Paracetamol Is Used To Treat A Human Disease Biology Essay

Published: Last Edited:

This essay has been submitted by a student. This is not an example of the work written by our professional essay writers.

Paracetamol also recognised as acetaminophen, due to being extremely safe as well as it doesnt bother the stomach thus it is used extensively as fever reducer (antipyretic) and over the counter analgesic (pain reliever). Commonly it is used for the relief of slight aches, headaches and it's the most important constituent within many cold and flu medications. Paracetamol can be combined with opioid analgesics which can be subsequently utilized to manage severe post surgical pains and it also offers sedative care for advanced patients with cancer. Onset of analgesia is around eleven minutes following the administration of paracetamol orally. (assist pain relief, 2005) A crystalline odourless compound which has a bitter taste was recognized when paracetamol was revealed; patients who took phenacetin, paracetamol was originally found in their urine and prior to this information it was verified that paracetamol was found to be a urinary metabolite of acetanilide. Aniline analgesics is the class of drugs and paracetamol is a part of this particular class, it's known to be an active metabolite of phenacetin. However contrasting phenacetin, at therapeutic doses paracetamol isn't believed to be carcinogenic. The words such as paracetamol and acetaminophen are used in different countries nevertheless both names arrive from chemical names used for compound which includes para-acetylaminophenol and para-acetylaminophenol; in some circumstances it is shortened as APAP which comes from N-acetyl-para-aminophenol.

Mode of administration

Dispersible paracetamol tablets meant to be dissolved in water or paracetamol can be taken as a tablet or capsule orally with water. It is also obtainable as a suppository which has to be taken in liquid forms through injection into veins and (IV or intravenous use) and rectally, intramuscular is another form of administration. Every day it is normally taken at the same time but certain medical circumstances may possibly necessitate diverse dosage directions. The dosage is usually based on gender, use of other interacting medications, age, response towards therapy and medical conditions. Medication should be taken continually even if the patient feels healthy except if told by a doctor to discontinue the dosage (Boots WebMD, 2010). Whilst safe for taking at suggested doses (up to 4,000mg/day for adults and 1,000mg/single dose, equivalent to 2,000mg/day should be taken if drinking alcohol, infants and children are also safe to take paracetamol in suggested doses even though amounts below 2.5g/day have been linked to odd cases of liver injury) acute paracetamol overdose can lead to potentially lethal liver damage; as well as this a normal dose can have a similar effect in rare individuals, the danger is increased through alcohol utilization. The leading cause of acute liver failure is paracetamol toxicity, (Maddrey WC, Zimmerman HJ, 1995) continual extreme alcohol usage can initiate CYP2E1which belongs to cytochrome p450 oxidase system, consequently enhances the toxicity of paracetamol. The cheapest and easiest way of paracetamol administration is to take it orally however this isn't an alternative for patients who have bowel obstacle or during a surgery process for instance, hence offering paracetmol intravenously is the finest method. Administration through rectum is erratic and unreliable since it gives an incredibly inconsistent plasma concentration peak which is reached later on at 2-3 hours. Just like other drugs administration intravenously arrives at peak concentration quicker in contrast to oral routes and it's more reliable as verified for paracetamol. At 1.43g per 100 cm3 inside cold water the active constituent is not believed to be water soluble, solubility rises at high temperatures. Water loving (hydrophilic) constituents in perfalgan such as disodium phosphate and mannitol formulate it soluble. A pH buffer of disodium phosphate and sodium hydroxide controls hydrolysis; addition of oxygen free mechanized process and cysteine hydrochloride averts oxidation.

