Pharmacology: Block 5: Analgesics

Front 1

What are the classic effects of NSAIDs?

Back 1

Anti-inflammatory
Anti-pyretic
Analgesic

Front 2

What did sleeping on a pillow of pine needles supposedly help?

Back 2

Headache. The methyl salicylate in the pine.

Front 3

What was the mistaken hypothesis about the COX isoenzymes?

Back 3

That COX-1 was "good" and was necessary for GI and renal function, and that COX-2 was "bad" and caused inflammation, fever, and pain.

The idea was that fever, inflammation, and pain could be reduced if COX-2 was inhibited.

Front 4

What pathway creates the prostaglandins, thromboxanes, and leukotrienes?

Back 4

The arachadonic acid pathway

Front 5

What can we tell about COX-1 from the crystal structure?

Back 5

There is a more superficial cyclooxygenase domain and a deeper peroxidase domain.

Front 6

COX-2 has been found to have what types of protective functions?

Back 6

- Kideny: renin secretion
- Wound/ulcer healing
- Reproductive functions
- Bone metabolism
- Vascular protection

Front 7

Aspirin: what type of medication?

Back 7

NSAID

Front 8

Aspirin: what type of organic compound?

Back 8

Ester

(NSAID)

Front 9

Aspirin: what is the serum half-life?

Back 9

15-30 min

(NSAID)

Front 10

Aspirin: what is its official name?

Back 10

Acetylsalicylic acid

Front 11

Aspirin: what breaks it down?

Back 11

Esterases in blood and tissue


(NSAID)

Front 12

Aspirin: what are the functions of the metabolites?

Back 12

Aspirin ----esterases----> Acetic acid + Salicylate

Two reactions:

Acetic acid irreversibly acetylates COX.

Salicylic acid is a COMPETETIVE ANTAGONIST of COX. Longer half-life and accounts for many of the effects of aspirin.

Front 13

Aspirin: most of the theraputic effects are caused by what?

Back 13

By the salicylic acid (and not the acetic acid)

Front 14

Aspirin: theraputic effects

Back 14

1. Antiinflammatory
2. Antipyretic
3. Analgesic
4. Inhibit thrombosis in patients at risk of MI (?)

Front 15

Aspirin: AE

Back 15

1. GI irritation (because of its acidity)
2. Prolonged bleeding time
3. Prolonged labor!
4. Inhibit renal function
5. Can induce asthma

Front 16

Aspirin: why does it work on platelets?

Back 16

Inhibits COX-1 in all cells, but platelets lack the cellular mechanisms to re-synthesize COX.

Front 17

Aspirin: bioavailability

Back 17

Good. Well absorbed through the stomach.

Front 18

Aspirin: what used to be the old way of knowing you had given someone their max dose?

Back 18

You would titrate up until their ears rang! (tinnitus)

Front 19

Aspirin: which of its effects require the highest doses?

Back 19

The anti-inflammatory effects (and the uricosuric (for gout, but not recommended))

Front 20

Bengay: generic name?

Back 20

Methyl salicylate

Front 21

NSAIDs: class 1

Back 21

Competitive, reversible inhibitors that compete with arachidonic acid for the COX active site

Ibuprophen, Naproxen

Piroxicam, Sulindac, Mefenamic acid, and Salicylate

Front 22

NSAIDs: class 2

Back 22

Phase 1: Competitive, time dependent, reversible inhibitors

Phase 2: Conformational change --> tighter binding.

Indomethacin, Diclofenac

Flurbiprofen, Meclofenamic acid

Front 23

NSAIDs: class 3

Back 23

Competitive, time dependent, irreversible inhibitors that form an enzyme inhibitor complex after covalent conformational change.

Aspirin

Front 24

Ibuprofen vs. naproxen: potency

Back 24

Naproxen is more potent

Front 25

Ibuprofen vs. aspirin/indomethacin: AE

Back 25

Ibuprofen is better tolerated

Front 26

Ibuprofen: uses

Back 26

Used for "prolonged pain"

RA, osteoarthritis, ankylosing spondylitis, acute gouty arthritis, tendinitis, bursitis, dysmenorrhea. (not really for headache?)

Front 27

What are the proprionic acid derivatives?

