Metabolism of Paracetamol and Terfenadine Drugs - Case Study Example

Paracetamol and Terfenadine Introduction: Drugs are therapeutical agents in the management of diseases and conditions. Advances in medical science have led to an ever increasing number of drugs. All drugs do cause side effects, but are given as normally the benefits far outweigh the risks in the management of a given condition or disease. However, there is growing concern over the increase in advance drug reactions that arise from the toxicity of the drug or its metabolic products. The impact of these adverse reactions is that there are estimates from some studies that 6.7% of hospitalized patients in the a developed nation like the United States of America have a serious drug reaction with a fatality rate of 0.32%, and there are estimates that put the cost to the nation of the morbidity and mortality related to adverse drug reactions at $136 billion. (1). An essential factor in the toxicity of a drug is the manner in which it is metabolized and excreted from the body. Understanding drug toxicity requires an understanding of the metabolism of drugs in the human body, and the role that it plays in the toxicity of drugs. Metabolism of Drugs: Metabolism of drugs occurs after absorption of the drug and hence the route of administration and the absorption of the drug have a role to play in its metabolism. In oral administration of a drug, not all the drug is absorbed. Digoxin is a typical example with only seventy percent of the drug absorbed. This deficient absorption in the gut has been attributed to bacterial metabolism in the intestine and the drug being too hydrophilic or lipophilic. Another factor that has been identified in the poor absorption of a drug in the gut is the role of the reverse transporter associated with P-glycoprotein, which actively pumps the drug out from the gut wall into the gut lumen. Inhibition of this action of the reverse transporter even by nutrients like grape fruit juice, leads to more absorption of the drug. (2). Subsequent to the absorption of the drug, the portal blood system delivers the drug into the liver, before it can enter the systemic circulation. While the gut wall and the portal blood have the capacity for metabolizing the drug, it is essentially the liver that takes over the function of drug metabolism in what is known as the first-pass loss or elimination. (2). Drugs that are administered through other routes like injection or inhalation avoid this first pass effect of the liver and circulate in the body before reaching the liver. Some drugs do not even reach the liver, as they are taken up by other tissues and organs as they circulate in the body. (3). Morton & Hall, 2002, p. 598, define metabolism of drugs “as the process whereby the body detoxifies chemicals and excretes them as metabolites”. (4). Drugs are substances that are foreign to the human body and are treated as such in that the body tries to get rid of these chemical invaders. Polar drugs are easily excreted by the kidney, but non-polar drugs pose a problem for excretion and the objective of drug metabolism is to convert these compounds into polar molecules for easy excretion. (3). Non-specific enzymes, especially the cytochrome P450 enzymes in the liver have the capability of adding polar functional groups to a wide range of drugs. The addition of this polar functional group makes the overall drug more polar and increases the water solubility of the drug, which makes it easier for excretion as it passes through the kidney. An alternate set of enzymatic reactions unmask the presence of any polar functions that may be present in the drug. An example of this is the enzymatic action, which can demethylate methyl ether to reveal the more polar hydroxyl group. Here too the emphasis is on ease in excretion through the more polar product or metabolite. (3). Such reactions have been classified as phase I reactions in the metabolism of drugs. These reactions most commonly involve oxidation, reduction and hydrolysis. A very high proportion of these metabolic reactions occur in the liver, but it is not the only location, as metabolic reactions can happen in the gut wall, plasma and other tissues. Chemical structures of drugs that are susceptible to oxidation include the N-methyl groups, aromatic rings, the terminal positions of the alkyl chains and the minimally obstructed positions of the alicylic rings. Nitro, azo and carbonyl groups are susceptible to reduction by reductases and amides and esters to hydrolysis by esterases. In the case of some drugs these metabolic reactions result on the formation of more than one metabolite, while in the case of other drugs there is resistance to the metabolic action of the human body (3). Another series of metabolic reactions again mainly occurring in the liver are called phase II reactions. These metabolic reactions are essentially conjugation reactions, wherein a polar molecule is attached to a suitable polar handle that is originally present in the chemical structure of the drug or that which has been introduced by a phase I