E. g. C2 = C1 ? V1 V2 C2 = 250 ? 0. 3 C2 = 150mg/L 0. 5 C1 = Initial concentration of salicylate (250 mg/L) C2 = Final concentration of salicylate V1 = Initial volume and V2 = Final volume (0. 5) C. Refer to the graph attached d). Table below showing the volume of urine produced by patient A & B at different intervals and their absorbance at 540nm. |Patient A |Absorbance (540nm) |Specific Absorbance |Salicylate Concentration |Mean Salicylate |Volume of Urine |Volume of | |Sample No. | |(Abs – Blank) |(mg/L) |concentration (mg/L |produced (L) |salicylate | | | | | | | |excreted in urine| | | | | | | |(mg) | | |1 |2 |1 |2 |1 |2 | |
e). Calculation of Volume of urine produced: E. g. Unknown sample A3: 130 1000 = 0. 130 L Calculation of Volume of salicylate excreted in urine : E. g. Volume of urine produced ? Mean salicylate concentration Patient A3: 0. 130 ? 155 = 20. 15mg. Total salicylate excreted in urine = 285. 89mg f. The dipstick test result for patients B displayed a light purple colour and ++2 ketone level (40-100mg/dl). This suggests presence of ketone in the patient urine sample and very low amount of aspirin. g. Patient A: David Beckham. Gender: Male Age: 35 Patient B: Cruz Beckham. Gender: Male Age: 6 Estimation of Paracetamol in serum 1 a).
Table showing the absorbance reading at 430nm for paracetamol serum for patient C, D and Blank and standard paracetamol. |Patient sample |Absorbance (430nm) |Average absorbance – Blank |Paracetamol in serum (mg/L) | | | |(430nm) | | | |1 |2 | | | |Blank |0. 012 |0. 012 |0. 012 | – | |Standard |0. 147 |0. 138 |0. 131 |322. 58 | |C |0. 108 |0. 105 |0. 095 |200 | |D |0. 027 |0. 027 |0. 015 |8. 06 | b). Calculation of Serum paracetamol concentration in patient samples C&D: Average reading of unknown – Blank ? 300 ? 100 Average reading of standard – Blank 93 Sample C: 0. 074 ? 300 ? 100 0. 199 93 = 200mg/L Sample D: 0. 003 ? 300 ? 100 0. 119 93.
= 8. 06mg/L c). Patient C: Katy Perry. Age: 27 Patient D: Russell Brand. Age: 37 General questions: a). Aspirin being a weak acid it’s protonated in the acidic environment in the stomach facilitating it’s passage accross the gastrointestinal mucosa. It’s rapidly hydrolysed by esterases in the plasma and tissues mainly the liver yeilding salicylate. Almost 25% of salicylate is oxidised to gentisic acid, some is conjugated with glucuronide to form salicyl acyl glucuronide or salicyl phenolic glulcuronide, majority of the drug is conjugated with glycine to form saliycuric acid, some of the drug is excreted in unchanged form (Brody et al.1994).
Similarly paracetamol is also primarily metabolised in the liver but metabolised into an inactive form by conjugating it to form glucuronide or sulphate, the hepatic cytochrome p450 enzyme metabolises the drug in which, a toxic intermediate product NAPQ is yielded, but at a therapeutic dose of paracetamol under normal mechanisms, it’s irreversibly conjugated with sulphydryl groups of glutathione which allows it to be excreted by the kidneys. Salicylate is rapidly distributed throughout most body fluids and tissues (liver, kidney and heart and lungs), low concentration of the drug crosses the brain barrier but readily crosses the placental barrier.
In comparison, a therapeutic dose of paracetamol is widely distributed in the liver, kidney, GI tract in high concentrations. But it slowly diffuses through the blood brain barrier compared to a much faster rate seen in blood vessels in adipose muscle tissue. (Rang et al. , 2007). Salicylate half life in the circulation is 13-19 minutes and the plasma half life is approximately 4 hours, as for paracetamol it ranges between 2-4 hours depending on age, gender and likely to rise 4-8 hours at toxic levels.
Salicylate as an non steroid anti-inflammatory drug, it therapeutically acts by irreversibly inactivating both cyclo-oxygenase (COX)- 1 and COX-2, thus acting in pain relief, fever and inflammation. Low dose of aspirin is effective in cardiovascular disorders through antiplatelate action. However there are potential side effects, minimal gastric bleeding is common in a therapeutic dose of salicylate, with higher doses salyclism and compensated alkalosis may occur.
Paracetamol has analgesic and antipyretic actions, a therapeutic doses of paracetamol is effective in relief of mild pain and fever, although not categorised as NSAID due to it’s weak anti-inflammatory effects. High dose of paracetamol does not increase the chance of gastrointestinal complications such as stomach bleeding (Rang et al. , 2002). Therapeutic side effects of paracetamol are uncommon but allergic skin and hypersensitive reaction do occur occasionally, however toxic dose causes nausea and vomiting, after 24-48 hours untreated potential liver damage could occur.
b). An over dose of Paracetamol can cause potential fatal hepatotoxicity, whereby the liver enzymes involved in the catalysis of the normal conjugation reactions become saturated, thus causing the drug to be metabolised by mixed function oxidases instead of glucuronidation. Glutathione which is involved in conjugating with the toxic metabolite NAPQ1 inactivating it becomes depleted thus NAPQ1 accumulates as a result and reacts with necleophilic constituents of the cell causing necrosis in the liver (Rang et al., 2007).
