Antagonistic pharmacodynamic

Antagonistic pharmacodynamic interactions, for example reversal of nondepolarizing muscle relaxants, or reversal of the toxic effects of opioids or of BDZs, are sometimes of value in critical situations. 

Pharmacodynamic drug interactions include the cases where drugs show additive or antagonistic pharmacodynamic effects. 

Algorithm for identification of pharmacodynamic drag interactions is based on comparison of biological activity spectra of the compounds (in the block diagram they are labeled as compound 1 and compound 2), predicted by PASS, together with information from the PharmaExpert knowledge base ( activity-activity relationships). Antagonistic pharmacodynamic effects are determined by ... 

Smith, B. J., Doran, A. C., Mclean, S., Tingley III, F. D., O Neil, C. A., Kajiji, S. M., P-glycoprotein efflux at the blood-brain barrier mediates differences in brain disposition and pharmacodynamics between two structurally related neurokinin-1 receptor antagonists, J. Pharmacol. Exp. Ther. 2001, 298, 1252-1259. 

Extensive medicinal chemistry optimization of potency, selectivity pharmacokinetic, and pharmacodynamic properties finally led to potent, selective, and orally bioavailable GSK-221149A, which is synthesized as shown on Scheme 17 [35, 37, 38]. Peptidic oxytocin receptor antagonists are currently used to treat preterm labor, the main reason for infant death. The peptide derivatives by their nature are not orally bioavailable but must be administered i.v. Surprisingly, the peptide derivatives are less potent and less selective against several related receptors than GSK-221149A with half the molecular weight [39]. 

Pharmacodynamic interactions generally involve additive, synergistic or antagonistic effects of drugs acting on the same receptors or physiological systems. These interactions are more difficult to classify than those with a pharmacokinetic basis. They are fairly common but may not always be recognised. 

Huang JQ. Pharmacological and pharmacodynamic essentials of H(2)-receptor antagonists and proton pump inhibitors for the practicing physician. Ballieres Best Pract Res Chn Gastroenterol 2001 15 355-370. 

In pharmacodynamic interactions, the pharmacological effect of a drug is changed by the action of a second drug at a common receptor or bioactive site. For example, low-potency antipsychotics and tertiary amine TCAs have anticholinergic, antihistaminic, a-adrenergic antagonist, and quinidine-Kke effects. Therefore, concurrent administration of chlorpromazine and imipramine results in additive sedation, constipation, postural hypotension, and depression of cardiac conduction. 

P. A. van Zwieten (1993). An overview of the pharmacodynamic and therapeutic potential of combined a and P-adrenoceptor antagonists. Drugs 45 509. 

These various pharmacokinetic and pharmacodynamic properties have enabled the identification of four basic structure-activity rules for the 1,4-DHP antagonists ... 

The second generation H -receptor antagonist cetirizine is a reacemate consisting of equal quantities of 2 enantiomers, levocetirizine [(R)-enantiomer] and dextrocetirizine [(S)-enantiomer]. In vitro and human pharmacodynamic studies have provided evidence that levocetirizine is the more active enantiomer, accounting for most or all clinical antihistaminic activity of racemic cetirizine this activity of levocetirizine is seen at half the dose of cetirizine. 

Alosetron is a 5-HT3 antagonist that has been approved for the treatment of patients with severe IBS with diarrhea (Figure 62-5). Four other 5-HT3 antagonists (ondansetron, granisetron, dolasetron, and palonosetron) have been approved for the prevention and treatment of nausea and vomiting (see Antiemetics) however, their efficacy in the treatment of IBS has not been determined. The differences between these 5-HT3 antagonists that determine their pharmacodynamic effects have not been well studied. 

One of the factors that can alter the response to drugs is the concurrent administration of other drugs. There are several mechanisms by which drugs may interact, but most can be categorized as pharmacokinetic (absorption, distribution, metabolism, excretion), pharmacodynamic (additive or antagonistic effects), or combined interactions. The general principles of pharmacokinetics are discussed in Chapters 3 and 4 the general principles of pharmacodynamics in Chapter... 

In conclusion, the investigation of peptidic and non-peptidic tool compounds for the 5 receptor have demonstrated the potential use of 5 agonists and antagonists for a variety of clinical applications, especially for the treatment of pain. Full exploitation of this potential will however only be possible with ideal non-peptidic compounds having high potency, selectivity and, above all, optimal drug metabolism and pharmacodynamic characteristics. 

The trials described so far have commonly shown a lack of usefulness of NKi receptor antagonists in the treatment of pain. But we do not know whether the failure of the selected compounds is a matter of pharmacodynamics (e.g. poor penetration of the blood brain barrier) or a genuine discrepancy between animal and human pain pathophysiology (Urban and Fox, 2000). Hence, animal tests should carefully be chosen whether they are predictive or not, and it would be helpful if a wider range of conditions could be examined (Hill, 2000a). Therefore, new preclinical analysis methods should be developed for a more effective judgement of likely clinical outcomes. 

Shoaf SE, Wang Z, Bricmont P, Mallikaarjun S. Pharmacokinetics, pharmacodynamics, and safety of tolvaptan, a nonpeptide AVP antagonist, during ascending singledose studies in healthy subjects. J Clin Pharmacol 2007 47(12) 1498-507. 

Shoaf SE, Bramer SL, Bricmont P, Zimmer CA. Pharmacokinetic and pharmacodynamic interaction between tolvaptan, a non-peptide AVP antagonist, and fur-osemide or hydrochlorothiazide. J Cardiovasc Pharmacol 2007 50(2) 213-22. 

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