Case Study 4 Paracetamol

TABLE 22, Calculated Differences between Molecular Descriptors for 35 Experimentally Tested Coformers and Paracetamol 

Compound Decision to Proceed with Coformer AM/L Ratio AS AS/L Ratio ADipole Moment (Debye) AFNO 

A calculated difference in molecular descriptor which indicates a cocrystal is unlikely (falls outside of the allowed pass mark) is highlighted in bold and italics. 

NAVIGATING THE SOLID FORM LANDSCAPE WITH STRUCTURAL INFORMATICS 

TABLE 2.3 Multi-component HBP Screening Results Summary for Paracetamol with Potential Coformer Molecules Ranked in Order of Their MC Score 

---

J. M. Tredger et al, Metabolic basis for high paracetamol dosage without hepatic injury a case study , Human and Experimental Toxicology, 14 (1995), 8-12. 

Case studies in the literahire concerning acute paracetamol (acetaminophen) poisoning are no longer reported due to the high incidence of such poisonings seen in hospital accident and emergency departments and the routine treatment of such cases. Here is a report of a rarer chronic paracetamol (acetaminophen) poisoning. 

This procedure is illustrated by using the case studies of aspirin (nonpolymorphic system) and paracetamol (polymorphic system), both widely used as antipyretic (fever suppressant) and analgesic (painkiller) drugs. 

In a prospective, case-control study, designed to determine causes of INRs over 6.0 in an outpatient anticoagulant unit, there was a clear dose-dependent association between the use of paracetamol (acetaminophen) and having an INR greater than 6.0 (212). The authors studied 93 patients with INRs over 6.0 (cases) and 196 patients with INRs of 1.7-3.3 (controls) during warfarin therapy. The likelihood of an INR greater than 6.0 increased from an odds ratio of 3.5 for doses of 2275 549 mg per week, to 6.9 for doses of 4550-9099 mg per week, to a 10-fold increase at a dose of over 9100 mg per week. 

Paracetamol also potentiates the effects of acenocou-marol (211) and although a study with phenprocoumon showed no interaction (271), the study was too small and not well designed to detect an effect of the sort that has been shown in case-control studies. 

Despite the high prevalence of the use of minor analgesics (aspirin and paracetamol) there is little information available on the association between the use of these analgesics and the risk of hypertension. A prospective cohort study in 80 020 women aged 31-50 years has provided some useful information (5). The women had participated in the Nurses Health Study II and had no previous history of hypertension. The frequency of use of paracetamol, aspirin, and NSAIDs was collected by mailed questionnaires and cases of physician-diagnosed hypertension were identified by self-report. During 164 000 person-years of follow-up, 1650 incident cases of hypertension were identified. Overall, 73% of the cohort had used paracetamol at least 1-4 days/month, 51% had used aspirin, and 77% had used an NS AID. Compared with non-users of paracetamol the age-adjusted relative risk... 

An observational study, part of a population-based case-control study of dietary antioxidants and asthma, has shown an association between the regular use of paracetamol and the incidence of asthma and rhinitis in adults (10). After controlling for potential confounding factors the OR for asthma in daily users, compared with never users, was 2.38 (Cl = 1.22,4.64). Not unexpectedly, there was also an association in users and non-users of aspirin, strongest when cases with more severe disease were compared with controls. This adverse effect of paracetamol may be due to depletion of the antioxidant glutathione in the lungs. However, further studies are needed before paracetamol can be blamed for an increase in the prevalence and severity of asthma. 

In contrast to these results, another large case-control study (60) in 1732 patients with renal cell carcinoma and 2039 controls showed no increase in the risk of renal cell carcinoma among regular users of phenacetin, paracetamol, and aspirin. There is no clear explanation of these disparate findings. 

Paracetamol crosses the placenta readily. However, there has been no published evidence of a teratogenic effect in the offspring of mothers who have taken paracetamol during pregnancy. A case of fetal death after a maternal overdose of paracetamol (30 g) has been described (SEDA-10, 73), but in another similar case, in which 22.5 g was taken in the 36th week, the fetus survived (SEDA-9, 96). PreUminary data from a longitudinal study have shown no adverse effects of therapeutic doses of paracetamol on either pregnancy or infant development (69). 

However, in a case-control study of the risk factors for excessive warfarin anticoagulation the investigators studied 289 patients prospectively, 93 with an International Normalized Ratio (INR) over 6.0 and 196 with an INR of 1.7-3.3 during warfarin therapy (125). Paracetamol intake was independently associated with a high INR and the effect was dose-related. At a dosage of about 2-4 g/week the adjusted odds ratio (OR) for having an INR over 6 was 3.5 (95% Cl = 1.2, 10) compared with no intake of paracetamol. At an intake of 4-9 g/week the adjusted OR was 6.9 (95% Cl = 2.2, 22), and at an intake over 10 g/week the OR was 10 (95% Cl = 2.6, 38). 

The renal safety of aspirin used as single ingredient is easier to evaluate. From the seven case-control studies, only 3 showed an increased risk. All 3 suffered from the same ingredient bias as previously mentioned for paracetamol. In contrast however, both observational studies reported a robust, slightly decreased, odds ratio for the use of aspirin (Figure 1). In both studies, calculated odds ratio s were based on hundreds of regular users of aspirin [41, 42]. 

The intention in many chapters has been to enable the reader to refer to the original literature wherever possible. Mechanistic aspects have not been depicted except in the first chapter. It is thought and hoped that many of the chapters provide a fund of tutorial material and problems for undergraduate studies and further, that these will encourage perusal of the literature. Relevant to this there are almost 2,000 references to applied and academic papers. Phenols are ubiquitous substances and now it is more widely accepted that there are pros and cons concerned in their usage. The pros for compounds are well-known and are illustrated by perennial panaceas such as aspirin, paracetamol, codeine and many others. The cons are less obvious because they are also materials deeply involved in our standard of fiving and in most cases hazards involved have only recently come to light. 

Many case reports describe severe liver damage, sometimes fatal, in some alcoholics and persistent heavy drinkers who take only moderate doses of paracetamol. However, other controlled studies have found no association between alcoholism and paracetamol-induced hepatotoxicity. There is controversy about the use of paracetamol in alcoholics. Some consider standard therapeutic doses can be used, whereas others recommend the dose of paracetamol should be reduced, or paracetamol avoided. Occasional and light to moderate drinkers do not seem to be at any extra risk. One study found that chronic alcohol intake, bnt not acute alcohol intake, enhanced paracetamol hepatotoxicity following overdose. 

---