SM_244a: Pharmacology, Opioids, and Pain Concepts III

Question 1

NSAIDs are related only because ____ and ____

Answer 1

NSAIDs are related only because they inhibit enzyme making prostaglandins and inhibit cyclooxygenase

(different structures)

Question 2

Describe prostaglandins

Answer 2

Prostaglandins

• Arachidonic acid is major precursor
• Cannot be stored and are released right after synthesis
• Involved in pyretic response
• Acetaminophen (not NSAID) blocks brain prostaglandins (antipyretic)

Question 3

NSAIDs block ____, preventing formation of ____ from ____

Answer 3

NSAIDs block COX, preventing formation of prostaglandin H2 from arachidonic acid

(note arachidonic acid also converted into leukotrienes via lipooxygenase)

Question 4

Describe the types of COX

Answer 4

COX

• Both make prostaglandins from arachidonic acid
• Each has its own gene
• COX1: present in most tissues all the time, constitutive, GI tract / platelets / kidneys

COX2: inflammatory, appears when inflammation/injury, responsible for pain, inducible, normally found in CNS / kidneys / uterus

Question 5

COX __ is inflammatory

Answer 5

COX 2 is inflammatory

(COX-2 specific inhibits such as celexocib)

Question 6

Describe the systems prostaglandins affect

Answer 6

Prostaglandins affect

• PNS and CNS (pain)
• GI
• Renal and CV
• Platelets (hemostasis)
• Other: bone, reproductive systems

Question 7

Describe role of prostaglandins in pain

Answer 7

Prostaglandins in pain

• Cause allodynia (touch causes pain) and hyperalgesia (pain amplified)
• Sensitize pain nerve endings: triggered by touch (allodynia)
• Enhance pain in CNS (hyperalgesia)

Question 8

Describe peripheral mechanisms of pain mediated through COX-2

Answer 8

Peripheral mechanisms of pain mediated through COX-2

1. Tissue injury
2. COX-2 expressed
3. Increased Na influx into nerve
4. Threshold becomes less negative
5. Nociceptor ready to fire

Question 9

Prostaglandins ____ the inhibitory pathway and ____ the ascending pathway

Answer 9

Prostaglandins inhibit the inhibitory pathway and upregulate the ascending pathway

(opioids decrease transmission of pain, NSAIDs decrease excitation of pain)

Question 10

Prostaglandins enhance pain in the CNS via ____, ____, and ____

Answer 10

Prostaglandins enhance pain in the CNS via increased Substance P and glutamate release, increased sensitivity of 2nd order neurons, and decreased release of inhibitory transmitters

Question 11

NSAIDs ____ but do NOT ____

Answer 11

NSAIDs blunt PNS/CNS sensitization but do NOT block pain transmission

(able to prevent self injury)

(analgesia is peripheral and central)

Question 12

NSAIDs cause GI toxicity via ____ and ____

Answer 12

NSAIDs cause GI toxicity via direct gastric irritation and decreased cytoprotection in the stomach

• Often silent ulceration
• All but 1 NSAIDs are weak acids
• NSAIDs reduce bicarbonate secretion, blood flow, epithelial cell turnover, and mucosal immunocyte function

Question 13

GI ulcers after NSAIDs are often ____

Answer 13

GI ulcers after NSAIDs are often asymptomatic

Question 14

NSAID GI toxicity can be prevented through ____, ____, and ____

Answer 14

NSAID GI toxicity can be prevented through enteric coating, PPIs, and misoprostol

• Enteric coating: moves lesions into duodenum only
• PPIs prevent NSAID upper GI ulcer but not intestinal ulcers
• Misoprostol: synthetic PGE₁ that increases mucus formation

Question 15

Enteric coating protects against NSAID GI toxicity by ____

Answer 15

Enteric coating protects against NSAID GI toxicity by moving lesions into duodenum only

Question 16

PPIs protect against NSAID GI toxicity by preventing ____ but not ____

Answer 16

PPIs protect against NSAID GI toxicity by preventing upper GI ulcers but not intestinal ulcers

Question 17

Misoprostol is a ____ that protects against NSAID GI toxicity by ____

Answer 17

Misoprostol is a synthetic PGE₁ that protects against NSAID GI toxicity by increasing mucus formation

(causes diarrhea, sold as combo drug)

Question 18

Discuss prostaglandins in the kidney

Answer 18

Prostaglandins in the kidney

• Renal prostaglandins from COX-1 and COX-2 so COX-2 selectivity is no help
• Affect Na and H20 balance: affect BP
• In decreased perfusion states, PGs dilate afferent blood vessels - needed to prevent ischemia when low volume / BP/ CO

Question 19

NSAIDs ____ BP in treated hypertensives but not normotensives

Answer 19

NSAIDs increase BP in treated hypertensives but not normotensives

(increases risk for MI or CVA)

Question 20

Describe renal concerns of NSAID use

Answer 20

NSAID renal concerns

• BP elevation and diuretic interaction: altering prostaglandin levels leads to Na+/H2O imbalance
• Ischemic acute tubular necrosis: by preventing prostaglandin afferent blood vessel dilation in low perfusion states (e.g. hypovolemia, CHF)

Question 21

Describe hematologic effects of NSAIDs

Answer 21

NSAIDs hematologic effects

• NSAIDs reversibly bind COX: half life normal after a few half lives
• ASA irreversibly acetylates COX-1: need to make more COX to recover, platelets have no nuclei to make more COX, takes 7-10 days to make new platelets
• Low dose ASA is cardioprotective while NSAIDs (even at high dose) are not

Question 22

NSAIDs block formation of ____ from ____, ____ clotting

Answer 22

NSAIDs block formation of TxA₂ from COX-1, decreasing clotting

(note COX-2 selective blockers do not)

Question 23

Describe NSAID hepatic toxicity

Answer 23

NSAID hepatic toxicity

• Uncommon and not severe
• Idiosyncratic: not dose or duration related, exception is ASA

Question 24

Contraindications to NSAID use are ____, ____, ____, ____, and ____

Answer 24

Contraindications to NSAID use are ulcer, coagulopathy, renal disease, hepatic disease, and pregnancy

(low dose ASA is acceptable in CV disease)

Question 25

Describe COX-2 specific inhibitors

Answer 25

COX-2 specific inhibitors

• Celecoxib
• GI ulcer rate reduced by half (same as adding PPI to NSAID)
• Still increases BP and risk of MI/CVA
• No effect on platelets: can use during surgery, no interference with low dose ASA

Question 26

Describe IV NSAIDs

Answer 26

IV NSAIDs

• Ketorolac: generic potent analgesic, anti-inflammatory effect, worthless orally, limited to 5 days due to toxicity
• Ibuprofen: potent analgesic, anti-inflammatory effect, limited to 5 days due to toxicity
• Acetaminophen (not NSAID): more potent, less toxic when IV

Question 27

Describe topical NSAIDs

Answer 27

Topical NSAIDs

• Diclofenac: gel, ointment, or patch
• Useful on superficial joints
• Less toxic: no platelet effects, minimal GI effects, warnings are the same as for oral

Question 28

____ are used when something other than opioids is required during an operation

Answer 28

Perioperative NSAIDs are used when something other than opioids is required during an operation

• Opioids slow GI tract via peristalsis via direct action on gut, cause constipation in outpatients, can mean longer stay due to inability to take orals / leave hospital with ileus / slowed GI function due to pain