Non-barbituric intravenous hypnotics

A group of so-called non-barbiturate anesthetics combines heterogeneous chemical structures and medicines that differ in a number of properties (propofol, etomidate, sodium oxybate, ketamine). Common to all these drugs is their ability to cause hypnosis and the possibility of intravenous administration.

[1], [2], [3], [4], [5]

Place in therapy

Non-barbituric intravenous hypnotics are mainly used for induction, maintenance of anesthesia and for sedation, some also for premedication.

In modern anesthesiology, only barbiturates constitute competition as the induction of anesthesia in this group of drugs. Due to the high solubility in fats and the small size of the IV molecules, hypnotics quickly penetrate the BBB and cause the onset of sleep in one forearm-brain cycle. The exception is sodium oxybate, the action of which develops slowly. Accelerate induction can be the appointment of benzodiazepine premedication, the addition of subnarcotic doses of barbiturates, as well as glutamic acid. In pediatrics, it is possible to prescribe sodium oxy-bata or rectally as a premedication. It can also be used for caesarean section.

All intravenous hypnotics can be successfully used for co-induction of anesthesia.

Recent years are marked by attempts to further reduce the likelihood of adverse effects in / in hypnotics. One way is to replace the solvent with LS. An important step in the prevention of contamination with the use of propofol was the addition of antiseptic - ethylenediaminetetraacetate (EDTA) at a concentration of 0.005%. The frequency of occurrence of dangerous infectious complications with the use of this preservative has significantly decreased, which served as the basis for the creation of a new dosage form of propofol (not yet registered in Russia). The bacteriostatic effect of the preservative is associated with the formation of chelates with divalent calcium and magnesium ions responsible for the stability and replication of the microbial cell. The pharmacokinetic profile of propofol does not change. In addition, it was found that EDTA binds zinc, iron and copper ions and increases their excretion in the urine, which limits the possibility of implementing free radical mechanisms and a systemic inflammatory reaction.

The use of fat emulsions as solvents for diazepam, propofol and etomidate allowed to minimize the probability of irritating effect of these drugs on the veins without changing pharmacokinetics and pharmacodynamics. This is due to the use in the emulsion of not only triglycerides with a long chain, but also medium chain triglycerides, which better dissolve the active substance, reduce its "free fraction" responsible for the irritation of the veins.

When using a fat emulsion to dissolve etomidate, the excitation reactions and the probability of propylene glycol hemolysis are also less often noted. In addition, the likelihood of changing the lipid spectrum of blood caused by the administration of triglycerides decreases. However, when using all lipid-containing drugs, you must strictly follow the rules of asepsis. Attempts are still being made to create lean solvents for propofol (eg, cyclodextrins).

Another way to reduce the frequency of undesired reactions is the isolation of the active isomer from the racemic mixture. Similarly to barbiturates and etomidate, the ketamine molecule has an asymmetric chiral center, due to which the existence of two optical isomers or enantiomers - S - (+) and R - (-) is possible. They differ significantly in their pharmacological properties, which confirms their interaction with specific receptors. The affinity of the 5 - (+) - enantiomer with respect to NMDA and opioid receptors is shown.

The racemic mixture of two isomers is used most commonly in equivalent amounts. Recently, a pure S-enantiomer of ketamine has become available in a number of countries, which differs in equivalent amounts of more pronounced analgesia, has a faster metabolism and elimination, and a slightly lower probability of unwanted mental recovery reactions. The clearance of pure S - (+) ketamine is higher than racemic clearance.

In spite of the twice lower dose administered (equianesthetic force), the isomer S - (+) has similar side effects on the circulation. Its wide application is largely hampered by high cost.

For purposes of sedation, propofol, which is available as a 2% solution, is well suited. Its use is accompanied by a less metabolic (due to a smaller amount of lipids) and a water load than the traditional 1% solution.

Mechanism of action and pharmacological effects

The exact mechanism of the action of IV hypnotics is not completely clear. But most of the data indicate that they affect different parts of the central nervous system. The main hypotheses are related either to the activation of inhibitory (GABA-receptors) or to the blocking of activating (cation-selective n-methyl-b-aspartate (NMDA) glutamate receptor subtype) CNS factors.

All anesthetics (inhalation and non-inhaling) are also evaluated by the ability to protect the brain from hypoxia. Against the background of an acute ischemic stroke, propofol demonstrates a cerebroprotective effect comparable to that of halothane or thiopental sodium. Perhaps the protection of neurons is due to the stabilization of the concentrations of ATP and electrolytes. However, the good neuroprotective properties of propofol and etomidate are not confirmed by all investigators. There is evidence of their weak anti-ischemic protection of the brain stem structures. It is indisputable that propofol and etomidate, like barbiturates, reduce MC and PMO2. But the neuroprotective properties of the antagonist of these ketamine receptors in the clinic have not been proven. In addition, he (as well as other NMDA receptor antagonists) may exhibit neurotoxic effects.

Pharmacokinetics

The main feature of the pharmacokinetics of intravenous hypnotics is the absence of a relationship between the amount of injected drug, its concentration in the blood and the severity of the therapeutic effect. In practice, this manifests itself in a considerable variability (up to 2-5 times) of the individual need for drugs and in the weak predictability of the effect, which creates difficulties in the selection of doses.

The pharmacokinetics of intravenous hypnotics are affected by a number of factors.

