Pain

Question 1

Misoprostol*

Answer 1

Prostaglandin analogue used to counteract NSAID-induced dyspepsia.
Gastric symptoms arise due to inhibition of COX-1, as this synthesises PGs involved in inhibition of acid secretion, protecting the mucosa.

Question 2

Aspirin (acetylsalicylic acid)

Answer 2

NSAID
Irreversibly inactivates COX enzymes.
Anti-inflammatory, inhibits platelet aggregation - main use is treatment of CVD.
At low doses, it inhibits formation of the platelet activator TXA2, but not the vasodilator PGI2.
Therapeutic doses may cause gastric bleeding.
Larger doses cause salicylism (dizziness, deafness and tinnitus) and compensated respiratory alkalosis.
Toxic doses cause uncompensated metabolic acidosis.

Question 3

Paracetamol (acetaminophen)

Answer 3

NSAID with potent analgesic and antipyretic effect but a weaker anti-inflammatory effect.
COX inhibition seems to be specific to the CNS enzyme- no gastric or platelet side effects.
Larger doses over long periods - kidney damage
Toxic doses - hepatotoxicity

Question 4

COXIBs

Answer 4

Selective COX-2 inhibitors
Celecoxib and etoricoxib are licensed for symptomatic relief of osteoarthritis and rheumatoid arthritis.
Parecoxib is a prodrug of valdecoxib licensed for short-term treatment of postoperative pain.

Question 5

Local anaesthetics

Answer 5

Inhibit VGSCs by binding to the intracellular side.
Weak bases, cross the PM unionised but bind ionised.
Esters, such as Procaine, have shorter half-lives as they can be metabolised in the plasma or in tissues such as the liver.
Amides, such as Lidocaine, have longer half-lives as they can only be metabolised by amidases found in the liver.
CNS side-effects: agitation, confusion, tremors, convulsions and respiratory depression
CVS effects: myocardial depression and vasodilatation, leading to fall in BP

Question 6

Opioids

Answer 6

MOP receptors are Gαi coupled GPCRs.
αi subunit inhibits adenylyl cyclase
βγ subunit inhibits presynaptic VGCCs, inhibiting NT release, and activates postsynaptic GIRK potassium channels, hyperpolarising the membrane.
Endogenous opioids: enkephalins, endorphins, dynorphins and endomorphins.
Ligands: morphine, fentanyl, methadone, pentazocine
Cause analgesia, reducing the effective component of pain and the emotional burden.
Also cause euphoria, respiratory depression, and cough suppression (sub-analgesic doses of codeine)
Nausea and vomiting may occur.
Peripheral effects cause inhibited GIT motility and release of histamine from mast cells (pruritus, hypotension, bronchoconstriction).
Tolerance to analgesic effects.
In some individuals, chronic treatment causes opioid-induced hyperalgesia (OIH).

Question 7

Opioid addiction and overdose

Answer 7

Methadone - substitution - full agonist, longer half-life to heroin, does not produce a high.
Buprenorphine - substitution - partial agonist, has a ceiling effect, which reduces the danger of overdose but can precipitate withdrawal symptoms if other opioids (e.g. heroin) are in the system.
Naltrexone - opioid receptor antagonist used to reverse overdose
Suboxone is a combination preparation of buprenorphine with naloxone

Question 8

Tetrodotoxin (TTX)

Answer 8

Blocks neuronal VGSCs → abolishes AP but not the small initial depolarisation.

Question 9

Tetraethylammonium

Answer 9

Blocks neuronal VGPCs → slows repolarization, as this now only occurs due to the inactivation of VGSCs. There is also no hyperpolarization. Neurons are more excitable.

Question 10

Oubain

Answer 10

Na/K ATPase inhibitor → educes the size of the AP progressively, until the membrane Na gradient is reduced to the point where APs can be initiated but fail.