Mode of absorption

Paracetamol is absorbed swiftly from gastrointestinal tract (GI) which has peak plasma concentrations at around 10-60 minutes after the paracetamol has been administered orally. The soluble form gets absorbed quicker in comparison to the tablet form (solid); however peak level of blood for soluble and solid form are alike which is typically less than 20mg per litre subsequent to a 1000mg dosage. Serum levels are reached at the peak frequently thirty minutes to 2 hours following ingestion. Paracetamol spreads out inside most tissues of the body; the binding of plasma protein tends to be low at a typical therapeutic dosage however, the binding process rises along with increasing doses. The GI tract normally contains epithelial cells lined up consequently paracetamol has to pervade through these epithelial cells sequentially to be absorbed into the system. There is a cellular blockade which might avert absorption is the cell membrane, these membranes are semi permeable and are fundamentally lipid bilayers, cell membrane is only permeable to small uncharged molecules which can penetrate through the bilayer successfully. The absorption of paracetamol is increased through substances which increase emptying of gastric such as metoclopramide, the absorption is conversely decreased through substances which decrease emptying of gastric for example propantheline and antidepressants which have anticholinergic characteristics. Paracetamol is safe to be taken in normal therapeutic doses; it is mainly converted into non-hazardous metabolites through phase 2 metabolism by means of conjugation with glucuronide and sulfate (sulphate), along with an enzyme system cytochrome p450 which oxidizes a small fraction. Extremely reactive mediator metabolites are produced from conversion of approximately 5% paracteamol via cytochromes 3A4 and 2E1 which is termed NAPQI (Corcoran GB et al, 1980). In a normal state, NAPQI is converted to mercapturic acid conjugates and cysteine when detoxified through conjugation glutathione. When an overdose of paracetamol is taken the glucuronide and sulphate pathways grow to be saturated, consequently additional paracetamol is moved towards p450 system hence more NAPQI is produced. Because of this the requirement of glutathione is more than its restoration hence the hepatocellular supplies of glutathione turn out to be low, for this reason NAPQI inside liver stays in toxic form as well as it reacts with molecules of cellular membrane which result in extensive damage to hepatocyte and death, which leads towards acute hepatic necrosis (Dai Y, Cederbaum Al, June1995).

Fig 1. How Paracetamol is absorbed and metabolised via liver to glucuronide metabolites and sulfate. (D.A Razak, 2007).

Mode of elimination

The elimination of paracetamol from the body is very quick along with a half life of around 2 hours (or 1-3 hours). The metabolism of paracetamol occurs mainly in liver and it's eliminated through urine as inactive sulphate conjugates and glucuronide; approximately below 5% is eliminated unchanged. For paracetamol metabolism sulphate conjugation might account for 20 to 40%, it is understood that glucuronidation is accounted for about 40% to 2/3 of metabolism, (Hendrickson, Robert G, Kenneth E, 2006) the GSH conjugation, N hydroxylation and rearrangement is accounted below 15%. The enzyme cytochrome p450 system is responsible for metabolizes of paracetamol and converts it to negligible but an important metabolite acknowledged as N-acetyl-p-benzo-quinone imine (NAPQI), this metabolite then permanently conjugates with sulfhydryl clusters of GSH (glutathione) (Borne, Ronald F, 1995). These metabolism pathways generate the finishing products which is non toxic, inactive and which are finally eliminated via kidneys. However, NAPQI is toxic intermediate product which is largely accountable for the hepatotoxicity of paracetamol and this forms an illustration of toxication. Enzymes CYP1A2 and CYP2E1are the two isoenzymes which are mainly accountable for production of NAPQI, yet CYP2D6 is also considered to be a third isoenzyme which accounts for individual distinctions in toxicity of paracetamol. In enzyme CYP2D6, genetic polymorphism could adjoin towards considerably diverse NAPQI production rates; in addition individuals could be categorized as ultrarapid, poor and extensive metabolizers (these produce NAPQI depending on the expression levels of CYP2D6). At normal doses NAPQI is rapidly detoxified through conjugation, when overdose is taken and perhaps within unltrarapid and extensive metabolizers NAPQI builds up as soon as such detoxification pathway turns out to be saturated even though paracetamol is metabolised to NAPQ6 in a smaller amount in comparison to other p450 enzymes, its action could contribute towards toxicity of paracetamol in untrarapid and extensive metabolisers and when large paracetamol doses are taken. The symptoms of paracetamol toxicity might be vague or not clear hence overdose could lead towards liver failure and often death; the treatment is targeted at replacing glutathione and getting rid of paracetamol from the body. Activated carbon or charcoal could be utilized to reduce paracetamol absorption if the patient is approaches for treatment straight after the overdose. The antidote NAC (acetylcysteine) operates as antecedent for glutathione, assisting the body regenerate sufficient in order to avert liver damage. If damage to the liver increases then a liver transplant is often required.

