TEACHERS TOPICS. NSAIDs: Chemistry and Pharmacological Actions. American Journal of Pharmaceutical Education 2003; 67 (2) Article 63.

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1 TEACHERS TPICS American Journal of Pharmaceutical Education 2003; 67 (2) Article 63. SAIDs: Chemistry and Pharmacological Actions Ahmed S. Mehanna, PhD School of Pharmacy, Massachusetts College of Pharmacy and Health Sciences Keywords: nonsteroidal anti-inflammatory drugs, analgesics, aspirin-like drugs ITRDUCTI The term SAID is an abbreviation of a class of drugs known as nonsteroidal anti-inflammatory drugs. This nomenclature was given to the class as a differentiation from steroids, the other major antiinflammatory class of drugs. In addition to their antiinflammatory effects, agents belonging to the SAID class possess both analgesic and antipyretic activities. Hence, SAIDs are sometimes referred to as nonnarcotic analgesics or as aspirin-like drugs (aspirin was the first member of the class to be discovered). The class of SAID drugs illustrates the close relationship between the chemical structure of drugs on one side and their biological effects and kinetic properties on the other side. The chemical features of SAIDs explicitly explain different aspects of their behavior including kinetics (absorption, distribution, metabolism, and excretion, abbreviated ADME ), mechanism of action and potential adverse effects. General Statement of SAID Chemistry and Actions SAID is an important therapeutic class of drugs used to suppress pain and inflammation in cases of rheumatoid arthritis and other inflammatory diseases. Recently, some SAIDs have emerged as part of a new class of cancer chemotherapeutic and chemo- Corresponding Author: Ahmed S. Mehanna, PhD. Mailing Address: Associate Professor of Chemistry, Department of Pharmaceutical Sciences, School of Pharmacy, Massachusetts College of Pharmacy and Health Sciences, Boston, MA Tel: Fax: amehanna@mcp.edu. preventive agents. Members of the SAID class are characterized by having several common chemical and biological features. The following section outlines the major points to learn and observe about the SAID group of drugs. Each general statement will be addressed in detail. 1. Disease state of inflammation and the role of prostaglandins as the pain-causing elements during inflammation. 2. Chemistry and structure activity relationships of SAIDs. 3. SAID kinetic properties (ADME: absorption, distribution, metabolism, excretion). 4. Mechanism of SAID action as antipyretic, analgesic, and anti-inflammatory agents. 5. Ulcerogenic properties of SAIDs as the primary adverse effect and its relationship to the mechanism of action and chemical nature of the class members. 6. Effects of SAIDs on blood clotting and their relevance to both therapeutic use and adverse effects of class members. 7. SAID as a new emerging class of drugs for cancer chemotherapy and prevention. 1. Disease State of Inflammation and Prostaglandins Biosynthesis In a simplified term the inflammation process can be considered as an event of the immune response 1 through which tissue damage occurs. The latter is accompanied by the release of several biochemical mediators such as histamine, bradykinin, platelet-activating factor, and a group of lipid material known as leukotrienes (LTs) and prostaglandins (PGs). These mediators are responsible 1

2 Inflammatory Response Tissue Damage release of histamine, bradykinin, platelet-activating factor Release of Phospholipids (Cell Membrane) Phospholipases CH Leukotrienes (LTA 4, LTB 4, LTC 4, LTD 4, LTE 4 ) Linear Pathway by Lipoxygenases Arachidonic acid (1) Cyclic Pathway by Cyclooxygenases CH PGG 2 PGH 2 (Intermediate) (Intermediate) H H H PGE 2 (2) CH CH H H PGF 2 α (3) CH H TXA 2 (5) H H PGI 2 (4) Figure 1. Inflammation cascade and Formation of Prostaglandins and Leukotrienes from Arachidonic acid. for the symptoms that accompany the inflammation process. While histamine, bradykinin, and leukotrienes cause the swelling and redness of the inflamed area (due to vasodilation and increased capillary permeability), prostaglandins, on the other hand, increase tissue sensitivity to pain and cause elevation of body temperature. Figure 1 depicts a simplified scheme for the inflammation cascade. Due to the pivotal role of prostaglandins in mediating pain during inflammation, a full understanding of their chemistry, biosynthesis, nomenclature, and pharmacological actions becomes essential. The section below and Figure 1 provide the needed information. 2

