Der Abbau von Pentobarbital bei Lebersch�den

Held, H.; Oldershausen, H. F. v.; Remmer, H.

doi:10.1007/bf01488573

Cited by 18 publications

(3 citation statements)

References 12 publications

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“…Possible reasons for this difference include the following: 1, his subjects, shortly before biopsy, received a barbiturate, which may have been metabolized more slowly in the cirrhotic than in the control subjects (Held, von Olderschauen & Remmer, 1970) and therefore may have induced ALA synthase acutely to higher activity; 2, if the findings of Patton & Beattie (1973) are confirmed, the possibility will arise that mitochondria as isolated by Levere from livers were more permeable to citrate than those from control subjects, or the endogenous generation of succinyl-CoA from citrate was greater, leading to increased activity of the enzyme in uitro, perhaps without an equivalent increased amount of enzyme or activity in vivo. For reasons already given, the increased activities we observed cannot be.…”

Section: Discussionmentioning

confidence: 95%

Human Hepatic δ-Aminolaevulinate Synthase: Requirement of an Exogenous System for Succinyl-Coenzyme a Generation to Demonstrate Increased Activity in Cirrhotic and Anticonvulsant-Treated Subjects

Bonkowsky

Pomeroy

1977

Clinical Science

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1. We have studied activity of delta-aminolaevulinate synthase in needle liver biopsy specimens obtained from 12 human cirrhotic subjects, five subjects who had ingested anticonvulsants and from control subjects. Liver iron concentrations and quantitative urinary excretions of porphyrins plus their precursors were also determined. 2. In liver homogenates from subjects of each group, addition of an exogenous system for generation of succinyl-coenzyme A (CoA), including succinic thiokinase, resulted in appreciable enhancement of activity beyond that obtained without this system. 3. Mean activities for delta-aminolaevulinate synthease were not significantly different among patient groups when assayed without the exogenous succinyl-CoA-generating system, but liver homogenates from cirrhotic patients and subjects ingesting anticonvulsants had significantly higher activities than control subjects in the presence of the succinyl-CoA-generating system. 4. Although mean liver iron concentration in the cirrhotic group was slightly higher than in control subjects, and in control subjects there was some correlation between liver iron concentration and activity of delta-aminolaevulinate synthase, variations in this activity could not be accounted for solely on the basis of chronic hepatic deposition. Nor were these variations ascribable to differences among subjects in ingestion of ethanol before biopsy or severity of hepatic inflammation as judged biochemically and histologically. 5. Cirrhotic subjects excreted more uro- and copro-porphyrin than control subjects, whereas subjects ingesting anticonvulsants excreted more delta-aminolaevulinic acid and porphobilinogen than control subjects. However, these increases were small and not sufficient to account for all the increased delta-aminolaevulinic acid which potentially could have been formed by these subjects. 6. These considerations raise the possibilities that in vivo: (a) rate of human hepatic synthesis of delta-aminolaevulinic acid is modulated by the supply of succinyl-CoA; (b) the rate of hepatic synthesis of haem is increased in cirrhotic patients and subjects ingesting anticonvulsants; (c) other important routes exist for disposition of haem precursors in these subjects, besides utilization for haem synthesis.

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Section: Discussionmentioning

confidence: 95%

Human Hepatic δ-Aminolaevulinate Synthase: Requirement of an Exogenous System for Succinyl-Coenzyme a Generation to Demonstrate Increased Activity in Cirrhotic and Anticonvulsant-Treated Subjects

Bonkowsky

Pomeroy

1977

Clinical Science

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“…Held et al (71) calculated directly T 1 / 2 of pentobarbital after an intravenous infusion of 4 mg/kg in 14 volunteers and 12 female patients with parenchymal damage of the liver. The normal T 1 / 2 was 20 ± 6 h and only 2 of the liver patients with their T1/2 of 33 and 36 h were above the normal range.…”

Section: Drugs Acting On the Central Nervous Systemmentioning

confidence: 99%

Influence of liver disease on the elimination of drugs

Klotz

1976

European Journal of Drug Metabolism and Pharmacokinetics

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Av.ail~bl~literature contains some contradictory clinical evidence about the effect of liver disease on the metabolism a.nd elImmatIo~of~rugs. !n the ma!~rity of the cases, drugs are more slowly eliminated in patients with hepatic dysfunction, such as cirrhosis or viral hepatitis. However, there is no single biochemical liver test for the proper characterization of the functional s.tatus of the. liver. Since all drugs behave differently pharmacokinetically, no predictions can be made fr?~th~results with one particular drug for other drugs--each drug has to be investigated separately. Due to the slower elimination of. drugs observed in pa~ients with liver disease, caution should be applied in prescribing drugs with more ?ron?unced biological effects, especially those with a small therapeutic index. When calculating maintenance doses or infusion rates for a longer treatment, dosage reduction and a close drug monitoring seem to be advisable.

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“…In patients with liver cirrhosis, the half-life of pentobarbitone was substantially (50%) prolonged (Ossenberg 1977). In another group of cirrhotic patients, Held et al (1970) did not find such a large impairment of pentobarbitone elimination, but found a terminal half-life of 27.3 ± 6.76 hours.…”

Section: Pharmacokineticsmentioning

confidence: 84%

Clinical Pharmacokinetic Considerations in the Treatment of Increased Intracranial Pressure

Heinemeyer

1987

Clinical Pharmacokinetics

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Life-threatening increased intracranial pressure can be reversed by a variety of drugs. These compounds all have some disadvantages, producing rebound effects, severe coma or cardiovascular depression and electrolyte imbalance. However, reduction of intracranial pressure is a prerequisite for recovery and the benefits of treatment outweigh the risks. Dexamethasone is rapidly eliminated, the short half-life (about 3 hours) indicating that dosage intervals should be kept small. As yet, however, its therapeutic efficacy has not been clearly demonstrated. Therefore, an association between pharmacokinetics and pharmacodynamics cannot be established. Osmotic diuretics are the most widely used agents for reduction of intracranial pressure. Pharmacokinetics show a very close relationship to changes in serum osmolality, but there are large variations in the clearance. For the use of osmotics, the blood-brain barrier must be intact. Osmotic diuretics may lead to intracerebral oedema or to acute renal failure as serum osmolality increases. Considering the pharmacokinetics of each drug, and the dynamics of intracerebral pressure and osmolality, an intermittent, individually titrated dosage should be administered, with simultaneous monitoring of intracranial pressure. Frusemide (furosemide) can be used as an adjunct, to enhance the effect of osmotic diuretics. Its pharmacokinetics are limited by renal function, depending on age as well as on the extent of renal impairment. Altered renal elimination of concomitantly administered drugs, and electrolyte imbalances should be anticipated when diuretics are used. Barbiturates are certain to decrease intracranial pressure in humans by an as yet unknown mechanism. Their administration is recommended for patients that do not respond to conventional therapy. As barbiturates can result in deep coma, knowledge of their pharmacokinetics is of great importance for recovery. Following single doses, pentobarbitone has a relatively long elimination half-life (about 22 hours). However, after repeated administration for several days, its elimination may be enhanced due to autoinduction. Thiopentone kinetics are characterised by distribution and redistribution into deep peripheral compartments. Administration of high and frequent doses leads to considerably delayed recovery. This is not true for methohexitone, which shows comparable pharmacokinetics after single and multiple dose administration. Elimination depends on liver blood flow. Thus, recovery from methohexitone-coma is rapid. Rapid elimination is also an important characteristic of etomidate and alphaxalone/alphadolone, two non-barbiturate hypnotics.(ABSTRACT TRUNCATED AT 400 WORDS)

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Der Abbau von Pentobarbital bei Lebersch�den

Cited by 18 publications

References 12 publications

Human Hepatic δ-Aminolaevulinate Synthase: Requirement of an Exogenous System for Succinyl-Coenzyme a Generation to Demonstrate Increased Activity in Cirrhotic and Anticonvulsant-Treated Subjects

Human Hepatic δ-Aminolaevulinate Synthase: Requirement of an Exogenous System for Succinyl-Coenzyme a Generation to Demonstrate Increased Activity in Cirrhotic and Anticonvulsant-Treated Subjects

Influence of liver disease on the elimination of drugs

Clinical Pharmacokinetic Considerations in the Treatment of Increased Intracranial Pressure

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