Fig 3. NAQI metabolite reactivity as shown in red is a pathway resulting in paracetamol toxicity. Pawthways shown in purple and blue are non toxic. (Drug Discovery Opinion, 2009)

Fig 2. A reaction demonstrating events of paracetamol metabolism. (World of Molecules, 2007.

Mechanism of action

The most important paraceatmol mechanism is believed to be the inhibition of COX (cyclooxygenase), it was also recently discovered that it's provides extreme selectivity for COX 2 (Hinz B, Cherimina O, Brune K, 2008). On the other hand it contains antipyretic and analgesic characteristics equivalent to other NSAIDs and aspirin. A high level of peroxides present within inflammatory lesion is one of the factor by which paracetamol peripheral anti inflammatory action is frequently limited. Conversely, in some conditions such peripheral activity analogous to other NSAIDs could be observed. The production of pro clotting thromboxanes is not considerably inhibited because of its selectivity towards COX2. The prostaglandin H2 is formed when arachidonic acid is metabolized via COX family of enzymes, prostaglandin H2 molecule is unstable which is consecutively converted to several proinflammatory compounds. A usual antiinflammatory like NSAIDs obstructs this action, simply once properly oxidized is the COX enzyme very dynamic. The oxitized COX enzyme is reduced by paracetamol which stops it can't be formed to proinflammatory substances; this process is responsible for the deficient quantity of Prostaglandin E2 in central nervous system (CNS), consequently hypothalamic set point within thermoregulatory centres in lowered. AM404D is a compound to which paracetamol is metabolized into; this compound has numerous activities, most essentially being the inhibition of the uptake of endogenous vanilloid/cannabinoid anandamide through neurons. Such uptake of anandamide would end up activating the chief pain receptor known as nociceptor of the body, also known as vanilloid receptor (TRPV1). Also AM404 is involved in inhibition of sodium channels like do the anesthetics procaine and lidocaine. Any of these activities through themselves are a probable mechanism intended for paracetamol which decrease the pain. However, it's been shown that blocking cannabinoid receptors using synthetic antagonists, palliative effects of paracetamol's are averted, which suggests that activating endogenous cannabinoid system is involved in pain reducing action (Ottani, A et al, 2006). The subject is still being discussed regarding the mechanisms of how COX in different conditions is inhibited, because of the variation in paracetamol activity, other NSAIDs and aspirin; it has been assumed for additional COX variants to be present. COX enzymes family is known to be inhibited by aspirin and since the action of paracetamol is partly related to aspirin there has been a lot of research concerning if paracetamol also involved in inhibits COX. However, it is apparent that paracetamol operates by means of at least two pathways. Some hypothesis suggest that paracetamol inhibition of COX3 isoform of the COX enzyme family is the explanation of how paracetamol works, when articulated into dogs, such enzyme generates pro inflammatory substances, its selectively is inhibited via paracetamol and this discloses a strong resemblance towards other COX enzymes. Nevertheless, other investigations suggest that in mice and human being the COX3 enzyme lacks inflammatory action (Kis b, Snipes JA, Busija DW, 2005). An added possibility is the blockage of cyclooxygenase by paracetamol (just like in aspirin) however that occurs within inflammatory setting where the concentration of peroxides tends to be high and paracetamol in high oxidation state averts its operations. Thos suggests that paracetamol doesn't directly affect the inflammatory location however as a substitute it acts in the central nervous system which is a non-oxidative environment in order to decrease temperature and vice versa.

Fig 4. AM404, an active metabolite of acetaminophen. (Mahalo, 2009)

Fig 5. Anandamide, an endogenous cannabinoid (neurotransmitter). (Mahalo, 2007).