Section 2. Drug Metabolism
1. i. Referring to the primary literature, investigate the metabolism of paracetamol; Using a diagram as an aid, explain the metabolism of paracetamol noting the types of reaction (functionalisation, conjugation) and enzyme families (CYP, UGT, SULT) involved in these pathways.
There are two primary metabolic pathways for paracetamol within the liver – the first and most common is glucuronidation, wherein the paracetamol binds to the glucuronic acid enzyme. Sulfation, which accounts for most of the rest of these occasions, has the paracetamol combining with a sulphate to form a nontoxic conjugate (Hendrickson et al., 2006).
(Hendrickson e al., 2006)
ii. Explain how the metabolism of paracetamol contributes to the hepatotoxicity caused by this drug. One of the metabolites of paracetamol, n-acetyl-p-benzoquinone imine (NAPQI), has a toxic reaction with proteins and nucleic acids as a result of the rearrangement of paracetamol mediated by the cytochrome pathway (CYP). This is caused by NAPQI failing to conjugate with glutathione; overdosing on paracetamol of more than 10 grams saturates the sulphate and glucorinide pathways, leaving little choice but to create NAPQI. Glutathione is used more than is needed, keeping NAPQI toxic and leading to hepatotoxicity (Toms et al., 2009).
iii. Explain how the mechanism of action N-acetylcysteine makes this drug an effective antidote for the treatment of paracetamol overdose.
Paracetamol overdose can, however, be treated through the intravenous application of N-acetylcysteine. The acetylcysteine allows more glutathione to be created in the body, binding to the toxic NAPQI and creating safe, nontoxic conjugates that can protect the liver from damage (Toms et al., 2009).
Section 4. Drug-Drug Interactions
2. i. Explain the mechanism of action of opioid agonists, such as morphine.
Morphine sets out to activate u-opioid receptors found in the nervous system, acting as a phenanthreme opioid receptor agonist. Morphine mimics endorphins in order to achieve its analgesic, anesthetic and euphoric effects.
ii. List the physiological effects observed with opioid overdose.
When one overdoses on opioids, the physiological effects are clear – consciousness is lowered, making the subject groggy and incoherent. In some cases, coma can result from opioid overdose. In most opioids, overdose causes shrinking of the pupils to a pin-point. Respiration can slow dramatically, making breathing difficult for the person undergoing an overdose. Low blood pressure and pulse are often found, which can lead to brain damage if not quickly treated (Buajordet et al., 2011).
iii. Investigate and explain the pharmacological basis for the treatment of opioid overdose with naloxone, including the time-course of naloxone treatment.
In the event of opioid overdoses, naloxone can be used in order to treat the problem. Given its status as a competitive antagonist for the u-opioid receptor, it will block those receptors from being acted upon by opioids, often bringing about very quick withdrawal symptoms. The time course for naloxone treatment is very fast, acting within a minute – its effects could take effect for up to an hour (Buajordet et al., 2011).
Amiodarone has the effect of making warfarin’s mechanism of action much more powerful. This is done by lowering the levels of coagulation factors that are dependent on vitamin K, either through reducing the metabolism of warfarin, increasing vitamin K metabolism, or a number of other factors. This results in the overall heightened potentiation of warfarin, which must be monitored carefully, and lowers the total body clearance of the drug (Hamer et al., 1982). The clinical implications of this interaction are substantial; for example, it can be used to administer less warfarin to a patient, as the effects would be evened out by the presence of amiodarone, there is no need to put as much in the system. This can extend the shelf life and diminish the amount of warfarin administered to patients (Sanoski & Bauman, 2002).
Midazolam’s metabolism is boosted with the addition of St John’s wort, resulting in reduced action within the system. Clearance of midazolam with St John’s wort in the system is double that of normal circumstances – this is due to CYP450 3A4-mediated intestinal induction carried out by St John’s wort constituents (Hall et al., 2003). Serum Midazolam levels also decrease substantially when interacting with St John’s wort. As a result, the oral contraceptive pill has a reduced efficacy due to the increased activity in the CYP3A enzyme that St John’s wort inspires (Hall et al., 2003).
Clinical applications of this discovery may involve the fast removal and metabolism of benzodiazepines from a patient’s system, in the event that they no longer want or need them, or an unforeseen complication requires the removal of these benzodiazepines.
Buajordet, I., Naess A.C., Jacobsen, D., Brors, O. (2011) Adverse events after naloxone
treatment of episodes of suspected acute opioid overdose. European Journal of Emergency Medicine, 11(1), 19-23.
Hall, S., Wang Z., Huang S., Hamman M. Et al., 2003. The interaction between St John's wort
and an oral contraceptive. Clinical Pharmacological Therapy, 74(6): 525-535.
Hendrickson, Robert G.; Kenneth E. Bizovi (2006). “Acetaminophen”, in Nelson, Lewis H.;
Flomenbaum, Neal; Goldfrank, Lewis R. et al. Goldfrank's toxicologic emergencies,
New York: McGraw-Hill.
Sanoski, C.A., & Bauman, J.L. (2002). Clinical Observations With the Amiodarone/Warfarin
Interaction. CHEST, 121(1), 19-23.
Toms L., Derry S., Moore RA., McQuay HJ. (2009). Single dose oral paracetamol
(acetaminophen) with codeine for postoperative pain in adults. Cochrane Database System Review, 21(1).