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

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"

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.

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!

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)

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

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

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

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

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.

NSAID administration?

NSAID Dosage Drug Recommended adult dosage Approximate lethal dosage Acetaminophen (paracetemal) 325 - 650 mg every 6 hours 6-12 grams per day Aspirin (acetyl-salicylate) 325 mg – 650 mg every 4 hours Ibuprophen (methyl propyl proprionic acid) 200 - 400 mg every 6 hours

 How do NSAIDs block COX? Inhibit Prostaglandin Release= COX enzymes Inhibit Prostaglandin Release= NO Inflammation Acetyl group http://www.time.com/time/covers/1101050228/map/

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

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

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

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

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.

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

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

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

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)

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;10.1073/pnas.162468699. 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.

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: http://en.wikipedia.org/wiki/Non-steroidal_anti-inflammatory_drug and read the "antipyretic activity" section.

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 7 2008 – nurses study 1980 -89, 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

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.

ERs for Lesson 22: OTC Analgesics Required Reading Liska – 14 (NSAIDs), 14.1-14.4, 14.6-14.7, 14.10 and questions 2, 6, 7, 12, 14-17 Internet http://en.wikipedia.org/wiki/Non-steroidal_anti-inflammatory_drug http://health.howstuffworks.com/diseases- conditions/pain/medication/nsaids.htm http://www.fda.gov/Drugs/DrugSafety/InformationbyDrugClass/ucm 165107.htm http://en.wikipedia.org/wiki/COX-2_inhibitor Video http://www.youtube.com/watch?v=MJ9pamb9lhc