Morphine Paracetamol

Apomorphine, dodecyl gallate, gallic acid, morphine, paracetamol, parachloro-phenol, phenol, tannic acid... 

Electrochemical detectors can be used in the oxidative mode for a wide range of drugs, including cannabinoids, haloperidol, morphine, paracetamol, phenothiazines, salicylic acid, and tricyclic antidepressants. Operation in the reductive mode is more difficult as dissolved oxygen must be removed from the eluent (K. Bratin et al, J. liq. Chromat., 1981,, 1777-1795). Reductive applications include chloramphenicol and benzodiazepines. 

Drugs must also be considered as foreign compounds, and an essential part of drug treatment is to understand how they are removed from the body after their work is completed. Glucuronide formation is the most important of so-called phase II metabolism reactions. Aspirin, paracetamol, morphine, and chloramphenicol are examples of drugs excreted as glucuronides. 

Other drugs are metabolised by Phase II synthetic reactions, catalysed typically by non-microsomal enzymes. Processes include acetylation, sulphation, glycine conjugation and methylation. Phase II reactions may be affected less frequently by ageing. Thus according to some studies, the elimination of isoniazid, rifampicin (rifampin), paracetamol (acetaminophen), valproic acid, salicylate, indomethacin, lorazepam, oxazepam, and temazepam is not altered with age. However, other studies have demonstrated a reduction in metabolism of lorazepam, paracetamol (acetaminophen), ketoprofen, naproxen, morphine, free valproic acid, and salicylate, indicating that the effect of age on conjugation reactions is variable. 

Opioids such as diamorphine, pethidine, and pentazocine strongly inhibit gastric emptying and greatly reduce the absorption rate of paracetamol. Codeine, however, has no significant effect on paracetamol absorption. Morphine and diamorphine have been shown to reduce the absorption of antiarrhyth-mics such as mexiletine in patients with myocardial infarction. 

In the drug discovery stage, suitable sources are explored. Sources of drug molecules can be natural, e.g. narcotic analgesic, morphine, from Papaver somnifemm (Poppy plant), synthetic, e.g. a popular analgesic and antipyretic, paracetamol, or semi-synthetic, e.g. semi-synthetic penicillins. 

Codeine, one of the principal alkaloids of opium, has an analgesic efficacy much lower than other opioids, due to an extremely low affinity for opioid receptors. It is approximately one-sixth as potent as morphine. It has a low abuse potential. In contrast to other opioids, with the exception of oxycodone, codeine is relatively more effective when administered orally than parenterally. This is due to methylation at the C3 site on the phenyl ring (Figure 7.3), which may protect it from conjugating enzymes. It is used in the management of mild-to-moderate pain, often in combination with non-opioid analgesics, such as aspirin or paracetamol. It is valuable as an antitussive and for the treatment of diarrhoea. Side effects are uncommon and respiratory depression, even with large doses, is seldom a problem. 

Fetal microcephaly has been attributed to cocaine abuse during pregnancy (323). Urine toxicology confirmed the presence of morphine, benzoylecgonine, barbiturates, paracetamol, and propoxyphene. Analyses of amniotic fluid, placenta, and fetal serum and urine were also positive for these substances. The authors suggested that vascular disruption was the likely major mechanism of anomalies, both behavioral and malformative, due to prolonged exposure to cocaine in utero. 

This chapter concentrates on some drug choices in acute rather than chronic pain, but the same principles can be used to determine the appropriateness of other types of analgesic. The drugs considered in this section are paracetamol, non-steroidal anti-inflammatories (NSAIDs specifically diclofenac, ibuprofen, indometacin, naproxen, sulindac and tenoxicam) and opioids (codeine, dihydrocodeine, morphine, pethidine and tramadol). Unless otherwise stated, all pharmacokinetic data originate from standard reference sources [1-5] and apply to adults only. 

Glutethimide Ethchlorvynol Paracetamol Clom ramine Nitrazepam Morphine... 

Amitriptjdine, aniylobarbitone, butobaibdtone, diazepam, imipramine, morphine, orphenadrine, paracetamol, p entobarb-itone, quinalbarbitone, saUcjlates... 