• pH. Most intravenous hypnotics are either weak bases or weak acids. In the blood plasma and body tissues, they exist in ionized and non-ionized forms in a ratio that depends on their pKa and pH of the medium. In non-ionized form, drugs are more easily bound to plasma proteins and penetrate through tissue barriers, particularly into the brain, which reduces their availability for subsequent metabolism. The change in the pH of the plasma has an ambiguous effect on the kinetics of the drug. Thus, acidosis increases the degree of ionization of LS bases and reduces their penetration into brain tissue. Ionization of more acidic drugs in conditions of acidification of the environment, on the contrary, decreases, which contributes to their greater penetration into the central nervous system.
• Binding to proteins. Medicines that are weak bases bind to albumin, alpha-acid glycoprotein and lipoproteins, which restricts access to the receptor sites. Examples of high binding to plasma proteins demonstrate propofol and pregnanolone (up to 98%). Only half or less of these drugs bind to plasma albumins, and the rest is predominantly with the alpha-acid glycoprotein. In conditions such as inflammatory diseases, myocardial infarction, renal failure, advanced cancer, recent surgery, rheumatoid arthritis, an increase in the content of alpha-acid glycoprotein and an increase in drug binding can occur. The increase in the bound fraction of the drug leads to a decrease in the volume of their distribution and simultaneously to a decrease in clearance, so that T1 / 2P may remain unchanged. Pregnancy and taking oral contraceptives, on the contrary, can reduce the content of a1-acid glycoprotein. Dilation of plasma proteins increases the free fraction of the drug.
• Dose. Intravenous hypnotics at clinically acceptable doses are usually eliminated by first-order kinetics (depending on the drug concentration). However, repeated doses or prolonged infusion may significantly alter the pharmacokinetics. T1 / 2p is the least affected by the continuous infusion of etomidate and propofol. If, once administered, the drug concentration in the blood and the brain decreases rapidly due to redistribution in tissues and the duration of action is determined by the rate of redistribution of the hypnotic, then when plasma dosages are introduced high or repeated, the plasma concentrations of the drug remain at a clinically significant level even after redistribution. In this case, the duration of action is determined by the rate of elimination of the drug from the body, which requires a longer time.
• Age. With age, the pharmacokinetics of the drug becomes susceptible to various factors, such as an increased amount of adipose tissue, reduced binding to proteins, decreased hepatic blood flow, and liver enzyme activity. In newborns, the clearance of the drug is lowered and T1 / 2beta is elongated due to decreased hepatic blood flow and underdevelopment of hepatic enzymes. Reinforced effects may be due to poor development of BBB and better passage of the drug into the brain. Low levels of a2-acid glycoprotein in newborns and infants also lead to an increase in the effects of anesthetics, an increase in the volume of distribution and a slowdown in elimination.
• Hepatic blood flow. The hepatic blood flow is normally about 20 ml / kg / min. A drug with low clearance (below 10 ml / kg / min), such as thiopental sodium, diazepam, lorazepam, tends to be less dependent on changes in hepatic blood flow. Hypnotics with a clearance approaching the hepatic blood flow, such as propofol and etomidate, are sensitive to a decrease in hepatic blood flow. Large abdominal operations can lead to a decrease in blood flow in the liver and reduce clearance of the drug, which lengthens their T1 / 2beta. Most hypnotics can cause dose-dependent hypotension, which can also help reduce blood flow in the liver.
• Liver diseases can alter pharmacokinetics by several mechanisms. With liver diseases, plasma protein levels can be lowered and total body water increased. Viral hepatitis and cirrhosis affect the pericentral zones of the hepatic lobules and reduce the oxidative processes of drug metabolism. Chronic active hepatitis and primary biliary cirrhosis affect the periportal zone and have a relatively small inhibitory effect on the metabolism of the drug. The kinetics of some drugs, for example propofol, for which extrahepatic metabolism is characteristic, is less dependent on liver diseases. Hyperbilirubinemia and hypoalbuminemia may increase sensitivity to many intravenous anesthetics, especially hypnotics with high protein binding. Bilirubin competes for binding sites on albumin and leads to an increase in the free fraction of the drug. Chronic alcoholics may require higher doses of anesthetics, which seems to be due to the stimulating effect of alcohol on the microsomal oxidative enzymes of the cytochrome P450 system involved in metabolism.
• Kidney diseases. Since I / O anesthetics are usually fat-soluble, their excretion does not directly depend on the function of the kidneys. However, their active metabolites, which are usually water-soluble, can be very sensitive to impairment of renal function. Renal failure is not a significant problem for most drugs used for IV induction of anesthesia, since their metabolites are usually inactive and non-toxic.
• Obesity. Since intravenous anesthetics are usually highly lipophilic, they can accumulate in fatty tissue in an increased amount and, therefore, have a larger volume of distribution, reduced clearance and a longer T1 / 2 in the elimination phase. Therefore, the dosage of the medicine is more correct to produce in the calculation of lean (corrected) body weight.
• The placental barrier. The intensity of drug transfer through the placenta is determined by many factors: the total surface of the placental membrane and its thickness, uteroplacental blood flow, the period of pregnancy, the tone of the uterus, the size of drug molecules, their solubility in lipids, binding to proteins, the degree of ionization, concentration gradient, etc. Other equal conditions in / in anesthetics easily penetrate the placental barrier and can have a pharmacological effect on the fetus and the newborn.