Non-narcotics Flashcards
Prostaglandin Pathway
Involves making Arachadonic Acid by Phospholipase A2 Further steps yield: Prostacyclins Prostaglandins Thromboxane A2 Leukotrienes
Role of COXs
COX1- GI protection, platelet aggregation, renal blood flow, renal electrolytes
COX2- Pain, fever, inflammation
COX3- Variant of COX1 mainly in CNS
Structural Classes
There are eight structural classes
Hydrophobic and carboxylic acid groups (except Acetaminophen)
Propionic Acids- Naproxen (safest)
Acetic Acids- Indomethacin (potent and CNS effects- danger)
NSAID Binding
NSAIDs bind at Arg120 via carboxylic group in both isoforms
One phenyl ring so small enough to enter COX1
Coxib Binding
Coxibs are 8-35 fold more selective for COX2
They are too big to enter COX1
Sulfonamide group binds Arg513 in hydrophillic side pocket not found in COX1 created b Valine523
Therapeutic Effects
COX2 Inhibition
Analgesia
Anti-inflammatory
Antipyretic
Side Effects
COX1 inhibition
GI toxicity
Sodium and water retention
Decreased endothelial prostacyclin
Analgesic Action
Blockade of prostaglandin production
Decrease PGE2 receptor activation
Stops depolarisation of secondary neurons
Stops peripheral desensitization
Anti-inflammatory Effects
PGE increase vasodilation, vascular permeability, oedema
NSAIDs decrease PGE- less vasodilation, less oedema
Anti-pyretic Effects
Inflammation releases pyrogens acting on thermoregulatory system increasing temp by PGE
Decreased PGE in hypothalamus reseting the thermostat
Do not affect temperature under normal circumstances
NSAID Adverse Effects
GI Effects
Dysepesia, nausea, vomiting, diarrhoea, haemorrhage, perforation
Cytoprotection: misoprostol
Ranitidine (H2 antagonist) and omeprazole prevent effects
Peptic Ulcer Disease
Decreased PGs= Increased acid, decrease bicarb and mucus, decrease blood flow
Increased neutrophil adherence to endothelium= mucosal damage
Skin Reactions
Mild rash, utricaria, photosensitivity
Resp Effects
Bronchospasm in asthmatics
Renal Effects
Disturbed renal blood flow from PG inhibition
Care in patients with renal disease or compromised function
Celecoxib & Rofexocib
Similar efficacy to NSAIDs 50% reduction in GI effects Rates of MI, stroke and death increase Rofecoxib withdrawn in 2004 Three phenyl rings
Drug Interactions
ACE Inhibitors Analgesics Anticoagulants Antiepileptics Antihypertensives Glycosides Diuretics
Salicylates
Aspirin: irreversible inhibitor- acetylates Ser in active site
Weak acids
Considerable first pass metabolism
Unevenly distributed: high in liver and kidney
Toxicities: Salicylism( tinnitus, vomit, vertigo), Reyes syndrome
Paracetamol- Acetaminophen
Analgesic & Antipyretic NOT ANTI-INFLAMMATORY
No effects on blood clotting
Weak inhibitor of COX1,2 but as potent as aspiring with COX3
Absorption (oral) is rapid, metabolised by liver- glucuronidation
Treat overdose- N-Acetyl Cysteine- increase glutathion
Acetaminophen: Liver Necrosis
Acute toxicity> 5-15g
Converted to reactive metabolite NAPQI by CYP in liver
Attacks nucleophilic thiol groups
Mitochondrial damage block ATP dependent apoptosis
Necrotic cell death
NSAID Indications
Ankylosing Spondylitis Rheumatoid Arthritis Osteoarthritis Acute gouty arthritis Dysmenorrhoea
Use of Analgesic Drugs
Choice and route depends on nature and duration of pain
Progressive approach: NSAID->Weak Opioid-> Strong Opioid
Severe acute pain: Opioid
Mild inflammatory pain: NSAID
Severe pain (cancer): Strong opioids orally or injected