metabolic action. The resulting conjugate or metabolite has increased polarity and hence solubility, leading to ease in excretion. (3) Metabolism of drugs leads to their conversion into two kinds of metabolites in the body namely stable or inactive metabolites or reactive metabolites. More often drugs are converted into metabolites that are stable or inactive. (1). Role of Metabolism in Drug Toxicity: According to Guengerich, 2006, drugs toxicity is caused by five factors. These five factors are on-target toxicity, hypersensitivity and immunological reactions, off-target pharmacology, bio-activation to reactive intermediates and idiosyncratic drug reactions. Metabolism is responsible for the bio-activation to reactive intermediates through its conversion of the drug to stable and reactive metabolites. These metabolites in particular the reactive metabolites may be toxic to the body in through their interactions. The reactive metabolites bind covalently to macromolecules. Impaired metabolism can also lead to off-target drug toxicity, as can be seen from the example of terfenadine. Terfenadine is metabolised to fexofenadine, which does not have the toxic potential of terfenadine, through the blocking of the human ether-a-go-go (hERG) channels. When there is impaired metabolism of terfenadine, terfenadine circulates in the body with potential for this toxic effect (5). The chemistry involved in the toxicity of the reactive metabolites, is fairly well understood. The basic toxicity is governed by two chemical reactions. The first is the reaction between an electrophile formed from the drug and a nucleophile in the tissue. The second is the propagation of free radicals. The half-lives of the reactive metabolites in water may range from a second to several hours causing biological damage to cells and on to tissues and thereby organs. The potential risk for toxicity of the stable metabolites is not very clear. There is the possibility of toxicity from the stable metabolites too, with the FDA requiring the testing of stable metabolites, particularly those unique to the human body, to the same extent of the drug itself. (5). Drug Interaction: Drug-drug interactions are associated with the effect that one drug has on the other, when both the drugs are taken together. According to Brown, 2000, drug-drug interaction may be defined as “the modulation of pharmacologic activity of one drug (i.e., the object drug) by the prior or concomitant administration of another (i.e., the precipitant drug)”. (6) Drug interaction can lead to the pharmacological properties of the either of the drugs being severely enhanced or diminished. Among the several causes for drug interaction is the metabolism of the drug. Other causes are drug dose, serum drug level, route of administration, duration of the therapy and patient factors. Drug interactions are classified into those that are pharmacokinetic in nature and those that are pharmacodynamic in nature. Pharmacokinetic drug interactions have an influence on the disposition of the drug in the body and are associated with the absorption, distribution, metabolism and excretion of another drug. Pharmacodynamic drug interactions are associated with pharmacologic activity of the interacting drugs. (6). The number of drugs involved in the management of the diseases or conditions of critical care patients, patients with complicated surgical procedures and elderly patients make these patient populations at high risk for drug interactions. Drugs with a high potential for drug interaction are those that a narrow therapeutic index, a very steep dose-response curve or potent pharmacological effects. (6). Paracetamol Metabolism: Paracetamol also known as acetaminophen is a non-narcotic analgesic used in the treatment of mild to moderate pain. It also has antipyretic properties and is used to reduce fever. It is the most commonly employed analgesic and antipyretic. Paracetamol is essentially safe within the therapeutic range of 1g-4g daily. However, it is also the most common cause for drug-induced liver disease, owing to its toxicity to the liver when the therapeutic range is crossed. The metabolism of paracetamol has a large role to play in the hepato-toxicity of paracetamol. (7). The liver is the site for the metabolism of paracetamol. Eighty-five to ninety percent of paracetamol gets converted into inactive metabolites by undergoing glucuronidation and sulphation. These processes make paracetamol more polar and hence water soluble through the chemical actions of binding or conjugation with glucuronide or sulphate. The water soluble inactive metabolites are excreted through urine. Five percent of the remaining paracetamol is excreted in an unchanged form though urine. It is the final remaining five to ten percent that gives rise to the toxic potential of paracetamol to the liver. This five to ten percent of paracetamol is metabolised through oxidation by the hepatic cytochrome P450 enzymes to highly reactive N-acetyl-p-benzoquinone imine (NAPQI). This metabolite of paracetamol has the potential to cause damage to the liver. Within