Anesthetics uptake

Adapted from Eger El II (ed.). Anesthetic Uptake and Action. Baltimore Williams Wilkins, 1974 82. 

The alveolar rate of rise toward the inspired concentration (Fa/Fi) is accelerated by an increase in alveolar ventilation from 2 to 4 and from 4 to 8 liters per minute (constant cardiac output). The increase is greatest with the more soluble agent, halothane, and smaller with the least soluble anesthetic, nitrous oxide. (Reprinted with permission from Eger El II [ed.]. Anesthetic Uptake and Action. Baltimore Williams Wilkins, 1974.)... 

Alveolar wash-in This term refers to the replacement of the normal lung gases with the inspired anesthetic mixture. The time required for this process is directly proportional to the functional residual capacity of the lung, and inversely proportional to the ventilatory rate it is independent of the physical properties of the gas. Once the partial pressure builds within the lung, anesthetic uptake from the lung begins. 

Return of gas-depleted blood to the lung As the venous circulation returns blood depleted of anesthetic to the lung, more gas moves into the blood from the lung according to the partial pressure difference. Over time, the partial pressure in the alveolar space closely approximates the partial pressure in the inspired mixture that is, there is no further anesthetic uptake from the lung. 

Eger E (ed) Anesthetic uptake and action. Williams Wilkins, Baltimore, MD, pp. 113-121... 

Parent substances and metaboHtes may be stored in tissues, such as fat, from which they continue to be released following cessation of exposure to the parent material. In this way, potentially toxic levels of a material or metaboHte may be maintained in the body. However, the relationship between uptake and release, and the quantitative aspects of partitioning, may be complex and vary between different materials. For example, volatile lipophilic materials are generally more rapidly cleared than nonvolatile substances, and the half-Hves may differ by orders of magnitude. This is exemplified by comparing halothane and DDT (see Anesthetics Insectcontholtechnology). 

Absorption of trichloroethylene in humans is very rapid upon inhalation exposure. Trichloroethylene has a blood/gas partition coefficient that is comparable to some other anesthetic gases (i.e., chloroform, diethylether, and methoxyfluorene), but it is much more lipophilic than these gases. As a consequence of these properties, the initial rate of uptake of inhaled trichloroethylene in humans is quite high, with the rate leveling off after a few hours of exposure (Fernandez et al. 1977). The absorbed dose is proportional to the inhaled trichloroethylene concentration, duration of exposure, and alveolar ventilation rate at a given inhaled air concentration (Astrand and Ovrum 1976). Several studies indicate that 37-64% of inhaled trichloroethylene is taken up from the lungs (Astrand and Ovrum 1976 Bartonicek 1962 Monster et al. 1976). 

Jakobson I, Wahlberg JE, Holmberg B, et al. 1982. Uptake via the blood and elimination of 10 organic solvents following epicutaneous exposure of anesthetized guinea pigs. Toxicol Appl Pharmacol 63 181-187. 

Cohen EN, Hood N. 1969. Application of low-temperature autoradiography to studies of the uptake and metabolism of volatile anesthetics in the mouse. Anesthesiology 30 306-314. 

Most models of gas uptake in the respiratory tract have been concerned with carbon dioxide, carbon monoxide, oxygen, and anesthetic gases like chloroform, ether, nitrous oxide, benzene, and carbon disulfide (e.g., see Lin and Gumming and Papper and Kitz ). Unfortunately, there are only a few preliminary models of pollutant-gas transport and uptake in the respiratory tract. 

Gases that do not react irreversibly with epithelial tissue, such as anesthetic gases, may diffuse into the bloodstream and will ultimately be eliminated from the body. A different and earlier model developed by DuBois and Rogers estimates the rate of uptake of inhaled gas from the tracheobronchial tree in terms of diffusion through the epithelial tissue, rate of blood flow, and solubility of the gas in blood. The rate of uptake from the airway lumen is determined by the equation ... 

Although this drug is categorized as a local anesthetic, I have chosen to put it in with the hallucinogens because of the psychotomimetic effects that it produces. Cocaine is not a phenylethyl-amine, but it produces central nervous system arousal or stimulant effects which closely resemble those of the amphetamines, the methylenedioxyamphetamines in particular. This is due to the inhibition by cocaine of re-uptake of the norepinephrine released by the adrenergic nerve terminals, leading to an enhanced adrenergic stimulation of norepinephrine receptors. The increased... 