3 Prostaglandins American Journal of Pharmaceutical Education 2003; 67 (2) Article 63. Prostaglandins are a group of autacoids (local hormones) that are endogenously synthesized from a 20-carbon polyunsaturated fatty acid common precursor called arachidonic acid (Figure 1, structure 1). Upon tissue exposure to any of the inflammationprecipitating factors (chemical, mechanical or hormonal), cell membranes release arachidonic acid by partial hydrolysis of lipids by the membrane-bound enzyme phospholipase. 2 Arachidonic acid is subjected to 1 of 2 biochemical transformation routes. ne route involves hydroxylation of the fatty acid by the enzyme lipooxygenase, resulting in the formation of a group of autacoids called leukotrienes (these were first discovered in leukocytes). The second route involves oxygenation and a process of cyclization by an enzyme called cyclooxygenase (or CX) to produce a class of autacoids known as prostaglandins (see Figure 1). Several of these prostaglandins were isolated and identified and given abbreviated names such as PGE 2, PGF 2, PGI 2 (the letters are given to different intermediates of the biosynthesis process, and the subscript indicates the number of double bonds in the molecule; see Figure 1, structures 2, 3, and 4). The cyclooxygenase enzyme also converts arachidonic acid into another cyclization product called thromboxane (TXA), first isolated from thrombocytes, having a 6-membered ring instead of the 5-membered ring found in prostaglandin (see Figure1, structure5). The biological effects of various prostaglandins and thromboxanes indicate that both PGE and PGF are responsible for increasing tissue sensitivity to pain. The major effect of PGI 2 (also called prostacycline) is inhibition of the platelet aggregation process, while TXA 2 has the opposite effect on platelets. Both PGE and PGF induce the secretion of polysaccharide material in the stomach known as mucin. This polysaccharide substance acts as a natural protective agent against potential stomach ulceration from the effects of HCl and the enzyme pepsin. This explains the ulcerogenic effects of the SAID class of drugs. Due to the apparent role of prostaglandins in the process of inflammation, inhibiting prostaglandin biosynthesis became an attractive approach to fighting inflammation. Prostaglandin biosynthesis inhibitors are the class of anti-inflammatory agents known today as SAID. 2. Chemistry and Structure Activity Relationships of SAID The mechanism of action of SAIDs involves reduction of prostaglandin synthesis by inhibition of CX enzyme through competitive antagonism for arachidonic acid binding to the cyclooxygenase enzyme (CX). For a drug to be an effective competitive inhibitor for arachidonic acid binding to CX, the drug must posses both high lipophilic and acidic properties to mimic the natural substrate chemistry. This is clearly apparent in the chemical structures of all SAIDs (Figure 2) such as Ibuprofen 3 (structure 6), flubiprofen 4 (structure7), ketoprofen 5 (structure8), naproxen 6 (structure9), indomethacin 7 (structure10), diclofenac 5 (structure11), and piroxicam 5,6 (structure12). The acidic functionality can be a propionic acid carboxylic group (see Figure 2, structures 6, 7, and 8), or an acetic acid carboxylic group (see Figure 2, structures 10 and11), or as an enolic group (acidic proton of 1,3 diketo group; see structure 12). SAIDs with a polar group in the lipophilic tail such as sulindac 8 (structure 13) are not effective CX inhibitors before being metabolized into a more lipophilic substance (structure 14) as further explained under the metabolism section of SAIDs kinetics. In a similar manner, lipophilic drugs lacking the acidic functionality, such as nabumetone 9 (structure 15), are metabolized into products with acidic functional groups (structure 16) before becoming active. Therefore, both sulindac and nabumetone are classified as prodrugs. It is worth noting the correlations between drug generic names and their chemical structures, eg, all propionic acid SAIDs include the letters pro in the name, while acetic acid derivatives include the letters ac. The names of both nabumetone and naproxen indicate that both are naphthalene derivatives. 