Analgesic Drugs

Question 1

What is the function of phospholipase A2 (PLA2)?

Answer 1

• cleaves FA’s from cell membrane
• generates arachidonic acid (AA) = widely used precursor
• cleaves unsaturated FA’s at ester bond

Question 2

What is arachidonic acid?

Answer 2

• polyunsaturated omega-6 fatty acid
• 20 C atoms, 4 C=C
• number of reactive = make it a versatile eicosanoid pre-cursor

Question 3

What is the role of lipoxygenases (LOX)?

Answer 3

Converts AA into eicosanoids = further modified to leukotrienes = role in chemotaxis, bronchoconstriction + vasc. permeability

Question 4

What is the role of PGHS?

Answer 4

Converts AA + O2 -> PGG2 + PGH2 -> modified to cell-specific prostaglandins

So role = create prostaglandins

Question 5

What are the roles of the 2 domains of PGHS?

Answer 5

COX domain: O2 + AA -> PGG2

Peroxidase domain: PGG2 -> PGH2

Question 6

What are the isoforms of PGHS?

Answer 6

PGHS-1
PGHS-2
PGHS-3

Question 7

What is the role of PGE2?

Answer 7

• GI mucosa + renal protection
• Causes uterine contraction
• Pain sensitiser
• Inflam mediator (local vasodilation, histamine + bradykinin release, eosinophil + basophil chemotaxis)

Question 8

What is the role of TXA2?

Answer 8

Causes platelet aggregation + local vasoconstriction

Question 9

What is the role of PGI2?

Answer 9

Inhibits platelet aggregation + local vasodilation

Question 10

How do PG receptors work?

Answer 10

GPCR

Cell/tissue effect depends on type of GP activated

Question 11

How do NSAID’s work?

Answer 11

Inhibit COX domain in PGHS so no PGG2 + PGH2 produced

Question 12

How do NSAID’s have an anti-inflammatory effects?

Answer 12

Inhibit PGHS-2 derived PG (e.g. PGE2) = reduced local inflammation due to

reduced vasodilation + increased vasc. permeability

Question 13

How do NSAIDs reduce pain + fever?

Answer 13

Anti-pyeretic - reduced PGE2 in response to pyrogens

Analgesic - reduced PGE2 = reduced sensitisation of A-delta and C fibres to serotonin, bradykinin + sub P

Question 14

What is the MOA of ibuprofen?

Answer 14

• Competes with AA for COX domain of PGHS 1 & 2

- Reversible competitive inhibitor

Question 15

What is the MOA of aspirin?

Answer 15

• Only irreversible inhibitor of PGHS

- Acetylation of serine in COX domain active site

Question 16

Why would paracetamol be chosen over an NSAID?

Answer 16

Can have better analgesic + anti-pyretic effects but v little anti-inflam activity

Question 17

What is the MOA of paracetamol?

Answer 17

May inhibit peroxidase domain activity in PGHS2 or 3 in CNS or its metabolites may be having affects in CNS

Question 18

What are the ADR’s of NSAID’s?

Answer 18

• gastric ulceration

- compromised renal function

Question 19

What are the contraindications of NSAID’s?

Answer 19

• pregnant
• sensitive/allergic
• already on NSAID
• > 16

Question 20

Describe the pain ladder from mild to strong pain

Answer 20

Paracetamol + NSAIDs
Co-codamol 
Weaker opioids 
Stronger opioids 
Diamorphine, fentanyl +/- sedation