The mechanism of action of inhalational anesthetics is unknown. The diversity of chemical structures (inert gas xenon hydrocarbons halogenated hydrocarbons) possessing anesthetic activity appears to rule out involvement of specific receptors. According to one hypothesis, uptake into the hydrophobic interior of the plasmalemma of neurons results in inhibition of electrical excitability and impulse propagation in the brain. This concept would explain the correlation between anesthetic potency and lipophilicity of anesthetic drugs (A). However, an interaction with lipophilic domains of membrane proteins is also conceivable. Anesthetic potency can be expressed in terms of the minimal alveolar concentration (MAC) at which 50% of patients remain immobile following a defined painful stimulus (skin incision). Whereas the poorly lipophilic N2O must be inhaled in high concentrations (>70% of inspired air has to be replaced), much smaller concentrations (<5%) are required in the case of the more lipophilic halothane. 

The rates of onset and cessation of action vary widely between different inhalational anesthetics and also depend on the degree of lipophilicity. In the case of N2O, there is rapid elimination from the body when the patient is ventilated with normal air. Due to the high partial pressure in blood, the driving force for transfer of the drug into expired air is large and, since tissue uptake is minor, the body can be quickly cleared of N2O. 

Gases diffuse from areas of high partial pressure to areas of low partial pressure thus, the tension of anesthetic in the alveoli provides the driving force to establish brain tension. In fact, the tension of anesthetic in all body tissue will tend to rise toward the lung tension as equilibrium is approached. Consequently, factors that control or modify the rate of accumulation of anesthetic in the lung (e.g., rate of gas delivery, uptake of gas from the lung into the pulmonary circulation) will simultaneously influence the rate at which tension equilibria in other body compartments is established. 

The alveolar tension-time curve always declines in an exponential manner, but the position of the curve can be greatly affected by the rate of delivery of anesthetic gases and the rate of their uptake into the pulmonary circulation. For this reason, it is important to consider factors that modify or regulate delivery and uptake. 

Frequently it is desirable to overcome the slow rate of rise of alveolar tension associated with such factors as the high blood solubility of some anesthetics and increased pulmonary blood flow. Since both of these factors retard tension development by increasing the uptake of anesthetic, the most effective way to alleviate the problem is to accelerate the input of gas to the alveoli. A useful technique to increase the input of anesthetic to the lung is to elevate the minute alveolar ventilation. This maneuver, which causes a greater quantity of fresh anesthetic gas to be delivered to the patient per unit of time, is most effective with highly soluble agents (Fig. 25.4). 

Fig. 2. Simultaneous detection of multiple fluorinated molecules in vivo. To explore the hypothesis that uptake of the anticancer drug 5FU by tumors is pH dependant, we infused 5FU (0.4 ml (50 mg/ml) IV), the extracellular pH reporter CF3POL (400 mg/kg IP), and the chemical shift standard NaTFA (200 mg/kg IP) into an anesthetized rat (1% isoflurane) with a subcutaneous 13762NF breast tumor (1.4 x 1.5 x 1.1 cm). Thirty minutes after administration, all four molecules were detectable simultaneously in 17 min. At this stage, no metabolites of 5FU were detected.

Ensuring an adequate depth of anesthesia depends on achieving a therapeutic concentration of the anesthetic in the CNS. The rate at which an effective brain concentration is achieved (ie, time to induction of general anesthesia) depends on multiple pharmacokinetic factors that influence the brain uptake and tissue distribution of the anesthetic agent. The pharmacokinetic properties of the intravenous anesthetics (Table 25-1) and the physicochemical properties of the inhaled agents (Table 25-2) directly influence the pharmacodynamic effects of these drugs. These factors also influence the rate of recovery when the administration of anesthetic is discontinued. 

Since blood levels are lowered up to 30% when vasoconstrictors are added to local anesthetics, localized neuronal uptake is enhanced because of higher local tissue concentrations in the region of drug administration, and the risks of systemic toxic effects are reduced. Furthermore, when used in spinal anesthesia, epinephrine acts directly on the cord to both enhance and prolong local anesthetic-induced spinal anesthesia by acting on a2 adrenoceptors, which inhibit release of... 

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