3. Kinetics of SAID (ADME) Absorption: Since all SAIDs are highly lipophilic substances, members of the class share similar, if not identical, absorption properties. Drug absorption after oral administration is generally rapid and complete. Most SAIDs are given as oral tablets or capsules; others are given by injection to avoid gastric irritation (see section 5). Distribution: The most significant aspect of SAID distribution is plasma protein binding. The chemical nature of these agents suggests strong binding to plasma proteins. The major plasma protein component is albumin, which has several basic and lipophilic residues. SAIDs with both acidic functionality and lipophilic tails bind to albumin through both ionic and hydrophobic forces of interactions. Plasma protein binding of SAIDs may pose the potential for drug-drug interaction with other drugs that bind with albumin at the same sites. Plasma protein displacement is common when SAIDs are concurrently administered with other drugs 3

4 CH American Journal of Pharmaceutical Education 2003; 67 (2) Article 63. F CH 2 CHCH CHCH C CHCH Ibuprofen (6) Flubiprofen (7) Ketoprofen (8) CH 2 CH CHCH C Cl H CH 2 CH Cl Cl aproxen (9) Indomethacin (10) Diclofenac (11) H S C H F - S + CH 2 CH CH F S CH 2 CH CH Piroxicam (12) Sulindac (13) CH 2 CH 2 C CH 2 CH Active metabolite of Sulindac (14) CH H abumetone (15) Active metabolite of abumetone (16) S 2 H 2 Acetaminophen (17) S 2 CH C Acetylsalicylic acid (18) CH 3 CF 3 Celecoxib (19) Rofecoxib (20) Figure 2. Chemical structures for common antiinflammatory agents. such as the oral anticoagulants, the anticancer agent methotrexate, the oral antidiabetic agents, and thyroid hormones. Displacement from albumin may increase the activity or toxicity of such drugs. The best example for such a drug-drug interaction is the observed increase of the anticoagulant effects by warfarin when 4 concurrently administered with aspirin and aspirin-like drugs. Metabolism: Knowledge of the mechanism of action of SAIDs, as competitive inhibitors for arachidonic acid binding to CX, provides a good tool to predict whether SAID metabolites are active or not. Generally, phase-i metabolism of SAIDs produces more polar products. These polar metabolites are not

5 polar products. These polar metabolites are not efficient CX inhibitors because they lack the lipophilic properties to compete with arachidonic acid and prevent its binding to CX. Accordingly, it is easy to conclude that most of the SAIDs are metabolized into inactive products, which is the case in reality. When the original drug is polar, like sulindac (due to the ionic sulfoxide group, structure 13), phase-i metabolism results in the conversion of the sulfoxide group into the very lipophilic sulfide group by a reduction mechanism to produce the nonpolar sulfide form of the drug (structure14). The latter (reduced form of sulindac) is the actual inhibitor for the enzyme CX. When the original drug lacks the acidic functional group, such as in nabumetone (structure 15), phase-i metabolism results in nabumetone conversion into the acetic acid derivative (structure 16) via an oxidative degradation process similar to that for fatty acids metabolism. Phase-I metabolism of SAIDs can be affected if these drugs are coadministered with drugs that alter the metabolism of other drugs. Enzyme inhibitors such as cimetidine and valproic acid and enzyme inducers such as carbamazepine and phenobarbital may enhance or decrease the anti-inflammatory activity of SAIDs depending on whether the drug is biologically activated or deactivated by metabolism. Excretion: SAIDs are mostly excreted as phase- II glucouronides and in a few cases as sulfate conjugates. In addition, small percentages of SAIDs are excreted unchanged in urine. If the drug is excreted unchanged, its rate of excretion is expected to increase if the drug is coadministered with agents that render the urine ph alkaline such as the antacids aluminum hydroxide and milk of magnesia. 