Non-barbiturate intravenous hypnotics

The group of so-called non-barbiturate anesthetics includes drugs that are heterogeneous in chemical structure and differ in a number of properties (propofol, etomidate, sodium oxybate, ketamine). Common to all these drugs is their ability to induce a hypnotic state and the possibility of intravenous administration.

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Place in therapy

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

In modern anesthesiology, the only competitors for this group of drugs as an induction of anesthesia are barbiturates. Due to their high solubility in fats and small size of molecules, intravenous hypnotics quickly penetrate the BBB and induce sleep in one forearm-brain cycle. An exception is sodium oxybate, the effect of which develops slowly. Induction can be accelerated by prescribing benzodiazepine premedication, adding subnarcotic doses of barbiturates, and glutamic acid. In pediatrics, sodium oxybate can be prescribed orally or rectally as a premedication. It can also be used in cesarean section.

All intravenous hypnotics can be successfully used for coinduction of anesthesia.

Recent years have seen attempts to further reduce the likelihood of adverse effects of intravenous hypnotics. One way is to replace the drug solvent. An important step in preventing contamination when using propofol was adding an antiseptic - ethylenediaminetetraacetate (EDTA) at a concentration of 0.005%. The incidence of dangerous infectious complications when using this preservative has decreased significantly, which served as the basis for creating 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 response.

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

When using a fat emulsion to dissolve etomidate, excitation reactions and the likelihood of propylene glycol hemolysis are also less common. In addition, the likelihood of changes in the blood lipid spectrum due to the introduction of triglycerides is reduced. However, when using all lipid-containing drugs, it is necessary to strictly observe aseptic rules. Attempts to create fat-free solvents for propofol (for example, cyclodextrins) continue.

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

The most widely used is a racemic mixture of the two isomers in equivalent amounts. Recently, a number of countries have become available pure S-enantiomer of ketamine, which is distinguished by the fact that in equivalent amounts it causes more pronounced analgesia, has a faster metabolism and elimination, and a somewhat lower probability of undesirable mental reactions of recovery. The clearance of pure S-(+) ketamine is higher than that of racemic.

Despite the half-lower administered dose (equianesthetic strength), the S-(+) isomer has similar side effects on blood circulation. Its high cost is a major obstacle to its widespread use.

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

Mechanism of action and pharmacological effects

The exact mechanism of action of intravenous hypnotics is not completely clear. But most data indicate that they act on various parts of the CNS. The main hypotheses are related either to the activation of inhibitory (GABAA receptors) or to the blockade of activating (cation-selective n-methyl-b-aspartate (NMDA) subtype of glutamate receptor) CNS factors.

All anesthetics (inhalation and non-inhalation) are also usually assessed by their ability to protect the brain from hypoxia. Against the background of acute ischemic stroke, propofol demonstrates a cerebroprotective effect comparable to that of halothane or sodium thiopental. Perhaps, neurons are protected due to stabilization of ATP and electrolyte concentrations. However, good neuroprotective properties of propofol and etomidate are not confirmed by all researchers. There is data on their weak anti-ischemic protection of brain stem structures. The only indisputable fact is that propofol and etomidate, like barbiturates, reduce MC and PMO2. But the neuroprotective properties of the antagonist of these receptors, ketamine, have not been proven in the clinic. In addition, it (like other antagonists of NMDA receptors) can exhibit a neurotoxic effect.

Pharmacokinetics

The main feature of the pharmacokinetics of intravenous hypnotics is the lack of dependence between the size of the administered dose of the drug, its concentration in the blood and the severity of the therapeutic effect. In practice, this is manifested in significant variability (up to 2-5 times) of the individual need for drugs and in the weak predictability of the effect, which creates difficulties in selecting doses.

