Non-narcotics

Question 1

Prostaglandin Pathway

Answer 1

Involves making Arachadonic Acid by Phospholipase A2
Further steps yield:
Prostacyclins
Prostaglandins
Thromboxane A2
Leukotrienes

Question 2

Role of COXs

Answer 2

COX1- GI protection, platelet aggregation, renal blood flow, renal electrolytes
COX2- Pain, fever, inflammation
COX3- Variant of COX1 mainly in CNS

Question 3

Structural Classes

Answer 3

There are eight structural classes
Hydrophobic and carboxylic acid groups (except Acetaminophen)
Propionic Acids- Naproxen (safest)
Acetic Acids- Indomethacin (potent and CNS effects- danger)

Question 4

NSAID Binding

Answer 4

NSAIDs bind at Arg120 via carboxylic group in both isoforms

One phenyl ring so small enough to enter COX1

Question 5

Coxib Binding

Answer 5

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

Question 6

Therapeutic Effects

Answer 6

COX2 Inhibition
Analgesia
Anti-inflammatory
Antipyretic

Question 7

Side Effects

Answer 7

COX1 inhibition
GI toxicity
Sodium and water retention
Decreased endothelial prostacyclin

Question 8

Analgesic Action

Answer 8

Blockade of prostaglandin production
Decrease PGE2 receptor activation
Stops depolarisation of secondary neurons
Stops peripheral desensitization

Question 9

Anti-inflammatory Effects

Answer 9

PGE increase vasodilation, vascular permeability, oedema

NSAIDs decrease PGE- less vasodilation, less oedema

Question 10

Anti-pyretic Effects

Answer 10

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

Question 11

NSAID Adverse Effects

Answer 11

GI Effects
Dysepesia, nausea, vomiting, diarrhoea, haemorrhage, perforation
Cytoprotection: misoprostol
Ranitidine (H2 antagonist) and omeprazole prevent effects

Question 12

Peptic Ulcer Disease

Answer 12

Decreased PGs= Increased acid, decrease bicarb and mucus, decrease blood flow
Increased neutrophil adherence to endothelium= mucosal damage

Question 13

Skin Reactions

Answer 13

Mild rash, utricaria, photosensitivity

Question 14

Resp Effects

Answer 14

Bronchospasm in asthmatics

Question 15

Renal Effects

Answer 15

Disturbed renal blood flow from PG inhibition

Care in patients with renal disease or compromised function

Question 16

Celecoxib & Rofexocib

Answer 16

Similar efficacy to NSAIDs
50% reduction in GI effects
Rates of MI, stroke and death increase
Rofecoxib withdrawn in 2004
Three phenyl rings

Question 17

Drug Interactions

Answer 17

ACE Inhibitors
Analgesics
Anticoagulants
Antiepileptics
Antihypertensives
Glycosides
Diuretics

Question 18

Salicylates

Answer 18

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

Question 19

Paracetamol- Acetaminophen

Answer 19

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

Question 20

Acetaminophen: Liver Necrosis

Answer 20

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

Question 21

NSAID Indications

Answer 21

Ankylosing Spondylitis
Rheumatoid Arthritis
Osteoarthritis
Acute gouty arthritis
Dysmenorrhoea

Question 22

Use of Analgesic Drugs

Answer 22

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