Charles F. George

Prescription information leaflets: a national survey.

Three thousand four hundred and ten patients recruited at 254 pharmacies took part in a national postal survey of the effect of prescription information leaflets. The patients had been prescribed penicillins, non-steroidal anti-inflammatory drugs (NSAIDs) or β-adrenoceptor antagonists. The 1809 patients who received leaflets knew more about their medicines, especially the side effects and were significantly more satisfied than the 1601 patients who were not given additional written information. The leaflets were found to be effective when issued in the north, in the south and in small, medium and large towns. Patients of both sexes, all age groups and social classes were found to benefit from the leaflets and almost everyone (97%) thought they were a good idea. These results confirm and extend our previous findings and add further support for the routine use of information leaflets with prescribed medicines.

Drug Metabolism by the Gastrointestinal Mucosa

Circumstantial evidence for first-pass metabolism across the gastrointestinal mucosa includes reduced bioavailability after oral administration, despite complete or good absorption. There may also be route-dependent variation in the pattern of metabolism with the latter occurring to a greater extent after oral administration than after parenteral injection. However, direct proof that first-pass metabolism takes place across the gastrointestinal mucosa relies upon cannulation of either the portal or mesenteric venous tree. Such studies are not possible in most patients because of the potential hazards involved and the attendant ethical considerations. Additional information has come from the study of enzyme activity in biopsies of intestinal mucosa and experiments performed on isolated loops of intestine in various animal species. Although the former have identified the fact that enzyme activity may vary along the length of the intestine and the latter have provided quantitative information on what can occur in vivo, these data cannot be extrapolated to intact man.Both phase I (preconjugation) and phase II (conjugation) reactions have been described. However, except for oxidative deamination, e.g. tyramine and hydrolysis of esters such as pivampicillin and aspirin, phase I reactions appear to be quantitatively unimportant. In contrast, synthetic reactions are much more active. Sulphate conjugation, in particular, is important for the β-adrenoceptor stimulants isoprenaline (isoproterenol), isoetharine and rimiterol, as well as for steroid hormones. Glucuronidation has also been demonstrated to occur in man for a small number of drugs. N-Acetylation is an important pathway and, as in the liver, there is evidence of polymorphism. Metabolism of hydralazine, isoniazid, p-aminosalicylic acid as well as certain sulphonamides by intestinal N-acetyl transferase has been demonstrated, but in all probability affects other drugs as well.Little is known concerning the physiological factors which alter the activity of the gastrointestinal drug-metabolising enzymes. However, significant drug-drug interactions have been demonstrated to occur at this site — particularly for drugs which undergo sulphate conjugation.

Drug Kinetics and Hepatic Blood Flow

SummaryIn adult man, liver blood flow amounts to roughly 100ml min−1 for every 100g of liver (range 1.1 to 1.8 litres min−1) of which 70 to 75% is supplied via the portal vein.For certain drugs, when given intravenously, the liver represents the sole site of metabolic transformation and less than 10 % is eliminated unchanged by other routes. For these chemicals, the amount removed from the body in unit time depends on their rate of presentation to the healthy liver: thus, clearance depends on and approximates to hepatic blood flow. Such agents undergo extensive extraction at each circulation through the liver, the magnitude of this being determined largely by the activity of drug metabolising enzymes located therein. When such drugs are administered orally, there is extensive presystemic elimination which limits their bioavailability even though they are almost completely absorbed. Drugs which exhibit this type of pharmacokinetic pattern, include the antiarrhythmic agents lignocaine (lidocaine), lorcainide and Verapamil; also lipid-soluble β-adrenoceptor antagonists including alprenolol, labetalol, metoprolol, Oxprenolol and Propranolol. The opiate analgesics, morphine, pentazocine, pethidine (meperidine) and propoxyphene, as well as the antagonist, naloxone, show a similar pharmacokinetic pattern. Other examples include the CNS active compounds, imipramine, nortriptyline, chlormethiazole and methohexitone. Because the liver is their almost exclusive site of metabolic clearance it is possible to use one or more of these drugs to estimate hepatic blood flow in intact man.Hepatic blood flow and hence systemic clearance of such drugs is influenced by posture, exercise and perhaps by food. Hepatic blood flow decreases in old age and results in a prolongation in the half-lives of intravenously administered Propranolol, lignocaine and chlormethiazole. In addition, there is evidence of diminished microsomal enzyme activity in the elderly, especially in the presence of inducers of microsomal enzyme activity, leading to an increased bioavailability of these drugs after oral administration.Thyrotoxicosis is associated with an increased clearance of such drugs and a reduction in their steady-stale plasma concentrations, whereas oppposite effects are seen in myxoedema. Similarly, heart failure leads to a reduction in their rates of elimination, either because of a diminished cardiac output or through an alteration in the distribution volume. Effects of hepatic disease are complex and vary according to the type and chronicity of liver pathology, the presence of hepatic failure and concurrent drug therapy. In general, acute viral hepatitis produces little change in drug pharmacokinetics whereas chronic liver disease (particularly cirrhosis) leads to a prolongation of their half-lives and diminished systemic clearances. The changes are most prominent after oral administration of such drugs and are manifest as an increased bioavailability.Concurrent drug therapy can affect the pharmacokinetics of drugs like Propranolol either by altering hepatic blood flow — catecholamines and glucagon for example — or by changing the extraction ratio through an effect on enzyme activity in the liver.

