Pharmacodynamics receptor pharmacology

Receptor Pharmacology Pharmacogenetics Autonomies Pharmacodynamics Antimicrobials Medicinal Chemistry [ Toxicology... 

The metabolism of heroin is of interest in connection with its pharmacological activities. Earlier opiate -receptor binding studies led to the belief that heroin is a prodrug acting through its metabolites 6-acetylmorphine and morphine [95]. However, heroin is now known to activate (5-receptors, whereas morphine activates -receptor and 6-acetylmorphine acts at both receptor types [96]. Thus, the pharmacodynamic profile of heroin results from both direct and metabolite-mediated effects. 

Elizabetli, C.M., Della, P., Oscar Ploeger, B.A. and Voskuyl, R.A. (2007) Mechanism-based pharmacokinetic-pharmacodynamic modeling hiophase distribution, receptor theory, and dynamical systems analysis. Annual Review of Pharmacology and Toxicology, 47, 357-400. 

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. 

Pharmacokinetic and pharmacodynamic studies lead to a greater understanding of chemical interactions at the molecular level and may identify specific receptors for drug activity. With more specific knowledge of how a drug works, it may become easier to more accurately establish what effects are actually caused by a particular drug. Thus, studies in these two areas of pharmacology will always be necessary. 

Changes in pharmacodynamics further complicate the pharmacology of many drugs in the neonate and infant. The blood-brain barrier is poorly developed, allowing more rapid transfer of drugs into the central nervous system (CNS). However, the response to higher brain concentrations may be tempered by an inadequate response due to lack of receptor maturation. 

Basic and Clinical Pharmacology > Chapter 2. Drug Receptors Pharmacodynamics >... 

While opioid peptides have been very useful for investigating the pharmacology of different opioid receptor subtypes, pharmacological investigations have established that no pharmacodynamic advantage is to be expected from opioid peptides with respect to analgesic activity or side-effects. Furthermore, they have their own shortcomings with respect to potential clinical applications. Most importantly their peptidic structure usually prohibits administration by the oral or transdermal route, which are the routes of choice for pain treatment. 

Due to its high selectivity and potency at H3 receptors (/ )-a-methylhistamine (12) is nowadays used as the standard agonist in pharmacological assays related to this receptor. With regard to its pharmacodynamic properties, which were substantiated in preclinical studies [40], (R)-a-methylhistamine (12) meets all criteria of a potential drug substance. However, in contrast to its pharmacodynamic potential (ft)-a-methyl-histamine (12) suffers from its pharmacokinetic drawbacks which limit its use in both pharmacological and conceivable clinical studies. 

The primary objective of the early efLcacy studies is to validate the pharmacology model with a compound that is known to interact with the desired receptor and develop the Pharmacokinetics-Pharmacodynamics (PK-PD) relationship for further screening during lead optimization (Neervan-nan, 2006). It is essential that the excipients selected forthe vehicle do not interfere with the measured end points especially, for a disease-relevant animal model that has no clinically effective drugs to validate an animal model. In this situation, vehicles should be used as negative controls in the studies. 

From Bourne, HR and von Zastrow, M. Drug receptors and pharmacodynamics. In Katzung, BG ed. Basic and Clinical Pharmacology. 9th ed. New York Lange Medical Books/McGraw-Hill 2004 21, with permission.)... 

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