Large numbers of these are offered particularly to bridge the efficacy gap between paracetamol and morphine. Doctors should consider the formulae of these preparations before using them. Caffeine has been shown to enhance the analgesic effect of aspirin and of paracetamol and to accelerate the onset of effect, but at least 30 mg and probably 60 mg are needed (a cup of coffee averages about 80 mg and of tea averages about 30 mg). 

Analgesia is indicated if the patient is in pain preoperatively or it can be given pre-emptively to prevent postoperative pain. Severe preoperative pain is treated with a parenteral opioid such as morphine. Nonsteroidal anti-inflammatory drugs and paracetamol are commonly given orally preoperatively to prevent postoperative pain after minor surgery. For moderate or major surgery, these drugs are supplemented with an opioid towards the end of the procedure. 

Relief of pain after surgery can be achieved with a variety of techniques. An epidural infusion of a mixture of local anaesthetic and opioid provides excellent pain relief after major surgery such as laparotomy. Parenteral morphine, given intermittently by a nurse or by a patient-controlled system, will also relieve moderate or severe pain but has the attendant risk of nausea, vomiting, sedation and respiratory depression. The addition of regular paracetamol and a NSAID, given orally or rectally, will provide additional pain relief and reduce the requirement for morphine. NSAIDs are contraindicated if there is a history of gastrointestinal ulceration of if renal blood flow is compromised. 

A number of common drugs contain the phenol functional group. These include paracetamol (pFCa 9.5), morphine (pKa 9.9) and levothyroxine (thyroxine) (pKa 10). Since these phenolic drugs are 50% ionised when the pH equals their pKa, it follows from the rule of thumb introduced in Chapter 1 that they will only ionise to approximately 1% at the pH of blood (7.4). See Figure 3.6. 

Drugs containing phenolic groups include the analgesics morphine (and related opiates) and paracetamol as well as the bronchodilator salbutamol, widely used in the treatment of acute asthma. See Figure 8.9. 

Several phase II enzymes may also be expressed as a function of age. Studies of paracetamol (acetaminophen) suggest that sulfation is the major metabolic pathway during the neonatal period and early infancy, changing to glucuronidation over several months (Miller et ai, 1976). The increase in morphine clearance due to glucuronidation is related to postconceptional age (Scott et ai, 1999). 

Diamorphine, morphine, oxycodone, pentazocine and pethidine delay gastric emptying so that the rate of absorption of paracetamol given orally is reduced. There is no pharmacokinetic interaction between codeine and paracetamol, but the combination may not always result in increased analgesia. 

A study in healthy subjects, who remained in the supine position, investigated the effect of morphine syrup (4 doses of 10 mg given every 4 hours) on the absorption of paracetamol. The time to the maximum plasma paracetamol level, for conventional tablets, was increased from 51 minutes to 160 minutes by morphine, whereas the time to the maximum plasma paracetamol level for dispersible tablets was only increased from 14 to 15 minutes. ... 

Kennedy JM, TyersNM, Davey AK. The influence of morphine on the absorption of paracetamol from various formulations in subjects indie supine position, as assessed by TDx measurement of salivary paracetamol concentrations. JPharmPharmacol(200y) 55,1345-50. 

Asthmatic attacks due to non-narcotic analgesics, mostly occur in patients with so-called intrinsic or idiosyncratic asthma (often associated with nasal polyposis, sinusitis and eosinophilia of the blood) (McFadden and Austen 1977). About 10% of patients with this kind of asthma show severe reactions to aspirin, methyl-salicylate, pyrazolone derivatives, indomethacin, ibuprofen, diclofenac and sometimes even phenacetin and paracetamol. (Sodium salicylate is often tolerated.) The special reactivity may appear only in later life and concerns a number of chemically unrelated drugs. In some of these patients analgesic therapy with a morphine derivative such as pentazocine (Fortalgesic) or hyoscine butylbromide (Buscopan) may be necessary. However, in other patients, those with aspirin urticaria rather than asthma, the reaction may also rely on a drug-specific allergic mechanism (de Weck 1971). 

---