Metabolic consequences exhibited with salicylate overdose results as a disturbance of the acid base and the electrolyte balance. Salicylate uncouples oxidative phosphorylation leading to increased oxygen consumption and carbondioxide, these metabolic changes stimulate respiration which again is stimulated by the direct action of the drugs through the respiratory centre resulting in hyperventilation which cause respiratory alkalosis, this is common in adults (Rang et al. , 2007).
In children, salicylate simultaneously causes primary acidosis due to extreme acid base disturbances, the salicylate disappears from the blood and enter the cells, poison the mitochondria thus occurrence of metabolic acidosis in children. c). Clinical management of salicylate overdose could be achieved by removing salicylate from the body. This could be done is by giving the patient activated charcoal within one hour of ingestion of more than 250mg/kg this helps to reduce absorption of salicylate in the gut salicylate since it’s absorbed slowly (Rang et al., 2007).
Thus measure the plasma concentration of salicylate to detect any changes, elimination is further increased by urine alkalinisation which is achieved by administration 1. 26% sodium bicarbonate. Correct the metabolic acidosis by administration of 8. 4% sodium bicarbonate. Alkaline diuresis can be used to increase urine pH to 7- 8 this increases salicylate excretion but salicylate levels need to be determined first before, because hypokalemia may interfere with the diuresis.
The decision whether to start the treatment is done on the basis of clinical grounds and laboratory data thus the clinical chemistry laboratory can aid in yielding, the salicylate plasma concentration is measured against the normal references values if it exceeds 600mg/L in adult and more than 300mg/L in child more than 6 hours after the overdose then can suggest that alkalinisation be considered, thus plasma concentration is very important diagnostic tool in clinical chemistry laboratory and also an important indicator of the efficacy of the treatment regimen.
(Marshall and Bangert 2008). Management of Paracetamol is very much dependent on the time of ingestion, if patient is seen soon after ingestion liver damage could be avoided by administration of agents that increase glutathione formation in the liver such as acetylcysteine intravenously and methionine orally, also within one hour the patient can be given 50g of activated charcoal, however if major over dose is suspected N-Acetyl cysteine is administered.
The clinical chemistry laboratory plays a vital role in this regard, as already mentioned the management is dependent to the time of ingestion, if patient sample is presented the plasma paracetamol concentration is measured as soon as possible, after 4hours elapse compare the concentration with the time on a nomograph thus reliably predicts the risk of hepatoxocity, it also reflects the saturation of conjugative pathways of paracetamol metabolism.
Thus if the patient paracetamol concentration is above the normal treatment line then can determine if they are at risk of liver damage or require antidote treatment (N-Acetylcysteine). (Wallace et al. , 2002) d). Toxic dose is an amount of a drug which may be suspected to produce a toxic effect, toxic level is when a high amount of toxic drug accumulates in the blood stream or serum and thus reaches a toxic level as result the person experience severe side effects such as hyperventilation, ringing sensation in the ears this may occur at serum concentration of 300-400mg/kg (Kaplan et al., 1995). e).
In order to conclusively decide that the measured plasma paracetamol level is toxic, you need to take a detailed clinical history of the patient such as any medication they may be taking could in case it could cause cross reaction, since paracetamol has a very narrow therapeutic index, factors such as gender, age, weight and genetic predisposition could directly or indirectly affect the metabolic and excretion rate of the drug in a individual. f).
Patient A and B were diagnosed by taking their urine samples whereas patient C and D looking at serum concentration, examining both methods the most effective way to measure and manage overdose is by plasma level, it’s allows to specifically measure substance of interest whereas measuring urine is not so specific there are other substances that could be measured in the process. And also certain drugs are water soluble thus easily penetrate and reach the plasma membrane much quicker.
A with regards to managing overdose, there are body tissues and fluids excluding the liver which are efficient in metabolism such kidney, GI tract before the drug could reach the systemic circulation to cause metabolic consequences. g). Toxic dose of paracetamol is highly variable, in adults it’s considered greater than 150mg/kg, patient C had paracetamol plasma concentration of 200 mg/l indicates the patient has had overdose which if not treated quickly may cause hepatotoxicity.
Patient D had drug plasma concentration of 8. 06mg/l, the patient was not accurate with the amount of paracetamol taken as it’s very below the toxic level. Toxic dose of salicylate is considered to be more than 150 mg/kg patient A is claiming to have taken 60 aspirin tablets (18g) had total of 285. 89 mg of salicylate excreted in his urine which is over 150mg thus patient is expected to have a moderate over dose (150-300mg).
In patient B the dipstick test revealed very low aspirin but presence of ketone acetoacetic acid which indicates that patient has not had aspirin overdose but further investigations may need to be carried out to find out if the patient is suffering from diabetes, particularly type 1 which is common in children with ketone production among it’s features. References: Brody, T, M. , Larner, J. , Minneman, K, P. , Neu, H, C. (1994) Human Pharmacology Molecular to Clinical. , 2nd Edition, Mosby-year book. Kaplan, A., Rhona, J. , Kent, E. , Bert T. (1995).
Clinical chemistry interpretation technique 4th Edition. Marshall, J, W and Bangert,S,K. (2008). Clinical chemistry 6th edition. , Mosby London. Rang, H, P, Dale, M. , Ritter,J,M. , Flower,R,J. (2002) RAND and DALE Pharmacology, 5th Edition Churchill, Livingstone, Elsevier. Elsevier Limited. Wallace, C, I. , Dargan, P I. , Jones, A. (2002) Paracetamol overdose; an evidence based flowchart to guide management. , Emerg Med Journal (19):202-205 doi:10. 1136/emj. 19. 3. 202.