Dec 1, Repaglinide, Meglitinide, Type 2 diabetes, Bidstrup et al. .. metabolism of taxoids by human CYP3A4 and 2C8: structure–activity relationship. CYP2C8, and CYP2D6 in the metabolism of (R)- and (S)-methadone in vitro. thetic properties, adverse effects. Anaesthetic adjuvants ammonium compounds, sanguinarine, bis-biguanides, phe- phine, codeine, meperidine, methadone, propoxyphene, Benzodiazepines (chemistry and structure-activity relation-. Local anaesthetics, structure-activity relationship , Local anaesthetic clinical features 42 Medical gas supplies Meglitinides (in diabetes Metaraminol Metformin Methadone Methaemoglobin
Subsequently, we supplied one of the four preparations containing levothyroxine commercially available at that time, reinforced the importance of the medication by giving lectures to the patients, and undertook a simple pill counting control compliance measure. Indicating they had already been prescribed a levothyroxine dosage higher than they were really in need of.
And, certainly, the fact that they became hyperthyroid when they started to take their pills appropriately represents a risk. None of our patients had any cardiac symptom or complained of any problem, but they could have had serious problems especially considering that most of these patients were elderly and presented comorbidities.
Excluding poor medication-taking behavior is usually a difficult task. After exhausting every usual measure for compliance such as pill counting, counseling methods, motivational interviewing and problem solving treatment, a clinical test to estimate levothyroxine absorption may be proposed.
The test consists of a single large dose of thyroxine administration, usually 1, mcg, and then monitoring serum T4 levels over time 6. Unfortunately, there are no well-established standards for this test. Even though it indicates that the patient absorbs thyroxine when exposed to a large dose, it does not rule out impairment of normal dose absorption. Moreover, the test does not quantify the absorption impairment caused by the edema produced by the hypothyroidism on the small bowel mucosa.
Hence, simply increasing the levothyroxine dose may have the same practical effect of submitting the patient to the single dose test, with the advantage of treating him. It is important to remember that certain conditions may physiologically require higher doses of thyroid hormone replacement, such as pregnancy or childhood Table 1. Obesity may also be a cause of a higher levothyroxine requirement. In fact, individual levothyroxine requirements are more related to the lean body mass than to the total body weight 7.
On studying more than 27 thousand Norwegians without previously known thyroid disease, Asvold and cols. Two hypotheses have been proposed to explain the relation of thyroid function with body mass.
The first one involves the effect of leptin and other adipokines 9which is favored by the following facts: The second hypothesis suggests that low thyroid function may lead to obesity, probably reducing basal metabolic rate Requirement also seems to be associated with hormonal status.
Studying 50 patients after thyroidectomy, Jackeline Jonklaas 14 found that the weight-based levothyroxine dosage required to normalize TSH was 1. Of course, dose requirements are also age-dependent, possibly because of the combination of weight loss, lean mass loss and decreased clearance of T4 14, Another very common problem is that the patient may be using an inadequate preparation or a preparation with no bioequivalence.
Levothyroxine is a narrow therapeutic range drug for which precise and consistent dosing are essential, particularly in the elderly and in high-risk thyroid cancer patient treatment. It is not unusual to see patients using "natural medicines" that do not contain appropriate doses of the active principals, formulas or manipulated preparations that lack a proper control. There are different brand-name and generic levothyroxine products being manufactured in Brazil and many patients switch from one to another at their convenience or at the pharmacist's or relatives' advice, frequently without the prescribing physician's knowledge.
Generic levothyroxine is considered equivalent to the brand names and, because there is a cost differential between generic levothyroxine and many of the brand name products, physicians and patients have been turning to generic levothyroxine. However, there is considerable concern on the bioequivalence standards for levothyroxine product comparisons 9 and the American Thyroid Association ATAalong with the American Association of Clinical Endocrinologists AACEand The Endocrine Society TES have endorsed a joint statement expressing concern about the flawed methodology used to determine bioequivalence and the potential harm it could bring to patients In fact, there have been a series of adverse event reports Patients should be alerted that they will be required to perform additional blood tests and dose adjustments after switching preparations.
The absorption of levothyroxine occurs within an interval of 3 hrs of ingestion, mainly in the jejunum and ileum Absorption is maximal when the stomach is empty, reflecting the importance of gastric acidity in the process 21, In fact, the complexity of the acid producing machinery in the stomach may contribute to the individual variability observed in daily thyroxine requirement in a longitudinal evaluation There is an increase in the requirement of oral thyroxine in all conditions characterized by impaired gastric acid secretion, which is more pronounced in adult patients presenting with atrophic gastritis and concomitant H.
In an attempt to reduce the size of their goiters or at least to minimize further growth, Centanni and cols. The dose was progressively increased until a low serum thyrotropin level 0. There were patients with multinodular goiter and impaired gastric acid secretion. Interestingly, there was an additive effect: Although the clinical importance of these findings is fairly clear, the mechanism by which intestinal absorption of thyroxine is impaired in patients with hypochlorhydria is unknown.
We may only speculate that oral thyroxine is administered as sodium salt, which is less lipophilic than the native hormone, which enters target cells both through passive diffusion and in a carrier-mediated, inhibitable way 25, In this respect, achlorhydria due to atrophic gastritis 27,28 and ammonia production, or both, which are characteristic of H.
It is important to remember that atrophic gastritis and serum parietal-cell antibodies are associated with Hashimoto's disease and serum thyroid peroxidase antibodies. Therefore, patients with Hashimoto's disease are more susceptible to present a concomitant autoimmune atrophic gastritis.
