Anaesthetics interaction

J.R. Trudell, E. Bertaccini, Molecular modeling of specific and non-specific anaesthetic interactions. Br. J. Anaesth. 89, 32-40 (2002)... 

At the molecular level intravenous anaesthetics interact mainly with GABAa receptors (thiopental, propofol...) or with other ligand-gated ion channels (ketamine) synthetic opioids (phentanyl congeners) act in a more specific way as agonists of p-opioid receptors. However, all the anaesthetics, in addition to their action at the level of central nervous system, have also a variety of effects at other levels in particular, a temporary impairment of the immune system involving phagocytes can be induced. 

As anaesthetic potency is closely related to lipid solubility rather than to chemical structure, the lipid theory proposes that general anaesthetics interact with the lipid bilayer of the cell membrane. Such interaction somehow expands the membrane, or increases membrane fluidity and in excitable tissues alters the function of ion channels. 

The mechanism of action of general anaesthetics is unknown, but there are two theories to explain their action the lipid theory and the protein theory. The lipid theory states that general anaesthetics interact with lipids in the neuronal cell membrane and disrupt neurotransmission and the protein theory states that general anaesthetics interact with membrane proteins to alter release of neurotransmitters. The protein theory is thought most likely. 

Nucleic acids like DNA are important drug receptors, e.g. for chemicals controlling malignancy such as inter-colator agents. Finally, general anaesthetics interact with and alter the structure and function of the lipids of the cellular membrane. 

In short, the above findings in (1) and (2) evidently drive out attention to a rather more intrieate and complex mechanism responsible for such distinct and apparent variations in their activities and that is the protein-anaesthetic interactions. ... 

General anaesthetics have been in use for the last 100 years, yet their mechanism of action are still not yet clearly defined. For many years it was thought that general anaesthetics exerted their effects by dissolving in cell membranes and perturbing the lipid environment in a non-specific manner. This theory derived from the observation that for a number of drugs which induced anaesthesia, their potency correlated with their oil-water partition coefficients. This Meyer-Oveiton correlation was accepted for a number of years, however in the last 15-20 years evidence has shown that a more likely theory is that of specific interactions of anaesthetics with proteins, particularly those within the CNS that mediate neurotransmission [1]. 

This review describes experimental techniques, then gives some selected results of H, and NMR studies of pressure effects on the structure, dynamics and phase transitions of phospholipid bilayers. Other examples deal with 2D-NOESY experiments on lipid vesicles and pressure effects on the interaction of anaesthetics with phospholipid bilayers. Furthermore, we discuss... 

Pressure effects on the interaction of anaesthetics with phospholipid... 

Preliminary studies [241, 249, 250] of the cardiovascular and sympatholytic properties of prenylamine demonstrated that coronary blood flow and oxygenation could be increased under experimental conditions (in dogs) and that the drug interacted in complex fashion with sympathetically innervated organs, but the picture presented was someudiat confused because of the many uncontrolled variables and limitations of the actual techniques used. Anti-arrhythmic activity of potency comparable with that of quinidine, plus local anaesthetic properties, were also demonstrated [251] but the same worker was notable to reproduce these effects in intact live animals with any consistency. Large doses of the drug actually provoked cardiac fibrillation in some cases. 

The development of alcoholism is often insidious, proceeding from frequent drunkenness to dependence over years. Since this is so, and since alcohol may interact with other treatment (other psychoactive substances and via its effects on the liver), a careful check of a patient s intake is an important part of the medical history. It is vital to know about alcohol abuse before anaesthesia, since it may make the anaesthetic difficult and alcohol withdrawal may complicate the recovery period. 

Separation of the enantiomers of a series of local anaesthetics through their interaction with dimethyl p-cyclodextrin included In the running buffer. Redrawn from Reference 6. 

Figure 14.11 shows the separation of R and S isomers of a series of structurally related local anaesthetics. Wide separations were achieved for the compounds in this series where it was proposed that the fit of the hydrophobic portion of the analyte into the cyclodextrin was optimal when one of the substituents at the chiral centre was able to interact with the chiral hydroxyl groups on the rim of the cyclodextrin cavity. Table 14.3 shows the association constants calculated for the interaction of the enantiomeric pairs with the dimethylcyclodextrin. The larger the value of K, the... 

Eilers H, Niemann C. Clinically important drug interactions with intravenous anaesthetics in older patients. Drugs Aging 2003,20 969-980. 

Marked inter-patient variability exists in the pharmacokinetics of intravenous anaesthetics. Factors that can influence drug disposition include the degree of protein binding, the efficiency of the hepatic and renal clearance systems, physiological changes with ageing, disease states, site of operation, body temperature, and drug interactions (premedicants, volatile anaesthetics). 

Pharmaceutical interactions and modified absorption will not be described here, as they are relatively unimportant in anaesthetic practice, where few drugs are given by the oral route. However, it should be noted that the absorption of drugs from the jejunum may be delayed by drugs, such as opioids or atropine, which reduce gastric motility. 

Table 18.1 Drug reactions and interactions and some special risk situations with anaesthetic drugs...

Recently, attempts have been made to reconcile the deficiencies in the dopamine hypothesis by focusing on other neurotransmitters that may interact with dopamine in discrete cortical and subcortical neural circuits. In particular, the involvement of the glutamatergic system has received considerable attention. This possibility has arisen from the finding that dissociation anaesthetics such as ketamine and phencyclidine (PCP) can cause a schizophreniform psychosis in normal individuals. Such effects bear a much closer resemblance to the positive and negative symptoms of... 

When planning functional studies it is important to consider that most anaesthetics cause cardiac and respiratory depression. For chronic studies it may only be important to ensure that the depth of anaesthesia is reproducible from imaging session to imaging session, however for acute studies it is necessary to consider interactions between the anaesthetic and the test substance. The complexity of cardiac structure and function needs to be understood to devise a well-planned imaging protocol. 

Naguib M, Koorn R. Interactions between psychotropics, anaesthetics and electroconvulsive therapy implications for drug choice and patient management. CNS Drugs 2002 16(4) 229-47. 

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