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

• pH. Most intravenous hypnotics are either weak bases or weak acids. In blood plasma and body tissues, they exist in ionized and non-ionized forms in a ratio that depends on their pKa and the pH of the environment. In non-ionized form, drugs more easily bind to plasma proteins and penetrate tissue barriers, particularly into the brain, which reduces their availability for subsequent metabolism. Changes in plasma pH have an ambiguous effect on drug kinetics. Thus, acidosis increases the degree of ionization of drug bases and reduces their penetration into brain tissue. On the contrary, the ionization of more acidic drugs in acidifying conditions decreases, which facilitates their greater penetration into the central nervous system.
• Protein binding. Drugs that are weak bases bind to albumin, alpha-acid glycoprotein and lipoproteins, which limits drug access to receptor sites. Examples of high plasma protein binding are propofol and pregnanolone (up to 98%). Only half or less of these drugs bind to plasma albumin, and the rest mainly to 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 may occur. An increase in the bound fraction of the drug leads to a decrease in their distribution volume and simultaneously to a decrease in clearance, so that T1 / 2P may remain unchanged. Pregnancy and oral contraceptives, on the contrary, can reduce the content of alpha-acid glycoprotein. Dilution of plasma proteins increases the free fraction of drug.
• Dose. Intravenous hypnotics in clinically acceptable doses are usually eliminated by first-order kinetics (depends on the drug concentration). However, repeated doses or prolonged infusion can significantly change the pharmacokinetics. T1/2p changes the least against the background of prolonged infusion of etomidate and propofol. If after a single administration, drug concentrations in the blood and brain decrease rapidly due to redistribution in tissues and the duration of action is determined by the rate of redistribution of the hypnotic, then with the introduction of high or repeated doses, plasma drug concentrations 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 the influence of various factors, such as increased adipose tissue, decreased protein binding, decreased hepatic blood flow and liver enzyme activity. In neonates, drug clearance is reduced and T1/2beta is prolonged due to decreased hepatic blood flow and underdeveloped liver enzymes. Enhanced effects may be due to poor development of the BBB and better passage of the drug into the brain. Low levels of alpha2-acid glycoprotein in neonates and infants also lead to increased effects of anesthetics, increased volume of distribution and slower elimination.
• Hepatic blood flow. Hepatic blood flow is normally approximately 20 ml/kg/min. Drugs with low clearance (below 10 ml/kg/min), such as thiopental sodium, diazepam, lorazepam, tend to be less affected by changes in hepatic blood flow. Hypnotics with clearance approaching hepatic blood flow, such as propofol and etomidate, are sensitive to decreases in hepatic blood flow. Major abdominal surgeries can reduce hepatic blood flow and decrease drug clearance, prolonging their T1/2beta. Most hypnotics can cause dose-dependent hypotension, which can also contribute to decreased hepatic blood flow.
• Liver disease may alter pharmacokinetics by several mechanisms. Liver disease may decrease plasma protein levels and increase total body water. Viral hepatitis and cirrhosis affect the pericentral zone of the liver 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 drug metabolism. The kinetics of some drugs, such as propofol, which are metabolized extrahepatically, are less affected by liver disease. Hyperbilirubinemia and hypoalbuminemia may increase sensitivity to many intravenous anesthetics, especially highly protein-bound hypnotics. 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 is apparently related to the stimulating effect of alcohol on the microsomal oxidative enzymes of the cytochrome P450 system involved in metabolism.
• Renal disease. Because IV anesthetics are usually lipid soluble, their excretion is not directly dependent on renal function. However, their active metabolites, which are usually water soluble, may be very sensitive to deterioration in renal function. Renal failure is not a significant problem for most drugs used for IV anesthesia induction because their metabolites are usually inactive and nontoxic.
• Obesity. Since intravenous anesthetics are usually highly lipophilic, they may accumulate in increased amounts in adipose tissue and, therefore, have a larger volume of distribution, reduced clearance, and a longer T1/2 in the elimination phase. Therefore, it is more correct to dose the drug based on lean (corrected) body mass.
• Placental barrier. The intensity of drug passage through the placenta is determined by many factors: the total surface area of the placental membrane and its thickness, uteroplacental blood flow, gestational age, uterine tone, size of drug molecules, their solubility in lipids, protein binding, degree of ionization, concentration gradient, etc. All other things being equal, intravenous anesthetics easily penetrate the placental barrier and can have a pharmacological effect on the fetus and newborn.