4. SAID Mechanism of Action as Antipyretic, Analgesic, and Anti-Inflammatory Agents As pointed out earlier, SAIDs act as antiinflammatory agents by inhibiting the biosynthesis of the prostaglandins that are classified as inflammationinducing substances. For a given drug to act as an SAID, the drug s chemistry must fulfill 2 major criteria: it must have lipophilic properties and the presence of an acidic functional group. Drugs having either weak lipophilic or weak acidic properties are not expected to be good anti-inflammatory agents. Acetaminophen (structure 17), shows weak properties regarding both lipophilicty and acidity; therefore, it is void of any anti-inflammatory actions. n the other hand, acetylsalicylic acid (structure 18) has poor lipophilic properties but a strong acidic functional group produces anti-inflammatory effects only at much 5 higher doses (10 g) than its analgesic dose of only 1g. Drugs with both strong lipophilic characteristics and strong acidic properties such as members of the acetic and propionic acid series show significant antinflammatory actions at much smaller doses (30 mg -100 mg). 5. Ulcerogenic Versus onulcerogenic SAIDs In general, SAIDs exhibit a similar pattern of adverse effects on the gastrointestinal tract including nausea, vomiting, and diarrhea. However, the most serious and detrimental adverse effect attributed to the prolonged use of SAIDs is the development of gastric ulceration. The ulcerogenic properties of SAIDs stem from the fact that they are organic acids, which can irritate the gastric mucosa, and also from their inhibitory effects on prostaglandin biosynthesis. Prostaglandins are the natural stimulatory agents for mucin secretion. The latter is carbohydrate polymer, normally produced by the stomach, and acts as an endogenous cytoprotective substance against the digestive effects of trypsin and hydrochloric acid. Accordingly, by inhibiting prostaglandin synthesis, mucin secretion will be indirectly reduced and an increased risk of ulceration arises. The enzyme CX has 2 sub-types: CX-1 and CX-2. The former exists throughout the biological system including in the stomach, while the second (CX-2) is much less abundant in the stomach. This discovery prompted investigators and researchers to develop selective CX-2 inhibitors to minimize the ulcerogenic potential of SAIDs. Two major drugs were produced by this approach: celecoxib 10 (Figure 2, structure 19), and rofecoxib 11 (Figure 2, structure 20). The medicinal chemistry of the 2 drugs indicates high lipophilic characteristics with an acidic functionality represented by the sulfonamido group in celecoxib, or the bio-isosteric group methylsulfone in rofecoxib. The subtype-cx-2 enzyme has a selective binding area for the sulfone group while the subtype-cx-1 lacks such an area. 6. SAIDs and Blood Clotting The inhibitory effects of SAIDs on the production of prostacyclin (PGI) and thromboxane (TXA) precipitate 2 opposing effects on the blood clotting process. Inhibition of PGI synthesis may promote blood clotting, while inhibition of TXA synthesis may inhibit blood clotting. However, the clinically observed effect accompanying SAID use is primarily increased bleeding. If a peptic ulcer is also present, this constitutes a serious problem, even with CX-2 selective drugs,. However, the effect of SAIDs on blood clotting is a clinically useful approach with acetylsalicylic acid (aspirin), a prophylactic agent against stroke. Aspirin was found to

6 decrease blood clotting by dual mechanisms; by inhibiting the thromboxane synthesis and through chemical acetylation of the blood platelets. The acetylated platelets have much slower rate of aggregation, a phenomenon that is needed for people with a high risk of developing internal blood clots after stroke. 7. SAIDs and Cancer Chemotherapy and Prevention CX-2 inhibitors have recently emerged as a promising new class of drugs that may be useful for cancer chemotherapy and prevention. 12 Celecoxib was reported to be useful in decreasing the risk of developing colorectal cancer for patients with familial adenomatous polyposis (FAP) A recent indicated a possible role of CX-2 inhibitors in breast cancer chemoprevention. 16 The interest in SAIDs in cancer treatment and prevention is not limited to the selective CX-2 inhibitors. Piroxicam (a nonspecific CX inhibitor) was recently reported to potentiate the anticancer effects of cisplatin on human invasive bladder cancer. 17 It must be indicated that the mechanisms through which SAIDs suppress cancer growth is not yet fully understood. However, future research in such an exciting area may reveal and establish such mechanisms. 