Back 27

Ibuprofen and naproxen

Front 28

What are the indole and indene acetic acids?

Back 28

Indomethacin, Etodolac

Front 29

Ibuprofen, naproxen: characteristics

Back 29

- Have all 3 activities
- Better tolerated than aspirin or indomethacin
- Share the other detrimental features of NSAIDs
- Rx for RA, osteoarthritis, tendinitis, bursitis, ankylosing spondylitis, acute gouty arthritis, dysmenorrhea.

NSAIDs

Front 30

Indomethacin, Etolodac: characteristics

Back 30

- Have all 3 activities
- High incidence of AE: N/V, GI distress, diarrhea, anorexia, HA
- Rx for gout, ankylosing spondylitis, osteoarthritis, refractory fever of Hodgkin's disease.

Front 31

Indomethacin vs. Etolodac: significant differences

Back 31

Etolodac has fewer GI side effects.

Etolodac binds COX-2 10x as strongly

Etolodac has a longer half-life

(both are indole and indene acetic acid NSAIDs)

Front 32

What is the NSAID that is "traditionally" used to treat gout?

Back 32

Indomethacin

It's not aspirin because the dose would have to be too high.

Front 33

What are the important heteroaryl acetic acids?

Back 33

Ketorolac
Diclofenac

Front 34

Ketorolac: characteristics

Back 34

- Potent analgesic
- Mild antiinflammatory
- Can be used for post-op pain, to wean pt off of opiods.
- 100-1000x COX-1 selective

VERY HIGH incidence of bleeding ulcers. Can only use for 5 days. Should basically only be used by anesthesiologists or surgeons.

Front 35

Diclofenac: characteristics

Back 35

- One of the most potent NSAIDs
- Lower incidence of GI bleeding than Ketorolac
- Often Rx as Dicolofenc + Misoprostol (= Arthrotec). Misoprostol is a med to prevent NSAID ulcers.

Front 36

Name the COX-2 specific drugs

Back 36

Rofecoxib (Vioxx)

Celecoxib (Celebrex)

Front 37

Rofecoxib: characteristics

Back 37

- COX-2 inhibitor
- 375x more selective for COX-2
- Its sulfonyl moiety is the key for COX-2 specificity
- Has all 3 NSAID activities
- Does NOT affect platelet function (because platelets don't have COX-2)
- Low incidence of GI ulcers
- Does have CV risks - this caused it to be withdrawn.

Front 38

How do COX-2 inhibitors affect platelets?

Back 38

They don't! Platelets don't have COX-2

Front 39

Celecoxib: characteristics

Back 39

- COX-2 inhibitor
- Only about 13x more selective for COX-2
- Similar properties as Rofecoxib
- Rx for osteoarthritis, RA, adenomatous colorectal polyps.
- Currently the only COX-2 inhibitor available.
- Effects are like Etodolac

Front 40

COX-2 inhibitors: potential uses

Back 40

- Colon cancer
- Alzheimer's disease
- Delaying premature labor

Front 41

A patient needs to take aspirin and another NSAID. How should you advise them to take the medication?

Back 41

Take the aspirin FIRST. The acetylsalicylate will get broken down into salicylate and acetic acid. The acetic acid will irreversibly bind COX, but only has a half-life of 15-30 min.

If you take an NSAID before you take aspirin, then the aspirin and the NSAID will be competing for the COX active site and you may not get the antiplatelet activities you want.

Front 42

NSAIDs: AE of COX-1 specific vs. AE of COX-2 specific

Back 42

More COX-1 selective: more GI upset (Uncomplicated/complicated events)

More COX-2 selective: more CV risk (HTN, CHF, Thrombotic events)

Front 43

Acetaminophen (APAP): characteristics

Back 43

- Para-amino phenol derivative
- Strong analgesic and ANTIPYRETIC activity
- Very WEAK antiinflammatory
- No real GI upset
- Main AE: If 5x a day and take more than 4g of acetominophen = fatal liver damage (metabolite interacts with liver proteins)
- M of A: Acetaminophin ----> p-Aminophenol ---> arachadonic acid (??) --> AM404. This seems to be the active metabolite.
- AM404 binds to brain receptors that make you feel good, and inhibit COX-1, 2