Unfortunately, most salicylates taste horrible and cause inflammation of the mouth, throat, and stomach. Furthermore, they block the synthesis of other prostaglandins that promote blood clotting so an excess of salicylates will lead to bleeding of ulcers and other problems.
Aspirin is a modified salicylate. The active ingredient is called acetylsalicylic acid. It was introduced as a commercial drug in 1887. It doesn't taste as bad as most other salicylates and doesn't produce severe side effects.
Although it's better than natural salicylates, aspirin can cause dizziness, ringing in the ears, and bleeding or ulcers of the stomach lining. The stomach problems are caused by inhibition of a different COX activity from the one leading to prostaglandin synthesis.
There are two different forms of PGHS or COX. COX-1 is a constitutive enzyme that regulates secretion of mucin in the stomach, thus protecting the gastric wall. COX-2 is an inducible enzyme that promotes inflammation, pain, and fever. Aspirin inhibits both isozymes.
There are many other nonsteroidal anti-inflammatory drugs (NSAIDS) that inhibit COX activity. Aspirin is the only one that inhibits by covalent modification of the enzyme. The others act by competing with arachidonate for binding to the COX active site. Ibuprofen (Advil®), for example, binds rapidly, but weakly, to the active site and its inhibition is readily reversed when drug levels drop. Acetaminophen (Tylenol®) is an effective inhibitor of COX activity in intact cells.
Physicians would like to have a drug that selectively inhibits COX-2 and not COX-1. Such a compound would not cause stomach irritation. A number of specific COX-2 inhibitors have been synthesized and many are currently available for patients. These drugs, while expensive, are important for patients with arthritis who must take pain killers on a regular basis. In some cases, the new NSAIDS have been associated with increased risk of cardiovascular disease and they have been taken off the market. X-ray crystallographic studies of COX-2 and its interaction with these inhibitors have aided the search for even better replacements for aspirin without the cardiovascular side effects.
[Modified from Horton et al. Principles of Biochemistry ©Pearson Prentice Hall]
Unfortunately, most salicylates taste horrible and cause inflammation of the mouth, throat, and stomach. Furthermore, they block the synthesis of other prostaglandins that promote blood clotting so an excess of salicylates will lead to bleeding of ulcers and other problems.
ReplyDeleteDetails, details.
X-ray crystallographic studies of COX-2 and its interaction with these inhibitors have aided the search for even better replacements for aspirin without the cardiovascular side effects.
ReplyDeleteIt's not clear to me how crystallography would have any role in elucidating or eliminating the cardiovascular side effects.
If you know the structure of COX-1 and COX-2, you can design inhibitors that block the action of COX-2 but not COX-1.
ReplyDeleteThis is how Vioxx and Celebrex were developed. Both of these inhibitors are larger than the traditional drugs because the protein structures showed that the active site channel in COX-2 is larger than the channel in COX-1. Thus, bigger drugs can enter the COX-2 active site and inhibit the enzyme but they can't enter the COX-1 channel so COX-1 activity is unaffected.
I understand about rational drug design, my concern is whether incomplete differentiation between COX-1 and COX-2 can explain the problems of Celebrin, Vioxx, etc., which after all were designed and touted as COX-2 specific inhibitors, or whether there is more to the story.
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ReplyDeleteSir,your blog is excellent.Especially so for me.I am a student of MD Biochemistry.Though coming from
ReplyDeletemedical ground,having done MBBS,I have found biochemistry intriguing.Just to complement your post.Here is something about
pain-killer addiction
have any doctors tried sucking the COX to relieve the pain?
ReplyDeleteCOX sounds like COCKS with means PENISES.
Just bang some black tar heroin, guys!
ReplyDeleteLook up Xango it does it no side effects
ReplyDeleteI'd like to see this on eioba.com
ReplyDeleteAspirin versus acetaminophen for pain control in patients with cardiovascular risk
ReplyDeleteIn his recent article Jacob Karsh(1) indicated that both coxibs and traditional NSAIDs should not be prescribed in patients at higher cardiovascular(CV) risk. He also noted that in many painful conditions treatment with NSAIDs is not necessary or can be substituted for acetaminophen. In my opinion the rational choice for patients with CV and gastrointestinal(GI) risk factors is the use of aspirin combined with a proton-pump inhibitor.
