1. UW Biology of Addiction Unit V: Depressants
Lecture 22: OTC Analgesics

2. Learning Targets for Lesson 22 OTC Analgesics
After successfully completing this lesson you will be able to:
understand the connection between inflammation and pain
understand why different analgesics are recommended depending upon the symptom
understand that over-the-counter is not synonymous with "safe under any circumstances"

3. What Do You Already Know?
Q1: What type of cell detects pain?
Sensory neurons called nocioceptors
Q2What are prostaglandins?
chemicals that stimulate inflammation
Q3: In what way is inflammation GOOD for healing: And how is it detrimental for healing?
inflammation brings blood and immune cells to an injured area to speed up clean-up, removal of damaged cells, and also to provide the nutrients necessary for recovery.
Prolonged or excessive inflammation is not only painful, it can reduce healing time by keeping an injured area congested.

4. P Pain Reception 2. Reception 3. Transmission 4. Pain Center Reception
Substance P =neuropeptide that functions like neurotransmitters associated with pain reception/transmission
2. Reception P
3. Transmission
Prostaglandin= hormone-like chemical messenger
excites nerve ending
Triggers inflammatory response
Prostoglandin-hormone-like chemical messenger made of fatty acids that is associated with inflammation
Contact with stimulus -- Stimuli can be mechanical (pressure, punctures and cuts) or chemical (burns).
Reception -- A nerve ending senses the stimulus.
Transmission -- A nerve sends the signal to the central nervous system. The relay of information usually involves several neurons within the central nervous system.
Pain center reception -- The brain receives the information for further processing and action.
Start Here
1. Contact w/ stimulus
4. Pain Center Reception
Pain stimulus picked up by peripheral nervous system
Pain signal amplified by central nervous system… OUCH!

5. Prostaglandins and Pain
Two anti-prostaglandins are acetaminophen and ibuprofen
Keep damaged cells from releasing prostaglandins which are the chemical our pain cells sense and transmit as “pain”.
How do you go from no pain to prostaglandin production and pain?
Need to convert molecules via enzymatic reaction.
Need catalyst (like gasoline is catalyst to car – makes it go).
Catalyst for this reaction is called cox – cyclooxygenase (comes in three forms: 1,2, and 3)

6. What’s the chemistry of pain?
no pain
COX
Catalyst for this reaction
Cyclo-oxygenase
BLOCK COX  BLOCK PAIN
prostaglandins 1
pain

7. How do prostaglandins worsen pain?
BLOCK COX  BLOCK INFLAMMATION
Prostaglandin’s MOST important role is to respond to injury by recruiting blood and nutrients to site of injury to help increase healing.
Prostaglandins are responsible for inflammation. Blocking prostaglandins with NSAIDS blocks inflammation (reducing swelling and slowing healing sometimes).
COX
prostaglandins
This new volume of material at the injury site causes the site to become puffy, swollen, inflamed. 2
inflammation

8. What conditions are associated with inflammation?
Arthritis
Crohn’s disease
Psoriasis
Alzheimer’s disease
Multiple sclerosis
Psoriasis

9. aspirin (acetylsalicylate) ibuprofen acetaminophen What are NSAIDs?
acetyl group to salicylic acid
ibuprofen
All NSAIDS block the production of prostaglandins
Aspirin, (acetyl group to salicylic acid) Ulrich – polyaspirin – polymer of aspirin…. – induce bone growth???
NSAID like acetaminophen, ibuprofen, and others (naprosyn – previously prescribed – now OTC - aleve)
all block the production of prostaglandins
acetaminophen

10. Test of Content: What are OTC Analgesics? Why do we use them?
Q: What is the relationship between inflammation, pain, and NSAIDs?
A: Inflammation is painful, NSAIDs block inflammation and thus treat the pain caused by inflammation.

11. NSAID administration?

12. NSAID Dosage Drug Recommended adult dosage Approximate lethal dosage
Acetaminophen (paracetemal)
mg every 6 hours
6-12 grams per day
Aspirin (acetyl-salicylate)
325 mg – 650 mg every 4 hours
Ibuprophen (methyl propyl proprionic acid)
mg every 6 hours

13.  How do NSAIDs block COX? Inhibit Prostaglandin Release=
COX enzymes
Inhibit
Prostaglandin
Release=
NO Inflammation
Acetyl group

14. Test of Content: NSAID Dosage
Q: Which OTC analgesic is the safest with respect to accidental, lethal overdose?
ibuprofen
acetaminophen
aspirin

15. NSAID metabolism? Mostly CYP2D6 1/2 life between 2 and 4 hours
NSAIDs can increase stomach acidity which increases absorption rate
Some formulations are buffered (coated with a substance that neutralizes the acidity)
Improves how well a person tolerates the medication by reducing stomach upset as a side effect
Other formulations are time-release
Mostly CYP2D6
Also CYP2C8 & CYP2C9
1/2 life between 2 and 4 hours
For Acetaminophen
Metabolite "NAPQ1" is very toxic to the liver

16. Test of Content
Vicodin is acetaminophen plus opiate analgesic. The components:
Are both metabolized by the same enzyme
Both impact prostaglandins
Both impact substance P
Both are addictive
Both are most effective if taken orally

17. Where Do OTC Analgesics Bind? Then What?
How are prostaglandins produced?
Synthesized from an intermediate (precursor)
Precursor molecule is always present but isn’t converted to prostaglandin until COX enzyme is from injured cells is present
If COX is inhibited, then the precursor stays unchanged and doesn’t get turned into prostaglandin.
Cell (s) Injured
chemicals are released that enable the message about that injury to be sent via prostoglandin
enables the circulatory and immune systems to respond to begin the healing process

18. Where Do OTC Analgesics Bind? Then What?
OTC analgesics bind to an enzyme target (cox)
A family of cyclooxygenases (cox) includes cox1, cox2, and theoretical cox3.
These cyclooxygenase enzymes are all bound by different NSAIDs and acetaminophen.
When the analgesics bind COX they inhibit its ability to catalyze its chemical reaction.