The influences of dose and ethnic origins on the pharmacokinetics of nifedipine

The pharmacokinetics of nifedipine capsules was investigated in healthy young Caucasian and South Asian subjects. Both the area under the plasma concentration–time curve (AUC) and terminal half‐life of nifedipine were significantly higher in South Asians compared with Caucasian subjects after single oral doses of 10 and 20 mg. The AUC and half‐life values of the nitropyridine metabolite were also higher in South Asians than in Caucasian subjects. The serum protein binding of nifedipine was similar in the two groups. The pharmacokinetics were essentially linear in both Caucasian subjects (0 to 30 mg; n= 27) and South Asians (0 to 20 mg; n= 16). There was no indication of a separate subgroup of Caucasian subjects with high AUC values equivalent to the poor metabolizers reported previously. Pharmacodynamic modeling for South Asians gave estimates comparable to those previously reported in Caucasian subjects. Patients of South Asian origin may require lower doses of nifedipine.

Sulindac metabolism: The importance of an intact colon

The pharmacokinetics of sulindac have been studied after a single 200 mg oral dose in six normal subjects and five patients with surgical ileostomies. The plasma concentration‐time curves for sulindac were similar in both groups up to 12 hours after dosing, indicating similar absorption of the drug. Higher plasma concentrations of sulindac were found in normal subjects after 12 hours, but this late phase accounted for only 12% of the total AUC in the subjects. The sulfone metabolite showed a similar pattern, with no statistically significant difference in the total AUC, but in patients with ileostomy there was a halving of the AUC after 12 hours. Plasma concentrations of the active sulfide metabolite were similar in both groups up to 12 hours, but negligible concentrations were detected in the plasma of patients with ileostomy after 12 hours. Thus the AUC after 12 hours, which represented 55% of the total AUC in normal subjects, was reduced to only 7% in patients with ileostomy. The rate of reduction of sulindac in vitro by ileostomy effluent was only one hundredth that by normal feces. Our results suggest that the gut microflora are an important site of reduction of sulindac in man. Comparison of AUC values suggests that about half the total sulfide is formed by the gut bacteria, probably from sulindac excreted in the bile.

The role of the gut flora in the reduction of sulphinpyrazone in the rat

Sulphinpyrazone underwent both reduction to a sulphide and oxidation to a sulphone after parenteral administration to normal Wistar rats. Oral administration was associated with a bioavailability of about 75% and with a 3-fold greater formation of the sulphide. However, no sulphide was detected in the plasma after oral administration of sulphinpyrazone to germ-free (BD/X) rats or normal rats treated with oral antibiotics. In vitro studies showed that the major site of reduction of sulphinpyrazone was the contents of the hind gut with little activity detected in the liver or other tissues. The sulphide was oxidised in vivo to sulphinpyrazone and small amounts of sulphone, while the latter underwent only slight reduction to sulphinpyrazone, but did not give detectable levels of the sulphide. These data suggest that the gut microflora are the main site of reduction of sulphinpyrazone in the rat in vivo.

The effect of monoamine oxidase inhibitors on 'first-pass' metabolism of tyramine in dog intestine.

Abstract The role of the intestine in metabolic inactivation of tyramine (TYR) has been studied in an isolated intestinal loop preparation in anaesthetized dogs. In control animals there was extensive metabolism of tyramine on passage through the intestinal wall and p-hydroxyphenylacetic acid (p-OHPA) was the only metabolite found in venous plasma from the loop (mean ratio p-OHPA/TYR = 5). Oral or intravenous pretreatment with the monoamine oxidase (MAO) inhibitors tranylcypromine or MD780515 significantly lowered the ratio of p-OHPA/TYR (range = 0.2–1.1) measured 3hr after the last dose. Twenty-four hours after the last dose of MAO inhibitor p-OHPA/TYR ratios in dogs pretreated orally with MD780515 had returned to control levels while ratios in dogs pretreated orally with tranylcypromine remained low (mean = 1.6). In vitro rates of deamination of the substrates 5-hydroxytryptamine (selective for the A form of MAO) and β-phenylethylamine (selective for the B form of MAO) in homogenates of intestine paralleled the in vivo findings in most cases. Tranylcypromine produced a nonselective irreversible inhibition of both MAO-A and MAO-B whereas MD780515 was found to be a selective inhibitor of MAO-A and also appeared to be reversible.