There is good evidence that analgesic doses of aspirin (up to 1500mg) are associated with protection from CV events.(2,3) Furthermore, aspirin dose or its higher lifetime use is not significantly associated with hypertension(4) or renal toxicity.(5,6) Importantly, a recent meta- analysis of 24 randomised controlled trials found no evidence of dose- responsiveness for bleeds over a wide range of doses (50 to 1500 mg/day).(7) Indeed, aspirin in doses commonly used in practice, has an excellent safety profile.(8)
On the contrary, recent evidence suggest that both NSAIDs and acetaminophen can raise cardiovascular risk. (9) High acetaminophen use may also increase the risk of hypertension(4) and a decrease of renal function.(5) Interestingly, increased acetaminophen use has now been linked to increased prevalence of asthma and chronic obstructive pulmonary disease, and with lowered lung function.(10)
Surprisingly, a recent case-control study showed that acetaminophen (>2 g per day) was associated with a greater risk of GI perforation or bleed(11) and one cohort study reported a dose-response relationship between acetaminophen and dyspepsia.(12) It appears that regular use of acetaminophen is also associated with symptoms of severe diverticular disease, particularly bleeding.(13)
Lastly, compelling evidence suggests that aspirin and other NSAIDs are superior to acetaminophen for improving moderate-to-severe pain in patients with osteoarthritis(14,15,16) and rheumatoid arthritis.(17) Likewise, in acute pain states aspirin provides significant and more rapid analgesia than paracetamol.(18)
References
1. Karsh J. Anti-inflammatory drugs: what is safe? CMAJ 2006;175:449.
2. Antithrombotic Trialists' Collaboration. Collaborative meta- analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients.
BMJ 2002;324:71-86.
3. Johnson ES, Lanes SF, Wentworth CE 3rd, Satterfield MH, Abebe BL,
Dicker LW.A metaregression analysis of the dose-response effect of aspirin on stroke. Arch Intern Med 1999;159:1248-53.
4. Forman JP, Stampfer MJ, Curhan GC. Non-narcotic analgesic dose and risk of incident hypertension in US women. Hypertension 2005;46:500-7.
5. Curhan GC, Knight EL, Rosner B, Hankinson SE, Stampfer MJ. Lifetime nonnarcotic analgesic use and decline in renal function in women. Arch Intern Med 2004;164:1519-24.
6. Dubach UC, Rosner B, Sturmer T. An epidemiologic study of abuse of analgesic drugs. Effects of phenacetin and salicylate on mortality and cardiovascular morbidity (1968 to 1987) N Engl J Med 1991;324:155-60.
7. Derry S, Loke YK. Risk of gastrointestinal haemorrhage with long term use of aspirin: meta-analysis. BMJ 2000;321:1183-7.
8. Fries JF, Ramey DR, Singh G, Morfeld D, Bloch DA, Raynauld JP. A reevaluation of aspirin therapy in rheumatoid arthritis. Arch Intern Med 1993;153:2465-71.
9. Chan AT, Manson JE, Albert CM, Chae CU, Rexrode KM, Curhan GC, et al. Nonsteroidal antiinflammatory drugs, acetaminophen, and the risk of cardiovascular events. Circulation 2006;113:1578-87.
10. McKeever TM, Lewis SA, Smit HA, Burney P, Britton JR, Cassano PA. The association of acetaminophen, aspirin, and ibuprofen with respiratory disease and lung function. Am J Respir Crit Care Med 2005;171:966-71.
11. Garcia Rodriguez LA, Hernandez-Diaz S. Relative risk of upper gastrointestinal complications among users of acetaminophen and nonsteroidal anti-inflammatory drugs. Epidemiology 2001;12:570-6.
12. Rahme E, Pettitt D, LeLorier J. Determinants and sequelae associated with utilization of acetaminophen versus traditional nonsteroidal antiinflammatory drugs in an elderly population. Arthritis Rheum 2002;46:3046-54.
13. Aldoori WH, Giovannucci EL, Rimm EB, Wing AL, Willett WC. Use of acetaminophen and nonsteroidal anti-inflammatory drugs: a prospective study and the risk of symptomatic diverticular disease in men. Arch Fam Med 1998;7:255-60.
14. Lee C, Straus WL, Balshaw R, Barlas S, Vogel S, Schnitzer TJ. A comparison of the efficacy and safety of nonsteroidal antiinflammatory agents versus acetaminophen in the treatment of osteoarthritis: a meta- analysis. Arthritis Rheum 2004;51:746-54.
15. Towheed TE, Maxwell L, Judd MG, Catton M, Hochberg MC, Wells G. Acetaminophen for osteoarthritis. Cochrane Database Syst Rev 2006;(1):CD004257.
16. Zhang W, Jones A, Doherty M. Does paracetamol (acetaminophen) reduce the pain of osteoarthritis? A meta-analysis of randomised controlled trials. Ann Rheum Dis 2004;63:901-7.
17. Wienecke T, Gotzsche PC. Paracetamol versus nonsteroidal anti- inflammatory drugs for rheumatoid arthritis. Cochrane Database Syst Rev 2004;(1):CD003789.
18. Seymour RA, Hawkesford JE, Sykes J, Stillings M, Hill CM. An investigation into the comparative efficacy of soluble aspirin and solid paracetamol in postoperative pain after third molar surgery. Br Dent J 2003;194:153-7.
Michal R. Pijak, Assistant Professor and Consultant in Internal Medicine, Rheumatology and Clinical Immunology, Department of Internal Medicine, Slovak Medical University, Bratislava, Slovakia
Nice write up Larry. Unfortunatley, you have a couple of goofs posting a couple immature comments, but other than that, nice!
ReplyDeleteThanks for that post. was wondering how pain killers work.
ReplyDelete