19. Where Do OTC Analgesics Bind? Then What?
Aspirin and ibuprofen block COX1 and COX2.
They effectively reduced pain and subsequent inflammation.
Acetaminophen seems to inhibit COX, perhaps by blocking COX2 and the theoretical COX3.
Several COX-2 specific inhibitors were developed and marketed
Each COX enzyme is encoded by an individual gene so each enzyme can be made in different places at different times (via regulation of gene expression).
Inhibition of each specific COX is a very effective way to ensure treatment with minimal side effects

20. TEST OF CONTENT A: More pain, more inflammation.
Q: What symptoms would you expect for a COX enhancer?
A: More pain, more inflammation.

21. Are NSAIDs Addictive? Nope No Reward Pathway activation
Tolerance?- perhaps, with long term use
Withdrawal-nope

22. Migraine Headaches are special – why?
Migraine – caused by “abnormalities” in the blood vessels of the brain – either constricted OR dilated (more often – dilated)
Increase blood volume in limited space
Action?
Success?
Opiates
Tranquilizers (depakote)
Medicine type
Anti-inflammatory meds
Reduce swelling
Fair
Caffeine-including meds
Migraine – caused by “abnormalities” in the blood vessels of the brain – either constricted OR dilated (more often – dilated)
Can treat by treating vessels – anti-inflammatory meds reduce vessel diameter OR can treat by treating neurons – sedating meds (such as used to treat mania or epilepsy) can calm over excited nerves that signal for blood vessel dilation.
Vasoconstrict
Moderate
Reduce pain perception
Better (addictive)
Calm neurons that call from blood delivery
Best (side effects)

23. Are all NSAIDs equal? Enzyme’s job General, including GI
Cox 1
Cox 2
Cox 3
Enzyme’s job
General,
including GI
Pain and inflammation
Unknown (brain function)
Aspirin
Acetaminophen
Vioxx and
Celebrex
Celebrex is a cox-2 inhibitor so no GI symptoms – just pain relief
UW researcher working on COX-2 specific treatments
Similar structure to aspirin. Absence of acidic group means less stomach distress.
BUT, does not cause reduction in peripheral inflammation and does not interfere with Cox 1 and 2! Newly discovered Cox 3 is only in the cns, and acetaminophen blocks this one .
Elevates pain threshhold (sends only larger signals to brain) No peripheral anti-inflammatory,
Exact mechanism disputed, some say it inhibits COX others say no. Utah team found out why. Cox 1 and 2 are not interfered with by tylenol, but CNS-specific Cox3 is!
Proceedings of the National Academy of Sciences 2002; /pnas
MAY inhibit prostaglandin release locally which may cause less signalling to brain. Also may inhibit substance P and subsequent signaling of pain. POORLY understood.
Overuse – associated with #1 ranked OD at poison emergency lines, chronic overuse associated with large number of kidney and liver failures.
Especially dangerous to alcohol users – even social drinkers.

24. Unexpected Benefits
In addition to treating pain and inflammation, OTC analgesics have a couple of other benefits.
All of them are antipyretic drugs – drugs that reduce fever.
Aspirin has the ability to impede blood clotting.
Low-dose aspirin are used to lower the risk of elevated risk of blood clots that can lead to stroke or heart attack.
Thromboxane is produced by platelets – allowing them to clump together to form a clot.
Aspirin interferes with this.
We will not go into how this occurs but if you want to know more –
return to: and read the "antipyretic activity" section.

25. OTC analgesic side effects
Aspirin
Acetaminophen
Cox2 blockers
Canadianparents.com
Increase risk
of heart attack
and stroke
sccollege.edu
Reye’s
Syndrome
Nausea
50,000 ER visits
500+ deaths
PER YEAR
Noaw.com
beliefnet.com
Overdose – acetaminophen very high rates – both accidental and intentional
Reye’s syndrome – aspirin (brain swelling, liver damage when aspirin is taken after viral infection with children)
Nausea – GI irritation for COX1 blockers
Increase risk of heart attack and stroke ! Vioxx scandal.
Increase risk of pancreatic cancer j. nat. cancer inst. Jan – nurses study , 88K subjects. If 14+ aspirin a week, 2x more likely to have pancreatic cancer. 4 – 6 tabs a week 29% more likely
Increase risk of
pancreatic cancer
If 14+ aspirin a week, 2x more likely to have pancreatic cancer. 4 – 6 tabs a week 29% more likely

26. Individual experience may vary…
CYP2D6
Food in gut
State of health
Degree of pain
Age
Strength of COX
OTC analgesics earned their over-the- counter status because they have very little variability from one user to another.
Relatively rare considerations are:
People with aspirin sensitivity (allergy to aspirin)
People with clotting disorders (those who take anti-coagulants or hemophiliacs)
Alcohol is the #1 drug to NOT use while using ANY drug.
Alcohol requires so much work by the liver that asking the liver to handle even an over-the- counter medication concurrently is unwise.

27. ERs for Lesson 22: OTC Analgesics
Required Reading
Liska – 14 (NSAIDs), , , and questions 2, 6, 7, 12, 14-17
Internet
conditions/pain/medication/nsaids.htm
htm
Video