W22 Drugs for Pain (MM)

Question 1

What is Codeine?

Answer 1

• True opiate used globally for pain relief,
  coughing and diarrhoea
• WHO list of essential medicines 2021
• Often combined with paracetamol or
  NSAIDs
• First isolated in France in 1832

Question 2

Discovery of Codeine

Answer 2

• Derived from Papaver somniferum
• Opium first explicitly mentioned by
  Theophratus (372-287BC)
• Used as a “pain soother” in England early
  19th century
• Morphine isolated 1804 in Germany leading
  to isolation of codeine 1832
• Small molecule, selective agonist for μ
  opioid receptors

Question 3

We have Morphine, so why isolate Codeine?

Answer 3

Morphine:
* Analgesic drug
* Binds extremely well to μ receptors
* Also binds to k receptors
* Significant side effects

Codeine
* Pro-drug
* Binds moderately with μ receptors
* Does not bind to k receptors
* Lesser side effects

Question 4

What are the Structural Differences between Codeine and Morphine?

Answer 4

Morphine:
* Hydroxyl group (OH)
* Log P = -0.21

Codeine:
* Methoxy group (OCH3)
* Log P = 1.19

Question 5

Properties of Fentanyl?

Answer 5

• Synthetic, lipophilic, opioid agonist
• Analgesic and anaesthetic properties
• Selectively binds to mu-receptor in CNS
• The analgesic effect is strong and rapid
• Developed in the 1950s
• Commonly used for chronic cancer pain or in anaesthesia
• Over 100k drug overdose deaths per year in the US
• 2/3 are fentanyl – National Fentanyl Awareness day 7th May 2024 (US)

Question 6

Fentanyl Vs Morphine:
which is more potent?
which passes through mucus membranes more easily?
which is more hydrophilic?
which passes through the BBB?

Answer 6

Fentanyl:
* More potent
* Pass through skin more easily
* Pass through mucus membranes more easily
* Pass through the BBB

Morphine:
* Remains at site it is administered for longer
* More hydrophilic
* Pass through the BBB

Question 7

Paracetamol

Answer 7

• Also known as acetaminophen
• Analgesic and antipyretic
• Does not have anti-inflammatory properties
• Excellent tolerability at therapeutic doses
• Hepatotoxicity in overdose is major issue
• First discovered in 1940s
• Synthesised today via acetylation of 4 -aminophenol (p-aminophenol

Question 8

Synthesis of Paracetamol:

Answer 8

P-aminophenol + acetic anhydride = Acetaminophen/Paracetamol

Question 9

Ibuprofen

Answer 9

• Non-Steroidal Anti-Inflammatory Drug (NSAID)
• Analgesic, antipyretic and anti-inflammatory
• Trivial name comes from fragments of chemical name (+/-)-2-(p-isobutylphenyl)propionic acid
• The commercial compound is racemic
• Risks especially for those with hypertension,
  cardiovascular disease or GI disorders
• First discovered in 1960s
• Synthesis of ibuprofen from Isobutylbenzene using the Boots process

Question 10

Synthesis of Ibuprofen:
Reagents, Conditions and Intermediates

Answer 10

AlCl3, NaOEt, H30+, NH2OH, Ac2O,