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And, of course, many individuals with atrophic gastritis and parietal-cell antibodies also present H. Among the multinodular goiter patients treated with thyroxine by Centanni and cols. TSH levels measured before and after H. Other 10 patients with multinodular goiter and gastroesophageal reflux disease, who were treated with both thyroxine and omeprazole, had their serum thyrotropin levels evaluated before and after treatment.
Omeprazole has also got an important effect per se, probably because it causes hypochlorhydria, likewise all proton-pump inhibitors PPI do 21, In addition to PPI, antacids also impair levothyroxine absorption.
There are other commonly used drugs that impair intestinal absorption such as ion exchange resins, bile acid sequestrants, and sucralfate, which have the same effect.
Ferrous sulfate, frequently used to treat anemia, may impair thyroxine as well as orlistat absorption, a drug that works by interfering with the action of gastrointestinal GI lipase in the GI tract, and calcium There is an increasing number of drugs that have been reported to affect levothyroxine absorption 33 Table 2.
Furthermore, a series of other diseases can impair levothyroxine absorption as well. Celiac disease is worth the mention. In fact, likewise atrophic body gastritis, celiac disease and other autoimmune conditions, including inflammatory small bowel disease, are frequently associated with autoimmune thyroiditis 34,35which in turn consists in the main cause of hypothyroidism in adult patients Celiac disease may have mild or subtle symptoms, and there is a case report in which resistant hypothyroidism appeared to be the only major manifestation of the disease The patient improved after a gluten-free diet was introduced Bariatric surgery and all surgeries that reduce gastrointestinal absorption surface may also impair thyroxine absorption It is especially relevant to remember that certain parasitic diseases may be an important cause of malabsorption in underdeveloped countries.
There is a report of a severe case of hypothyroidism reputed to have been caused by an intestinal giardiasis Other causes of malabsorption may include lactose intolerance However, these agents are associated with the rare, but serious, adverse effect of jawbone necrosis. A genome-wide association study found an intronic CYP2C8 SNP rs to be significantly associated with osteonecrosis of the jaw in multiple myeloma patients treated with bisphosphonate therapy [ ].
However, other studies in different patient populations have not been able to replicate the findings of the genome-wide association study [ — ].
As such, additional clinical and mechanistic work is needed to determine whether CYP2C8 SNPs are predictors of bisphosphonate-related osteonecrosis of the jaw. Data suggest that CYP2C8 polymorphisms may influence the risk for renal dysfunction in liver and kidney transplant patients treated with these agents. CYP2C8 is responsible for the metabolism of endogenous arachidonic acid to vasodilatory epoxyeicosatrienoic acid EET metabolites, which are thought to have protective functions in the kidney.
Similar findings have recently been observed in renal transplant recipients [ ]. As a result, CYP2C8 has emerged as a significant pharmacogene. Additional clinical studies are needed to further elucidate the impact and clinical significance of key CYP2C8 variants and haplotypes on heterogeneity in drug disposition and response pheno-types in humans. Footnotes There are no conflicts of interest. Biochemistry and molecular biology of the human CYP2C subfamily.
Interindividual variations in human liver cytochrome P enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: J Pharmacol Exp Ther. Human cytochrome P enzymes: J Biochem Mol Toxicol. Structure of human microsomal cytochrome P 2C8.
Evidence for a peripheral fatty acid binding site. Determinants of cytochrome P 2C8 substrate binding: The structure of human microsomal cytochrome P 3A4 determined by X-ray crystallography to 2. Structural diversity of human xenobioticmetabolizing cytochrome P monooxygenases. Biochem Biophys Res Commun.SAR of Parasympatholytic agents/ antimuscarinic agents/ anticholinergic agents
A significant role of human cytochrome P 2C8 in amiodarone N-deethylation: This theory relies heavily on the stereochemistry of the opioids to explain pharmacologic activity of opioids and opioid peptides. Although computational measurements from other authors are considered, the focus has been to describe the pharmacologic activities through comparisons of enantiomers which become evident in the presence of virtual or known heterocyclic rings.
Steric effects hindering the heterocyclic ring by various isomers explain agonist and antagonist characteristics of the molecule. Further work in the form of computational chemistry and experimental pharmacology may support or refute this theory.
Previous Structure Activity Theories Beckett and Casy proposed that an aromatic and a basic amine, which is protonated at physiologic pH, exists to form a 3 point model consisting of an anionic site Nhydrophobic region of a piperidine ring, and a phenolic site tyrosine.
Kane et al described an opioid agonist model suggesting that multiple epitopes exist for ligand binding. They did not extend their theory to opioid peptides.
Cometta-Morini et al proposed a structure activity relationship for the fentanyl classes of compounds which relied upon four key moieties. Rationale for Selection of Opioids to Investigate The opioids considered for this paper represent a subset of those compounds known to produce analgesia through the mu opioid receptor in man excluding many of the analgesics where bioavailability, lipid solubility, or metabolism may predict differences in action.
Just as clinical data is prioritized in reviews or meta-analysis, the selected compounds of highest priority clinical response in man were investigate which by- passed the in vitro—in vivo correlation discrepancies.
Many second class opioids were excluded which were investigated in earlier years before subpopulations of opioid receptors were discovered. The conclusions from this argument may or may not explain some of the prior experimental observations, particularly of second class opioids. Proposition 1 The structure of morphine provides a template In humans, within the central nervous system, morphine is a mu receptor agonist.
It is fortuitous that the morphine rings are nearly rigid with little rotational movement and therefore can be considered a template.