NSAIDS - Week 1 B

Question 1

NSAIDS

Answer 1

Non-steroidal anti-inflammatory drugs
Alleviation of Pain (analgesia) is the most common use of pharmaceuticals ….
So…we will start with ones you most probably use!

Question 2

Evolution of a Drug / Medicine

Answer 2

Investigate a ‘folk medicine’ Isolate the ‘active ingredient’ and prove structure
Synthesize ‘natural’ compound to confirm structure and provide material Test for physiological effects; often multiple effects Synthesize compounds with modified structure; to emphasize desired properties to ‘delete’ unwanted effects Test for efficacy and safety

Question 3

Active constituent is salicylic acid

Answer 3

Salicylic acid is “corrosive” and produces stomach discomfort
Acetyl derivative (ASA) is less destructive to the stomach lining
So..long term (daily) protection vs blood clots

Question 4

Binders and fillers

Answer 4

All solid pill formulations contain these
Promote ease of swallowing etc
Use corn starch and microcrystalline cellulose for this purpose
Also, hypromellose and triacetin
General term is Excipient:a pharmacologically inactive substance formulated with the active component

Question 5

Excipients in aspirin

Answer 5

Cellulose: insoluble fibre: Present in celery etc
Cornstarch: starch is a digestible carbohydrate : energy storage in plants (glucose polymer)
Hypomellose: hydroxypropylmethylcellulose: insoluble cellulose derivative. Binds all other inactives together

Question 6

Triacetin as an excipient in ASA

Answer 6

Triacetylpropanetriol (source of acetate)
Used to stabilize the formulation against humidity and keep pills from sticking to bottle
Old aspirin: smells of vinegar due to partial hydrolysis of ASA to acetic acid and salicylic acid

Question 7

Aspirin - Multiple Physiological Effects

Answer 7

Analgesic – reduces or eliminates pain. Antipyretic - lowers or eliminates fever.
Anti-inflammatory agent - reduces or eliminates inflammation. Anti-coagulant - inhibits the formation of blood clots by decreasing platelet concentrations, ie. decreases incidence of heart attacks resulting from the formation of internal clots that can block the flow of blood to the heart.

Question 8

Daily Low Dose of 75-81 mg aspirin

Answer 8

Maintains normal blood platelet aggregation
Recommended for all men (particularly) over 50 to reduce risk of strokes and heart attacks due to blood clotting
This new use was patented in 1990’s
See Liska pp 359-60 for more discussion

Question 9

Emergency treatment if a heart attack is suspected

Answer 9

Chew 1 standard 325 mg aspirin (after calling 911) or on the way to the hospital Emergency
Studies show this reaches the bloodstream to act as an anticoagulant in ~ 5 minutes vs. 12 minutes for an aspirin taken with water

Question 10

Enterically coated Aspirin

Answer 10

Coating of wax, cornstarch, methylcellulose, KOH, methacrylic acid copolymer prevents capsule from dissolving in stomach-goes to small intestine before dissolution, thus helping to prevent stomach irritation

Question 11

Reye’s Syndrome

Answer 11

Follows flu, small pox, chicken pox (or other viral infection) in children and teenagers
Fatal in ~25% of cases: due to brain swelling (edema) & liver failure
Some correlation with use of salicylates for treatment of flu symptoms
So….NO ASPIRIN to children or teenagers with fever ..
Acetaminophen used instead!!

Question 12

Anti-inflammatory effects of Aspirin

Answer 12

Rheumatoid arthritis: an auto immune condition (body’s immune system generates antibodies vs. tissue proteins
Result: inflammation/swelling of fingers, toes, knees etc
Prostaglandins : implicated as a chemical factor
COX2 inhibition by Aspirin inhibits prostaglandin synthesis

Question 13

Acetaminophen

Answer 13

Due to bleeding risks from aspirin and Reye’s syndrome, alternative anti-pyretic analgesics are important
A “coal tar’ analgesic (it is an aniline derivative)
Aniline was 1st obtained by destructive distillation of coal tar

Question 14

Coal tar

Answer 14

React pulverized solid coal with a stream of hot air and steam: produces 1000’s of products in a viscous oil
Destructive distillation produces many compounds used as starting materials for synthesis
Aniline can be used to make acetaminophen

Question 15

Advantages of Acet. over Aspirin

Answer 15

No tendency to induce bleeding (not a blood thinner)
Less potential for nausea
Used if aspirin allergies
No risk of Reye’s syndrome in children

Question 16

Disadvantages of Acet. over Aspirin

Answer 16

Not anti-inflammatory
Potentially toxic to the liver and kidneys
Combined with alcohol, increased risk of liver damage
Extra strength use over a long period can induce hepatitis
See p362 Liska for 2 case histories

Question 17

Ibuprofen (Advil or Motrin)

Answer 17

Antipyretic, analgesic, anti-inflammatory, minor platelet inhibitor (< ASA)
A hydrophobic aromatic bearing an acidic function (3 C sidechain)

Question 18

Why Ibuprofen?

Answer 18

Effective at lower doses (~1/3) than aspirin or acetaminophen
Should not exceed 1200mg (1.2 g) per day
Effectiveness vs. dysmenorrhea (menstrual pain) :main reason approved for OTC use

Question 19

Rare but dangerous side effects of ibuprofen reported 2013

Answer 19

Should NOT be taken by adolescents or children if a viral infection is suspected
Stephens Johnson syndrome
Blistering and loss of skin
11 year old boy lost 65% of his skin when taking OTC ibuprofen (Motrin) for what was thought to be a viral infection
Severe allergic reaction..

Question 20

Aleve

Answer 20

Longer half life than ibuprofen: thus remains effective longer (t1/2 ~12 hours in blood plasma), thus less frequent dosing needed
Also effective vs. menstrual pain (cramps)

Question 21

Celebrex and Vioxx

Answer 21

Y2K “wonder drugs” for osteoarthritis and rheumatoid arthritis……
Antipyretic,analgesic, anti-inflammatory
No effect on blood platelets
Both COX-2 inhibitors
Much less likely to cause bleeding or stomach irritation than aspirin

Question 22

Celebrex and Vioxx -

Downsides

Answer 22

Expensive (~25 x more than older analgesics  ASA, ibuprofen)
Cardiovascular issues (fatal for Vioxx) 
Merck withdrew Vioxx in 2004
Lawsuits totalling 45Billion $
Very potent, hence prescription only
Gastrointestinal erosion side effect

Question 23

Vioxx deadly side effects

Answer 23

Were only discovered when Merck repurposed it (ie.new usage) for treating colon polyps, not when it was used as an analgesic
But…the deadly cardiovascular side effects had to be reported to regulators and the “blockbuster” drug Vioxx was completely withdrawn from the market