nausea, vomitting, ulceration, hemmorage, perforation
- Skin:
- - rashes, photosensitivity
- Kidneys:
- - Papillary necrosis
- - interstitial nephritis
- - hypertension
- Liver:
- - Reye’s syndrom in children
- Bone:
- - bone marrow toxicity
- Lungs:
- - bronchospasm
- CNS:
- - headache, confusion, seizures, drowsiness
- Salicilism:
- - fatal
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Name 3 main uses of aspirin
- Thrombosis
- Inflammation
- Allergy
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What is the mechanism of action of Aspirin?
- Irreversible acetylation of: Ser529 on COX active site
- Prevents: eicosanoid production in platelets
- Duration: life cycle of platelet
*Note: in higher doses it causes toxicity and prevents PGI in endothelium
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How does Aspirin affect the GI mucosa?
- Inhibits prostaglandins
- PG are responsible for protection
- - mucous production
- - bicarbonate production
- - inhibition of acid
- causes bleeding and ulceration
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Breifly discuss ibuprofen in terms of:
- Indications: RA, Osteoarthritis, pain, Dysmenorrhea, fever
- Mode of Action: inhibition of COX 1 more than 2 less GI reactions
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Briefly discuss Diclofenac in terms of:
- Indications: RA and osteoarthrits, spondylitis
- Mode of Actions: COX inhibition, inhibition of DNA synthesis
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Discuss the actions of paracetemol
- Analgesic, anti-pyretic
- Inhibits COX 2 more than COX 1
- Does not inhibit TXA2 production
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Discuss the properties of Parecetemol
- half life of 1-4 hours
- metabolized in liver
- excreted in urine
- few side effects: (allegic skin rxn and GI disturbance)
- long term use: analgesic nephropathy
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Discuss paracetemol Overdose
- Hepatic necrosis
- - depletes glutathione
- - accumalation of toxic metabolites
- Hypoglycemic coma
- Thrombocytopenia
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What are the symptoms and treatment of Paracetemol overdose?
- Symptoms: nausea, vomitting, diaphoresis (excess sweating)
- Treatment: activated charcoal, N-acetylcystein (makes glutathione in liver)
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What is Nimesulide?
preferentially inhibits COX-2
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Discuss COX-2 inhibitors
- Examples: rofecoxib; celecoxib
- Anti-inflammatory agents
- Less risk of GI damage
- Greater risk of Myocardial Infarction and Stroke
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State 3 types of corticosteroids
- glucocorticoids
- minealocorticoids
- androgens
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Discuss mechanism of action of corticosteroids
- 1. Activation of anti-inflammatory genes
- annexin-1, SLPI
- 2. Inhibition of pro-inflammatory gene
- - Activator Protein-1 and Nuclear factor kappa B
- -- responsible for IL-1, IL-2, IL-6, IL-8, TNF-a and TNF-b
- - NO
- - Phospholipase A2, COX-2
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Discuss side effects of cortocosteroids
- Osteoperosis
- Growth retardation
- Metabolic effects
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