L6 OTC Analgesics

Question 1

Neurons that detect sensory info in the periphery are called:

Answer 1

Primary afferents

Question 2

Where do primary afferents synapse?

Answer 2

Onto secondary afferents in the spinal cord which then pass sensory info up to the brain

Question 3

Pain is detected by a specific class of primary afferents called _________

Answer 3

Pain is detected by a specific class of primary afferents called nociceptors

Question 4

What are polymodal nociceptors?

Answer 4

receptor that responds to many types of painful stimuli

(thermal, mechanical, chemical, electrical)

Question 5

What channels are temperature sensitive ligand-gated ion channels?

Answer 5

Transient Receptor Potential (TRP) channels

• different types of TRP channels are tuned to respond to very specific temperatures
• TRPM8 - activated in cold temperatures (<10C)
• TRPV1 - activated at hot temperatures (>43C)

Question 6

What ligands can activate TRPV1 and what ligand can activate TRPM8?

Answer 6

• TRPV1 - activated at hot temperatures = can be activated by capsaicin
• TRPM8 - activated at cold temperatures = can be activated by menthol

Question 8

What are three examples of inflammatory molecules that would be released during an immune response?

Answer 8

1. Bradykinins
2. Cytokines
3. Prostaglandins

Question 9

What is arachidonic acid?

Answer 9

A fatty acid present in phospholipids of cell membranes

• Freed from the phospholipid molecule by the enzyme phospholipase A2
• key inflammatory mediator
• Metabolized by 3 enzymes

Question 10

The enzymes _______ and _______ metabolize arachidonic acid into prostaglandins, protacyclins and thromboxanes

Answer 10

The enzymes cyclooxygenase-1 and -2 metabolize arachidonic acid into prostaglandins, protacyclins and thromboxanes

Question 11

The enzymes cyclooxygenase-1 and -2 (COX1 and COX2) metabolize arachidonic acid into:

Answer 11

The enzymes cyclooxygenase-1 and -2 metabolize arachidonic acid into prostaglandins, protacyclins and thromboxanes

Question 12

The enzyme 5-lipoxygenase (LOX) metabolizes arachidonic acid into:

Answer 12

Various leukotrienes

Question 13

The enzyme __________ metabolizes arachidonic acid into various leukotrienes

Answer 13

The enzyme 5-lipoxygenase metabolizes arachidonic acid into various leukotrienes

Question 14

How do prostoglandins and leukotrienes drive inflammation?

Answer 14

• They are potent vasodilators
• they are pyrogenic
• they attract immune cells (leukotactic) and coordinate the immune response

Question 15

______ is primarily expressed in non-inflammatory cells (blood vessels, platelets, gastric mucosa)

Answer 15

COX-1 is primarily expressed in non-inflammatory cells (blood vessels, platelets, gastric mucosa)

Question 16

________ is expressed mainly in inflammatory cells

Answer 16

Cox-2 is expressed mainly in inflammatory cells

Question 17

COX-1 is primarily expressed in ________ whereas COX-2 is expressed mainly in ________

Answer 17

COX-1 is primarily expressed in non-inflammatory cells (blood vessels, gastric mucosa, platelets) whereas COX-2 is expressed mainly in inflammatory cells

Question 18

Aspirin and other non-selective NSAIDS inhibit:

Answer 18

Both Cox isoforms (COX1 and COX2)

Block Arachidonic Acid binding site to prevent conversion to prostaglandins

Question 19

What is the effect of aspirin and Non-selective NSAIDS?

Answer 19

• Aspirin and other non-selective NSAIDS inhibit both COX isoforms thereby decreasing prostaglandin production = inhibits inflammation and reduces pain
• Also suppress prostaglandin synthesis in the brain that is stimulated by pyrogens and reduce fever (antipyretic action)

Question 20

Why are non-selective NSAIDS associated with gastric toxicity?

Answer 20

Inhibition of COX1 enzymes in the gastric mucosa decreases:

• mucus secretion,
• bicarbonate secretion and
• blood flow

Question 21

What was developed in an attempt to bypass the gastric toxicity resulting from non-selective NSAIDS?

Answer 21

Specific COX2 inhibitors were developed

(eg celecoxib)

Question 22

Specific COX2 inhibitors are effective at reducing _______ but not at _________.

What does this suggest?

Answer 22

Specific COX2 inhibitors are effective at reducing inflammation but not at treating acute pain

• Suggests that mechanisms beyond blocking inflammation drives analgesic effects

Question 23

What is a side-effect of Selective COX2 Inhibitors?

Answer 23

higher risk of cardiovascular toxicity (therefore you cannot buy these OTC)

Question 24

What is acetaminophen?

Answer 24

• A weak COX1 and COX2 inhibitor.
• Inhibits a third COX isoform (COX3) found most abundantly in the cerebral cortex.
• Analgesic and antipyretic
• Lacks Anti-inflammatory effects

Question 25

What can result from an overdose on acetaminophen?

Answer 25

Liver damage

• Acetaminophen is normally metabolized in the liver

Question 26

What are three alternatives to cocaine?

Answer 26

• Lidocaine
• Bupivicaine
• Procain

Question 27

Most local anesthetics contain a _______ moiety, a _______ and a __________.

What part of the molecule determines its pharmacological properties?

Answer 27

Most local anesthetics contain a hydrophobic (aromatic) moiety, a linker region and a hydrophilic substituted amine

• The LINKER REGION determines the pharmacological properties

Question 28

How do local anesthetics work to reduce pain? Why is hydrophobicity relevant?

Answer 28

Local anesthetics bind reversibly to a specific site within the pore of sodium channels and block ion movement through this pore thus blocking the ability for the neuron to fire

• ONLY accessible intracellularly (anesthetics must pass the PM)
  
  • Hydrophobicity increases both the potency and duration of action

Question 29

How does capsaicin block pain?

Answer 29

Capsaicin is an agonist for the TRPV1 receptor

• Activates TRPV1 receptors eventually leading to desensitization and loss of TRPV1+nociceptors leading to analgesia