the normal therapeutic range of paracetamol, NAPQI gets inactivated through conjugation with hepatic glutathione. The product of the reduction reaction between NAPQI and glutathione is then excreted through urine. (8). Glutathione is a compound essentially a product that is synthesized in the liver with antioxidant properties. When the therapeutic range of paracetamol is exceeded the glucuronidation and sulphation pathways are unable to cope with the paracetamol reaching the liver, leading to an increase in the quantity and the rate at which NAPQI is formed. The available glutathione is insufficient to neutralize this increased quantity of NAPQI. As a result the NAPQI binds covalently with the hepatocytes resulting in hepatotoxicity. This in turn causes dysfunction of the liver and cellular death. The liver is the prime target for the toxic action of NAPQI, but other organs like the kidney are also targets for toxic action of NAPQI. (8). Terfenadine Metabolism: Terfenadine belongs to the group of antihistamine drugs, which was used for relief from allergic symptoms like hay fever and urticaria. The absorption of orally consumed terfenadine is approximately seventy percent, with most of it essentially metabolized into an active acid metabolite and a dealkylated inactive metabolite. This metabolism of terfenadine results in very low systemic availability of the drug. However terfenadine was withdrawn from the market in1998, because of the possibility of life threatening toxic effects associated with terfenadine. (9). The metabolism of terfenadine is essentially through the cytochrome P450 enzyme system CYP3A4 in the small intestine wall and the liver. The metabolism of terfenadine is easily inhibited by inhibitors of the cytochrome P450 enzyme system, leading to less of the metabolites and more of terfenadine entering systemic circulation. Grapefruit juice is a common example of an inhibitor of the metabolism of terfenadine. This inhibition of the metabolism of terfenadine leads to higher plasma concentrations of terfenadine. (10). The antihistamine action seen with terfenadine is really due to the active metabolite fexofenadine. While terfenadine has cardiac toxic properties, fexofenadine is not cardio-toxic. The inhibition of terfenadine metabolism leads to a greater concentration of the toxic parent drug terfenadine and less of the active antihistamine metabolite fexofenadine in the plasma. These high concentrations of terfenadine cause a lethal arrhythmia called torsade de pointes. This has led to the withdrawal of terfenadine from the market, while fexofenadine is marketed as an antihistamine drug in its own right. (11). Conclusion: Metabolism of drugs is essentially a function of the kidney. Metabolism is done by the body, as a means of riding itself of the foreign chemicals introduced into the body as drugs. However metabolism of drugs could at times lead to toxic metabolites that could damage the liver or other organs with fatal consequences. Paracetamol presents an example of this effect of metabolism, when therapeutic ranges are exceeded. Interestingly at times it is the metabolite that produces the active beneficial action, while the parent drug is the culprit for toxicity. In such cases impaired metabolism leads to the availability of a greater concentration of the parent drug and less of the metabolite with possible fatal consequences due to the toxicity of the parent drug. Terfenadine is an example of a toxic parent drug, with a beneficial active metabolite. . . , Works Cited 1. “Preventable Adverse Drug Reactions: A Focus on Drug Interactions”. CENTER FOR DRUG EVALUATION AND RESEARCH. 2002. U.S. Food and Drug Administration. 22 Oct. 2007 . 2. Nicholas, H. G. & Holford, M. B. “Pharmokinetics & Pharmacodynamics: Rational Dosing & the Time Course of Drug Action. Basic & Clinical Pharmacology. Ed. Bertram D. Katzung. New York: Lange Medical Books/McGraw-Hill, (2001). 35-50. 3. Patrick, L. Graham. An Introduction to Medicinal Chemistry. Third Edition. Oxford: Oxford University Press, (2005). 4. Morton, Ian, and Hall, Judith. MEDICINE. Sixth Edition. The Royal Society of Medicine. London: Bloomsbury, (2002). 5. Guengerich, Peter, F. “Cytochrome P450s and Other Enzymes in Drug Metabolism and Toxicity”. The AAPS Journal 8.1 (2006), 22 Oct. 2007 . 6. Brown, Charles, H. “Overview of Drug Interactions”. U.S. Pharmacist. 2000. 22 Oct. 2007 . 7. Ward, Fiona and Daly, Mike. “Hepatic disorders”. Adverse Drug Reactions. Ed. Anne Lee. London: Pharmaceutical Press (2001). 77-97. 8. Farley, A., Hendry, C. and Napier, P. “Paracetamol poisoning: physiological aspects and management strategies”. Nursing Standard 19.38 (2005): 58-64. 9. “Seldane”. Clinical Pharmacology. 22 Oct. 2007 . 10. Maclean, Fiona and Lee, Anne. “Cardiovascular disorders”. Adverse Drug Reactions. Ed. Anne Lee. London: Pharmaceutical Press (2001). 217-240. 11. Katzung, Betram G. and Julius, David, J. “Histamine, Serotonin & the Ergot Alkaloids”. Basic & Clinical Pharmacology. Ed. Bertram D. Katzung. New York: Lange Medical Books/McGraw-Hill, (2001). 265-291. Read More