ASSIGNMENT ON

Toxicity concern of combination of paracetamol and caffeine

Course name: Medicinal Chemistry II Course code: PHRM 304 Section 1 Semester: Fall 2012

SUBMITTED TO: Apurba Sarker Apu Senior Lecturer Department of Pharmacy East West University

SUBMITTED BY: Joynab Akhter Jolly (ID: 2010-1-70-016) Bushra Rahman (ID: 2010-1-70-017) Zenifar Karim (ID: 2010-1-70-042) Jannat Mahal Rume (ID: 2010-1-70-048) Samiya Khondaker Rinta (ID: 2010-3-70-048)

Submission date: 15th November, 2012

INTRODUCTION Paracetamol is the most widely used drug. It has mild analgesic (pain relieving) and antipyretic (fever reducing) properties. It is also known as acetaminophen and N -acetyl-p-aminophenol (APAP). It produces analgesic action by elevation of the pain threshold and antipyresis through action on the hypothalamic heat regulating center of the brain. Caffeine is an alkaloid which is a theophylline - like xanthine derivative. By intermolecular association with paracetamol, caffeine increases the solubility and transmembrane permeation of paracetamol. It enhances the pain relieving effects of paracetamol (Square Pharmaceuticals, 2012). It has also an intrinsic power to raise vessel tone in the cranial of the brain, which provides another benefit to treat migraine and headache. So it is often combined with paracetamol in over-the-counter and prescription analgesics (Frey, 2003). This combination is used to treat mild to moderate pain including headache, migraine, neuralgia, toothache and dysmenorrhoea pains. It is also used for symptomatic relief of sprains and strains, rheumatic pain, fibrosis, muscular aches and pains, influenza, feverishness and feverish colds (Square Pharmaceuticals, 2012). However, according to the Chemical Research in Toxicology study of USA it has been recently found out that this combination increases the risk of paracetamol toxicity (BBC News, 2007). METABOLISM OF PARACETAMOL AND CAFFEINE IN THE BODY Paracetamol is metabolized primarily in the liver, where its major metabolites include inactive sulfate and glucuronide conjugates, which are excreted by the kidneys. A minor metabolite is produced in minute amounts by cytochrome P450 isoenzymes in the liver and kidney. Cytochromes P450 2E1 (CYP2E1) and 3A4 (CYP3A4) convert paracetamol to a highly-reactive intermediate metabolite, N-acetyl-p-benzo-quinoneimine (NAPQI). Under normal conditions, NAPQI is detoxified by conjugation with glutathione as shown in Figure 1.
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Caffeine is metabolized in the liver by the cytochrome P450 oxidase enzyme system into three metabolic dimethylxanthines as shown in Figure 2. Each of these metabolites is further metabolized and then excreted in the urine (Dyson and May, 1959).

Figure 1: Safe and unsafe metabolic pathways of paracetamol

Figure 2: The primary three metabolites of caffeine TOXITIES AND OTHER PROBLEMS OF CAFFEINE RELATED PARACETAMOL Each 500 mg of paracetamol contains 65 mg of caffeine. The amount of caffeine that can be ingested per day from caffeine containing paracetamol lies between 65 mg (1 tablet) and 520 mg (8 tablets). However, even 50 mg caffeine can cause tachycardia, anxiety and ectopic beats. Toxicity is normally seen at doses > 500 mg, but this depends on tolerance (NPS Medicinewise, 2010). Different types of toxicities and caffeine-induced problems are discussed below. HEPATOTOXICITY: In cases of paracetamol toxicity, the sulfate and glucuronide pathways become saturated, and more paracetamol is shunted to the cytochrome P450 system to produce NAPQI. A large amount of NAPQI is generated which overwhelms the detoxification process and NAPQI is free to react with cellular membrane molecules where it covalently binds to proteins and other macromolecules (Frey, 2003). This causes dysfunction of the enzymatic systems, structural and metabolic disarray, and cellular damage, resulting in widespread hepatocyte damage and leading to acute hepatic necrosis and death as shown in Figure 1 (James et al, 2003; Frey, 2003). Caffeine combined with paracetamol activates CYP3A activity and can triple the amount of NAPQI. This result in caffeine-enhanced APAP hepatotoxicity. Risk of hepatotoxicity of paracetamol may be increased in alcoholics (DiPetrillo et al, 2003).

NEPHROTOXICITY: Combination of caffeine with paracetamol enhances hepatotoxicity. Hepatotoxicity leads to acute tubular necrosis (ATN) and this result in nephrotoxicity or kidney damage. Although acute tubular necrosis mostly occurs in association with hepatic injury, isolated ATN can also occur. Here the mechanism of renal damage is similar to hepatic injury. Paracetamol is metabolized locally by the cytochrome P450 of the kidney to toxic metabolite NAPQI which ultimately leads to kidney cell damage (Migraine Awareness Group, 2012). PREGNANCY RELATED PROBLEMS: If pregnant women consumes more than 200 mg caffeine per day, the risk of spontaneous miscarriage develops. Consuming > 300 mg per day may also increase the risk of preterm delivery and fetal growth retardation. Caffeine is readily transferred to breast milk and young infants, who are poor metabolizers of caffeine, may become jittery and restless, and may experience sleep difficulties (Mills, 1993). REBOUND HEADACHE: Using too much pain relief medicine appears to interfere with the brain centers that regulate the flow of pain messages to the nerves, worsening headache pain. This rebound syndrome is especially dangerous if medicine contains caffeine, which is often included in pain relievers to speed up the action of the other ingredients. This makes patient more vulnerable to a rebound headache (Hicks, 2012). CONCLUSION People may not be aware from the brand name that a particular preparation contains caffeine and may face caffeine related paracetamol toxicities (NPS Medicinewise, 2010). Since drugs containing only paracetamol are present, paracetamol containing caffeine drugs should be banned to prevent development of these unnecessary toxicities and problems.

REFERENCE DiPetrillo, K., Wood, S., Kostrubsky, V., Chatfield, K., Bement, J., Wrighton, S., Jeffery, E., Sinclair,P., and Sinclair, J.(2002) Effect of Caffeine on Acetaminophen Hepatotoxicity in Cultured Hepatocytes Treated with Ethanol and Isopentanol. Toxicol Appl Pharmacol, Dec 1;185(2):91-7 Frey, R. J. (2003) Caffeine-related disorders. Gale Encyclopedia of Mental Disorders Goldstein, A. and Warren, R. (1962) Passage of caffeine into human gonadal and fetal tissue. Biochem Pharmacol; 11:1668. Hicks, R (2012) Rebound headaches. WebMD, 23rd October James LP, Mayeux PR, Hinson JA (2003). Acetaminophen-induced hepatotoxicity. Drug Metab. Dispos. 31(12): 1499506. Migraine Awareness Group: A National Understanding of Migraneurs (2012) Treatment & management: Drug Profiles: Acetaminophen or Tylenol. Retrieved November 14, 2012, from http://www.migraines.org/treatment/protylnl.htm NPS Medicinewise (2010) Paracetamol with caffeine (Panadol Extra) available over the counter from pharmacies. Retrieved November 14, 2012, from http://www.nps.org.au/health_professionals/publications/nps_radar/2010/august_2010/brief_ item_paracetamol_with_caffeine Dyson, G., M. and May, P. (1959) May's chemistry of synthetic drugs. 5th edn. London: Longmans. BBC News (2007) Caffeine painkiller risk claimed. Retrieved July 14, 2004, from http://news.bbc.co.uk/2/hi/health/7013877.stm