Membranes, cell , drug action

Systemic and coronary arteries are influenced by movement of calcium across cell membranes of vascular smooth muscle. The contractions of cardiac and vascular smooth muscle depend on movement of extracellular calcium ions into these walls through specific ion channels. Calcium channel blockers, such as amlodipine (Norvasc), diltiazem (Cardizem), nicardipine (Cardene), nifedipine (Procardia), and verapamil (Calan), inhibit die movement of calcium ions across cell membranes. This results in less calcium available for the transmission of nerve impulses (Fig. 41-1). This drug action of the calcium channel blockers (also known as slow channel blockers) has several effects on die heart, including an effect on die smooth muscle of arteries and arterioles. These drug dilate coronary arteries and arterioles, which in turn deliver more oxygen to cardiac muscle. Dilation of peripheral arteries reduces die workload of die heart. The end effect of these drug is the same as that of die nitrates. 

Mechanisms of drug action. To mediate a response the drug can bind to the desired therapeutic target or to other molecular targets such as G-protein-coupled receptors (GPCRs), ion channels, or transporters on the cell membrane, or to intracellular targets such as enzymes and nuclear hormone receptors. 

In view of the substantial current interest in drug actions at the cell membrane and the relationships between such effects and anticancer drug action, it is interesting to note that both vincristine and vinblastine produce crenellation (wrinkling) of cell membranes as a characteristic morphological effect (12). That cytotoxicity produced by treatment with vinblastine may be linked to perturbations of membrane function, suscep-... 

In this situation, cell lines are shown to be resistant to colchicine, doxorubicin, vinblastine, and actinomycin D. This syndrome is accompanied by an increase in measurable membrane glycoprotein (the P-170 or permeability glycoprotein). It is believed that this protein transports hydrophobic chemicals out of cells and thereby prevents drug action. Current efforts to inhibit this efferent transport protein are currently underway but, sadly, have to date been largely unsuccessful (i5). 

To make quantitative predictions of DDI for the new compound as perpetrator, a reliable estimate of a relevant in vivo concentration is needed. What is tmly needed is knowledge of the concentration of the inhibitor available to bind to the enzyme. For liver, if the well accepted free-dmg hypothesis (which underwrites fundamental drug action principles in pharmacology) is applied for DDI, then the use of a free intracellular liver concentration is needed. For inhibitors that are permeable through membranes, the free concentration in the portal vein should serve as the closest proxy for free intracellular concentration in the liver. Diminished permeability as well as active uptake and efflux from liver cells can confound this relationship. Nevertheless, use of estimates of unbound portal vein concentrations (which can be estimated from... 

The effect of solubility on drug action is, however, usually a question of equilibration of the drug between the aqueous phase and the lipid phase of the cell membrane. This leads us to a discussion of partition coefficients. 

Dmg transport during the pharmacokinetic phase represents a compromise between the increased solubility of the ionized form of a drug and the increased ability of the non-ionized form to penetrate the lipid bilayer of cell membranes. A drug must cross many lipid barriers as it travels to the receptor that is its site of action. Yet cell membranes... 

Nonreceptor-Mediated Drug Action. At least one important class of drugs, the general anesthetics, has been assumed not to owe its therapeutic activities to a specific receptor process. Anesthetic potency shows an excellent linear correlation with partition coefficient and this has been extrapolated to a definition of action at a lipid site. The phospholipids of cell membranes, particularly nerve cells, have been considered as principal targets for general anesthetic action. It has been hypothesized... 

It is astonishing that it has taken such a long time to appreciate the importance of drug-phospholipid interactions in membranes for cell functioning and drug action. This despite the fact that, as Thudicum stated as long ago as 1884, Phospholipids are the centre, life and chemical soul of all bioplasm whatsoever, that of plants as well as of animals. ... 

An overview of the mechanisms of drug action shows that drugs act on the cell membrane by ... 

This definition has been the basis for an enormous body of scientific investigation into the function and regulation of receptors and mechanisms of drug action. However, final proof of the existence of receptors did not occur until relatively recent applications of modern biochemistry and molecular biology to purify, sequence, clone, and express pure receptor proteins. This lack of proof notwithstanding, the therapeutic basis of many modern, and not so modern, drugs resides in their specific interactions with receptor molecules located in the plasma membrane or cytosol of target cells. In fact, these specific interactions have provided the experimental basis for their discovery and development. 

In order to have a therapeutic effect, a drug has to interact with a receptor or other site of action in the body. Receptors are divided into four types according to their location, structure and effects when activated. Types 1, 2 and 3 are found in cell membranes. Type 4 receptors are found in the cell cytoplasm or nucleus. Ion channels, carrier proteins and enzymes can also be targets for drug action. 

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