8. Summary and Conclusion Most members of the class predispose for the development of peptic ulcer disease; hence, they are classified as ulserogenic agents (ulcer-causing drugs). Gastric ulceration is attributed to the inhibitory effects of SAIDs on prostaglandin synthesis and its subsequent inhibitory effects on mucin secretion. Due to the inhibitory effects on thromboxane (TXA 2 ) biosynthesis, prolonged use of most of the class members results in decreased blood clotting, which can lead to serious bleeding problems if combined with the development of an ulcer. SAIDs, especially selective CX-2 inhibitors, represent a new class of cancer chemotherapeutic and chemopreventive agents. Several members of the class were found to be promising in treatment and prevention of colon, breast, and bladder cancer. Recommended Readings: Ronald R. Borne, onsteroidal Anti-inflammatory Agents, Chapter 32 in Foye s Principles of Medicinal Chemistry, 5 th edition, 2002, Williams, D.A. and Lemke T.L.(eds), Lippincott Williams &; Wilkins, ew York. REFERECES 1. Hamor GH. on-steroidal anti-inflammatory drugs. In: Foye W, ed. Principles of Medicinal Chemistry. 3 rd ed. Philadelphia, Penn: Lea &; Febiger; 1989;15: Campbell WB. Lipid derived autacoids. In: Gilman AG, Rall TW, The class of SAID represents an important ies AS, et al, ed. Goodman and Gilman s The Pharmacological group of drugs indicated for treatment of inflammation. The drugs suppress inflammation through 1990; Basis of Therapeutics, 8 th ed. ewyork, Y: Pergamon Press, inhibiting prostaglandins synthesis. 3. Kantor TG. Ibuprofen. Ann Intern Med. 1979;91: Chemistry and structure activity relationships of SAID show that all members of the class have 2 basic chemical entities: an acidic functional group and a highly lipophilic tail. Most members of the class share similar kinetic properties of good absorption after oral administration and strong plasma protein binding. Phase- I metabolites are generally inactive as CX inhibitors except for the prodrugs: sulindac and nabumetone, where phase-i metabolism generates the active metabolites. All members of the class act by the same mechanism of action, reduction of prostaglandin synthesis through inhibition of the enzyme cyclooxygenase (CX). All members of the class possess antipyretic and analgesic properties; however, only those with strong inhibitory effects on PGs synthesis are useful as anti-inflammatory drugs. 4. Rainsford KD, ed. ewer Anti-inflammatory Drugs. Vol. II. Antiinflammatory and Anti-Rheumatic Drugs. Boca Raton Fla: CRC Press; Lewis AJ, Furst DW, eds. onsteroidal Anti-Inflammatory Drugs: Mechanisms and Clinical Use. ew York, Y: Marcel Dekker; Todd PA, Lissold SP. aproxen. A reappraisal of its pharmacology and therapeutic use in rheumatoid diseases and pain states. Drugs. 1990;40: Rainsford KD, ed. Inflammation Mechanisms and Actions of Traditional Drugs. Vol. I, Anti-inflammatory and Anti-Rheumatic drugs. Boca Raton, Fla: CRC Press; Shen TY, Witzel BE, Johnes H, et al. US Patent, 3,654, 349,971. Chem Abst. 1971;74:141379v. 9. Friedel HA, Langtry HD, Buckley MM. abumetone: a reappraisal of its pharmacology and therapeutic use in rheumatoid diseases and pain states. Drugs. 1993;45: Davis M, McLachlan AJ, Day R, Williams KM. Clinical pharmacokinetics and pharmakodynamics of celecoxib, a selective cyclooxygenase-2 inhibitor. Clin Pharmacokinet. 2000, 38: Scott LJ, Lamb HM. Rofecoxib. Drugs.1999, 58:

7 12. Koki AT, Leahy KM, Masferrer JL. Potential Utility of CX- 2 inhibitors in chemoprevention and chemotherapy. Expert pin Investig Drugs. 1999,8: Reddy BS, Hirose Y, Lubet R, Steele V, Kelloff G, Paulson S, Seibert K, Rao CV. Chemoprevention of colon cancer by specific cyclooxygenase-2 inhibitor, celecoxib, administered during different stages of carcinogenesis. Cancer Res. 2000, 60, orth GL. Celecoxib as Adjunctive Therapy for Treatment of Colorectal Cancer. Ann Pharmacother. 2001;35: Gupta RA, DuBois R. Translational studies on CX-2 Inhibitors in the Prevention and Treatment of Colon Cancer. Annals Y Acad Sci. 2000;910: Davies G, Martin LA, Sacks, Dowsett M. Cyclooxygenase-2 (CX-2), aromatase and breast cancer: a possible role for CX-2 inhibitors in breast cancer chemoprevention. Annals ncol.2002,13: Mohammed SI, Craig BA, Mutsaers AJ, Glickman W, Snyder PW, degortari AE, Schlittler DL, Coffman KT, Bonney PL, Knapp DW. Effects of the cyclooxygenase inhibitor, piroxicam, in combination with chemotherapy on tumor response, apoptosis, and angiogenesis in a canine model of human invasive urinary bladder cancer. Mol Cancer Ther. 2003;2: