Klaus Mörike

Mechanisms and assessment of statin-related muscular adverse effects.

Statin‐associated muscular adverse effects cover a wide range of symptoms, including asymptomatic increase of creatine kinase serum activity and life‐threatening rhabdomyolysis. Different underlying pathomechanisms have been proposed. However, a unifying concept of the pathogenesis of statin‐related muscular adverse effects has not emerged so far. In this review, we attempt to categorize these mechanisms along three levels. Firstly, among pharmacokinetic factors, it has been shown for some statins that inhibition of cytochrome P450‐mediated hepatic biotransformation and hepatic uptake by transporter proteins contribute to an increase of systemic statin concentrations. Secondly, at the myocyte membrane level, cell membrane uptake transporters affect intracellular statin concentrations. Thirdly, at the intracellular level, inhibition of the 3‐hydroxy‐3‐methylglutaryl coenzyme A (HMG‐CoA) reductase results in decreased intracellular concentrations of downstream metabolites (e.g. selenoproteins, ubiquinone, cholesterol) and alteration of gene expression (e.g. ryanodine receptor 3, glycine amidinotransferase). We also review current recommendations for prescribers.

Secondary adrenal failure and secondary amenorrhoea following hydromorphone treatment

© 2007 The Authors Journal compilation

Ein bindegewebiges Halfter um das Matrixepithel des Nagels und der Krallen

ZusammenfassungUm das proximale Matrixende von Nägeln und Krallen legt sich ein sehr starker, querverlaufender Bindegewebszug halfterartig herum; Feliden besitzen dort sogar knöcherne Scheiden. Das Halfter strahlt seitlich in den Knochen nahe dem Fingergelenkende ein und ist auch weiter proximal an ihm befestigt. Zur Fixierung dienen die bei der menschlichen Endphalanx bekannten konsolenartigen Verbreiterungen an den Seiten und die wulstartige obere Verdickung vor dem Gelenk. An Klauen finden sich keine derartigen Halfter. Durch Messungen konnte nachgewiesen werden, daß sich die Nagelsubstanz hinsichtlich ihrer Quer-und Längsausdehnung nicht mehr ändert, nachdem sie einmal in der Matrix gebildet wurde und nach vorne geschoben wird. Das Halfter genügt offenbar, um dem Nagel seine charakteristische Form zu geben und das Nachvornewachsen zu veranlassen. Eine Haltefunktion des Halfters gegen Abhebelungen des Nagels ist wegen seiner dafür ungünstigen Lage abzulehnen.

Clinical practice guideline: Chronic heart failure

BACKGROUND Chronic heart failure (CHF) is the most common reason for hospital admissions in Germany. For the National Disease Management Guideline (NDMG) on CHF, a multidisciplinary expert panel revised the chapters on drug therapy, invasive therapy, and care coordination, following the methods of evidence-based medicine. METHODS Recommendations are based on international guideline adaptations or systematic literature search. They were developed by a multidisciplinary expert panel, approved in a formal consensus procedure, and tested in open consultation, as specified by the requirements for S3 guidelines. RESULTS The pharmacological treatment is based on ACE inhibitors, beta-blockers and mineralocorticoid receptor antagonists as well as diuretics to treat fluid retention, if present. Sacubitril/Valsartan and ivabradine showed positive effects on mortality in large but methodologically limited RCT. They are recommended if established combination therapy is not sufficient for symptom control, or if drugs are not tolerated/contraindicated. The indications for pacemakers or defibrillators have been confined to patient subgroups in which clinical trials have shown a clear benefit. Moreover, the goals of treatment and the patients expectations should be aligned with each other. Structured care programs, specialized nurses, remote, or telephone monitoring showed moderate effects on patient related outcomes in RCT. CONCLUSION All patients with heart failure are suggested to be enrolled in a structured program (e.g., a disease management program) including coordinated multidisciplinary care and continuous educational interventions. In patients with a poor prognosis, more intensive care is recommended, e.g. specialized nurses, or telephone support.

Problems in anticoagulation of a patient with antibiotic treatment for endocarditis: interaction of rifampicin and vitamin K antagonists

The cytochrome P450 is a superfamily of isoenzymes that are responsible for the metabolism of many drugs. Significant changes in pharmacokinetics and drug interactions may be due to induction of hepatic cytochrome P450 enzymes. Rifampicin is a common inducer of CYP3A4. We report a case of a 57-year-old woman who was suspected for endocarditis and therefore treated with rifampicin. Due to previous mechanical aortic valve replacement, she also received phenprocoumon for anticoagulation. Although continuing anticoagulant therapy, antibiotic coadministration led to normal international normalised ratio (INR) level. Fifteen days after the treatment with rifampicin ended, INR returned to therapeutic level.

Drug Use, Dosing, and Toxicity in Renal Disease

Numerous pharmacologic compendia exist to guide most medical treatments even in children with renal diseases. However, some basic principles of pharmacology may be needed to achieve optimal dosing of therapeutic agents in our patients. Drugs may affect kidney function, and kidney function may have a major impact on pharmacokinetics, and subsequently effects, of drugs with a predominantly renal elimination. Interindividual differences regarding pharmacokinetics and pharmacodynamics which depend on age (developmental pharmacology), gut motility, disease (acute or chronic), drug interactions and also pharmacogenetics of metabolizing enzymes and drug transporters have to be taken into account. On the other hand, drug-induced kidney failure in otherwise ill or even healthy children occur frequently in all age groups. The identification of drugs that cause nephrotoxicity in preterm infants or children who are seriously ill is a challenge.

Severe gastrointestinal haemorrhage after methimazole intake

A 65-year-old patient was admitted to the emergency room (ER) for palpitations. Besides, the patient reported on weight loss of 21 kg (20% of body weight), easy fatigability, hyperhidrosis, trembling and agitation in the past 3 months. Medical history was uneventful, without prior liver, haematological or malabsorption diseases. Exposure to contrast media or iodine-containing remedies and frequent intake of alcohol and drugs, including over-thecounter medications, aspirin or other salicylates, were credibly denied. ECG showed atrial flutter with 2:1 atrioventricular conduction at a rate of 153 bpm. Laboratory tests revealed thyrotoxicosis with increased free triiodothyronine [fT3; 20Æ9 pm (normal: 3Æ5–6Æ5)] and thyroxine [fT4; 48 pm (12–23)] levels and reduced thyroid-stimulating hormone [TSH; 0Æ01 mU/l (0Æ4–2Æ5)] levels. Positive antithyroperoxidase [2497Æ2 kU/l (<60)], antithyroglobulin [368Æ1 kU/l (<60)] and anti-TSH-receptor [7Æ5 IU/l (<1Æ5)] antibodies and markedly elevated perfusion of the normal-sized, hypoechogenic, inhomogeneous thyroid gland on colour Doppler ultrasound were consistent with the diagnosis of Graves’ disease. In the light of clinical course, it is worth mentioning that international normalized ratio (INR; 1Æ2), partial thromboplastin time [PTT; 30 s (<40)], aspartate amino transferase [37 U/l (<50)] and alanine amino transferase [39 U/l (<50)] were normal, whereas total protein was slightly diminished [6Æ3 g/dl (6Æ5–8Æ5)]. Haemoglobin [11Æ8 g/dl (14Æ0–18Æ0)], mean corpuscular volume [72Æ8 fl (80– 93)], mean corpuscular haemoglobin [22 pg (27Æ0–34Æ0)], iron [37 lg/dl (70–160)] and ferritin [1Æ1 lg/dl (3Æ0–30Æ0)] were reduced, indicating iron-deficiency anaemia. Treatment with 40 mg methimazole TID, 80 mg propranolol three times a day and 80 mg enoxaparine twice a day was initiated. Atrial flutter spontaneously converted to atrial fibrillation and, subsequently, to normal sinus rhythm. Given that the patient’s clinical condition as well as fT3 (12Æ2 pm) and fT4 (35 pm) levels significantly improved, he was discharged on day 7. Medication on discharge comprised methimazole 40 mg BID, propranolol 40 mg TID and enoxaparine 80 mg BID. The patient was scheduled for gastroscopy and colonoscopy for work-up of anaemia after normalization of thyroid function. Ten weeks after initial presentation, the patient was readmitted to the ER for fatigue, tachycardia and melaena. Laboratory test results revealed marked anaemia (haemoglobin 6Æ4 g/dl) and increased INR (>8Æ0) and PTT (122 s) levels. The vitamin K-dependent clotting factors II [prothrombin; 37% (70–130)], VII [7% (70–130)], IX [34% (70–140)] and X [24% (70–140)] were diminished. Plasma coagulation factor activities were measured by clotting assays using Thromborel S (factors II, VII, and X) or Pathromtin SL (factor IX) and the corresponding deficiency plasma at the BCS XP System (Siemens Healthcare Diagnostics Products, Marburg, Germany). Coefficients of variation ranged from 2% to 14% for these factors. The family history was negative for bleeding disorders, and the involved haematologist could not identify other reasons for the haemorrhagic diathesis. fT4 levels were nearly normalized (24 pm) under methimazole. Antithyroid treatment was discontinued, and substitution with erythrocyte concentrates, fresh frozen plasma and vitamin K was initiated. On upper gastrointestinal endoscopy, a source of the haemorrhage could not be localized so that a diffuse bleeding diathesis was assessed. INR normalized and the patient recovered without any sequelae. The patient underwent emergency thyroidectomy without complications. On enquiry, the patient reported that 3 weeks after initial presentation, INR had already been markedly increased (>8Æ0), prompting his general practitioner to discontinue enoxaparine and methimazole. After INR normalization, methimazole 40 mg BID, but not enoxaparine, had been restarted after a 5Æ5week medication-free interval. The patient got readmitted 10 days after re-exposure to methimazole. A score of 9 out of a possible 13 on the ‘Naranjo Adverse Drug Reaction Probability Scale’ indicated a definitive relationship between methimazole and depletion of vitamin K-dependent coagulation factors. Although rare, vitamin K antagonistic effects of the thioamide class of antithyroid drugs have been described previously. The underlying mechanism may be similar to the mechanisms of hypoprothrombinemia associated with cephalosporins containing the methyltetrazole-thiol leaving group. In vitro, methimazole was found to inhibit the vitamin K-dependent step in coagulation factor synthesis, the gamma-carboxylation of glutamic acid, and, in addition, the vitamin K epoxide reductase, an enzyme related to the carboxylation reaction. In line with this, administration of methimazole twice at a dose of 500 mg/kg to rats caused hypoprothrombinemia. Despite the plausible link between methimazole and hypoprothrombinemia, in clinical practice, the interplay between antithyroid drugs and vitamin K metabolism appears to be more complex given that even opposite effects have been reported. In a recent case report, INR levels did not raise under warfarin therapy whilst the patient remained on methimazole treatment and therapeutic INR levels could only be achieved after switching methimazole to lithium. One potential underlying mechanism, which could explain the controversial results, may be that sensitivity towards vitamin K antagonists depends on thyroid function. Thyroid hormone concentrations influence the metabolic rates of proteins and, thus, can alter the amount of vitamin K-dependent clotting factors. Clinicians should be alert to coagulation derangement as a potential adverse effect of thioamide antithyroid drugs, comprising methimazole and propylthiouracil, in addition to their well-known serious adverse events, such as liver damage and agranulocytosis. It is currently unclear why few users of thioamide antithyroid drugs Statement of Interest: none. Clinical Endocrinology (2011) 74, 657–660

Grundlagen der Arzneimitteltherapie und pharmakokinetische Grundbegriffe

Zum ThemaDie Kenntnis, wie ein Arzneistoff auf den Organismus einwirkt (Pharmakodynamik) und wie der Organismus auf das Arzneimittel einwirkt (Pharmakokinetik), stellt die Basis für eine individualisierte Therapie dar. Eine individualisierte Therapie ist deswegen für die Wirksamkeit und Sicherheit so wichtig, weil sowohl in der Dosis-Konzentrations-Beziehung als auch in der Konzentrations-Wirkungs-Beziehung beträchtliche Unterschiede von Patient zu Patient bestehen können. Denn die Praxis zeigt, dass die unterschiedlichen Dosis-Wirkungs-Beziehungen ein wichtiges Problem – wohl das wichtigste überhaupt – in der Arzneimitteltherapie darstellen, weil sie sich unmittelbar auf die Wirksamkeit (Risiko der Unterdosierung) und Sicherheit (Risiko der Überdosierung) auswirken.Besonders ausgeprägte interindividuelle Unterschiede werden vor allem in der Konzentrations-Beziehung beobachtet. Daraus resultiert die therapeutische Relevanz der Pharmakokinetik. Ziel der vorliegenden Übersicht ist, die einzelnen pharmakokinetischen Prozesse unter diesem Gesichtspunkt zu beleuchten. Pharmakodynamische Unterschiede, die z.B. auf den Ebenen der Rezeptordichte, Rezeptorpolymorphismen oder der Signaltransduktion bestehen können, sind nicht Gegenstand dieser Übersicht.