The reduction of sulphinpyrazone and sulindac by intestinal bacteria

1. Incubation of human or rabbit faeces with sulphinpyrazone gave greater reduction under anaerobic than under aerobic conditions. Reduction of sulindac by human faeces was more extensive than that of sulphinpyrazone. 2. Growth of mixed cultures of intestinal bacteria in nutrient media containing antibiotics produced a marked inhibition in their ability to reduce sulphinpyrazone. Sulphide formation was inhibited by metronidazole and lincomycin for human faeces and by tetracycline for rabbit faeces/caecal contents. 3. The formation of the sulphides of sulindac and sulphinpyrazone ex vivo was decreased in faeces from patients treated with metronidazole. Metronidazole, but not tetracycline, decreased the extent of reduction of sulphinpyrazone by rabbits in vivo. No reduction of either substrate occurred on incubation with ileostomy effluent. These data indicate that anaerobic intestinal bacteria are important in the reduction of these sulphoxide-containing drugs. 4. However, when incubated anaerobically with over 200 strains of bacteria isolated from human faeces, sulphinpyrazone was reduced by most of the aerobic but not the anaerobic organisms. Sulindac was reduced more extensively by the same aerobes and by some anaerobes. 5. The discrepancy between the apparent importance of anaerobes in vivo and in vitro may be due to their very large number present in the hind gut and to the production of an anaerobic environment suitable for the enzymic activity of other organisms, such as aerobes or facultative anaerobes.

Elimination of drugs by active intestinal transport

the frog spinal cord is in agreement with the earlier of Davidoff & Sears (1974) who suggested that this compound has a selective blocking action at central excitatory synapses. Later results (Potashner 1978; Ault & Evans 1978) suggest that the depressant action is confined to terminals which release excitatory amino acids. The present finding that transmission in the vas deferens is resistant to baclofen further emphasizes the selective action of this drug. It does not support the involvement of a 8-phenethylamine receptor in this action (Curtis et al 1974) since 8-phenethylamine, a sympathomimetic amine which acts indirectly by stimulating a-adrenoceptors in the mouse vas, would be expected to depress transmission in the vas deferens (Ambache et al 1972). This work was supported by the Medical Research Council. Metenkephalin was provided by Wellcome Research Laboratories, Beckenham and baclofen was provided by CIBA-Geigy, Basle. May 18, 1979 R E F E R E N C E S

Clinical Consequences of Abrupt Drug Withdrawal

SummarySyndromes due to the abrupt withdrawal of drug treatment occur mainly with adrenal corticosteroids and agents with an action on either the cardiovascular system or central nervous system.The abrupt withdrawal of antihypertensive therapy typically results in symptoms of overactivity in the sympathetic nervous system. Clonidine and β-adrenoceptor antagonists are clinically the most important of these agents, but numerous other drugs have been implicated. Overall, the problem is small when viewed in the context of the huge scale of prescribing of antihypertensive medicines. A more serious problem is the occurrence of crescendo angina following the abrupt withdrawal of β-adrenoceptor antagonists. Although other factors may be involved, adaptive up-regulation of β-adrenoceptor density is the most likely cause of crescendo angina, and renders the patient more susceptible to sympathetic nervous stimulation following withdrawal of treatment.Besides leading to a recrudescence of the disease being treated, the withdrawal of corticosteroids can cause a variety of syndromes. In particular, problems can arise as a result of treatment-induced suppression of the hypothalamic-pituitary-adrenal (HPA) axis. Another steroid withdrawal syndrome of unknown aetiology, without significant abnormalities of the HPA axis occurring, has been described. Benign intracranial hypertension may rarely follow steroid withdrawal in children.The syndromes associated with withdrawal of drugs which have an action on the CNS are poorly understood. Withdrawal of neuroleptic drugs can be followed by symptoms that resemble those described following withdrawal of anticholinergic drugs, and those agents with the greatest muscarinic-receptor-blocking properties are those which are most frequently implicated. However, the less common withdrawal dyskinesias are thought to reflect up-regulation of dopaminergic receptors during long term treatment. Gastrointestinal symptoms predominate following the abrupt withdrawal of antidepressants but hypomania and an ‘akathisia-like’ syndrome have been reported. Barbiturates are no longer recommended as hypnotics because of severe effects of withdrawal and the existence of safer alternatives. Short acting barbiturates can be withdrawn by replacement with either phenobarbitone (phenobarbitol) or diazepam and subsequent gradual reduction in dose.The recognition of dependency on benzodiazepines has been slow because of the similarity of mild withdrawal symptoms to the original problem which led to treatment being offered. Thus, long term benzodiazepine usage is common despite little evidence to support their long term efficacy in the treatment of mild affective disorders or insomnia. A reevaluation of their place in therapeutics is required. Substitution of long acting compounds is helpful prior to withdrawal. Sudden withdrawal of either benzodiazepines or barbiturates can also precipitate epilepsy in susceptible patients.The problems of opioid withdrawal are well recognised. Various mechanisms are thought to be involved including up-regulation of adrenoceptors and functional deficiencies of endogenous opioid release. Traditionally, withdrawal has been managed by substitution with methadone.