UW Biology of Addiction

Unit V: DepressantsLecture 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? ochemicals that stimulate inflammation

Q3: In what way is inflammation GOOD for healing: And how is it detrimental for healing? o 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. oProlonged or excessive inflammation is not only painful, it can

reduce healing time by keeping an injured area congested.

Pain Reception

Pain stimulus picked up by peripheral nervous system

Prostaglandin= hormone-like chemical messenger

• excites nerve ending

• Triggers inflammatory response

Pain signal amplified by central nervous system… OUCH!

Substance P =neuropeptide that functions like neurotransmitters associated with pain reception/transmission

1. Contact w/ stimulus

2. Reception

3. Transmission

4. Pain Center ReceptionStart Here

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?

prostaglandins

BLOCK COX BLOCK PAIN

1

Catalyst for this reaction

Cyclo-oxygenase

How do prostaglandins worsen pain?

2

prostaglandins

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.

This new volume of material at the injury site causes the site to become puffy, swollen, inflamed.

Prostaglandins are responsible for inflammation. Blocking prostaglandins with NSAIDS blocks inflammation (reducing swelling and slowing healing sometimes).

What conditions are associated with inflammation?

•Arthritis•Crohn’s disease•Psoriasis•Alzheimer’s disease•Multiple sclerosis

Psoriasis

What are NSAIDs?

acetyl group to salicylic acid

All NSAIDS block the production of prostaglandins

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 DosageDrug Recommended adult

dosageApproximate 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

6-12 grams per day

Ibuprophen (methyl propyl proprionic acid)

200 - 400 mg every 6 hours

6-12 grams per day

How do NSAIDs block COX?

COX enzymes

NSAIDs

Acetyl grouphttp://www.time.com/time/covers/1101050228/map/

Inhibit Prostaglandin

Release= NO Inflammation

Test of Content: NSAID Dosage

Q: Which OTC analgesic is the safest with respect to accidental, lethal overdose?

A. ibuprofenB. acetaminophenC. aspirin

NSAID metabolism?

Mostly CYP2D6Also CYP2C8 & CYP2C9

1/2 life between 2 and 4 hours

For AcetaminophenMetabolite "NAPQ1" is very toxic to the liver

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

Test of Content

Vicodin is acetaminophen plus opiate analgesic. The components:A. Are both metabolized by the same enzymeB. Both impact prostaglandinsC. Both impact substance PD. Both are addictiveE. Both are most effective if taken orally

Where Do OTC Analgesics Bind? Then What?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

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.

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

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?

Action? Success?

Opiates

Tranquilizers (depakote)

Migraine – caused by “abnormalities” in the blood vessels of the brain – either constricted OR dilated (more often – dilated)

Increase blood volume in limited space

Medicine type

Anti-inflammatory meds

Caffeine-including meds

Reduce swelling Fair

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

Pain and inflammation

Unknown (brain function)

Aspirin

Acetaminophen

Vioxx and Celebrex

Cox 3Cox 1 Cox 2

Unexpected BenefitsIn 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.

OTC analgesic side effects

Aspirin Acetaminophen Cox2 blockers

Noaw.com

beliefnet.com

Canadianparents.com

sccollege.edu

50,000 ER visits

500+ deaths

PER YEAR

Reye’s Syndrome

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

Nausea

Increase risk

of heart attack

and stroke

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, 14-17Internet• 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/ucm165107.htm • http://en.wikipedia.org/wiki/COX-2_inhibitorVideo• http://www.youtube.com/watch?v=MJ9pamb9lhc