The Impact Of Pharmacogenetics On Pharmacodynamics

It is already a given fact that with polymorphisms of drug-metabolizing enzymes

, the pharmacological aims of drugs likewise manifest genetic polymorphisms, and these too impact the drug response. The divergent alleles are famous for their occurrence not only at the genes expressing targeted enzymes, receptors and channels, but also at the genes which are responsible for intra-cellular signal transduction.

Among the pharmacodynamic polymorphisms better characterized are the targets engaged in cardiac arrhythmias, asthma, cardiac failure, and depression. Although majority of the patients may respond normally, individuals having a genetic divergent of a pharmacological purpose may manifest a qualitatively or quantitatively different response even when the concentration of a drug is within the normal therapeutic population-base range.

The QT gap of the surface electrocardiogram manifests the length of time of ventricular action pinpointed by a net balance between inward and depolarizing and outward repolarizing currents. This is particularly true in the phase 3 of the action. The major determining factor of the outward repolarizing current is the IKr. It is conducted by the swift part of the delayed rectifier potassium channel.

Decrease in this current leads in QT gap expansion. Exuberant expansion of the QT gap often results to deadly ventricular tachyarrhythmias, particularly the torsade de pointes. During the last 10 years, several of the non-antiarrhythmic drugs have drawn much clinical and regulatory interest due to their capacity to extend the QT gap and influence TdP. These drugs aim and prevent the IKr current.

After the advances in molecular biology took place, genetics and pharmacology of ion channels, it has become apparent that genes that control the expression of these potassium channels are widely diversified.

The gene mutations that encode the subunits of such channels are very common, give way to congenital long QT syndromes. But, with the low penetrance of most mutations, the size of population having dysfunctional potassium channels is bigger than that which is diagnosed by ECG only.

Because of this huge overlap, the measurement of the QT gap alone does not allow an accurate molecular diagnosis in people affected by the congenital long QT disorder. Only the DNA markers make it possible to achieve a genetic diagnosis in such people because not all allele carriers have symptoms.

Although the affected patients have a normal ECG phenotype, they have decreased repolarization reserve and are very vulnerable to drug-stimulated QT gap expansion and or TdP, notwithstanding the recommended doses that are regularly safe.

People who contract drug-stimulated expansion of QT gap with or withut TdP are not regularly genotyped. The available evidence suggests that a significant proportion of the cases of the drug-stimulated long QT disorder might represent cases of forme frusta of the congenital long QT disorder.

With polymorphism of aimed receptors, people who are a carrier of Arg16/Gly16 or Gly16/Gly16 variants of B2-adrenocpetors manifested less favorable instant bronchodilatory reaction to salbutamol, as opposed to people having a wild type receptor characterizd by Arg16/Arg16 genotype.

Today, there are now increasing numbers of researches of relevant polymorphisms in other pharmacological targets.

by: Charles Godbout

POST COMMENT

The Impact Of Pharmacogenetics On Pharmacokinetics Ii Pharmacogenetics And The Framework For Regulatory ACME Machinery Company Pvt. Ltd Thread Book Sewing Machine available only at ACME Machinery Platen Punching Machine available only at ACME Machinery Paper Bag Making Machine available only at ACME Machinery How Choose Filling Machines? Stomach Pain Causes And Prevention The Skills Of A Compound Pharmacist In Canada Improving Machine Inspection Speed And Accuracy Madeira's Brazen Head Macabre Past Create Awe-inspiring Scrapbooks And Crafts With The Cricut Machine Mazda Premacy