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Pharmacokinetics of Inhaled Anesthetics
It is important for the anesthesiologist to understand the pharmacokinetic properties of the different types of inhaled anesthetics for safe and optimum use.
Inhaled anesthetics get access to the central nervous system by gaseous diffusion of the alveoli. Accordingly, the effects of these anesthetics are dependent on the alveolar concentration. The partial pressure of the inhaled anesthetic and the alveolar ventilation are two important parameters that affect the alveolar concentration of a given anesthetic.
The partial pressure or intrinsic concentration is defined as the partial pressure of an inhaled anesthetic compared to the other components of the ventilated air, i.e. oxygen, nitrogen etc. Increasing the intrinsic concentration of the inhaled anesthetic is therefore directly related to an increase in the blood concentration of the anesthetic compound and also to the rate at which anesthetic induction can be achieved.
Alveolar ventilation also contributes in the equation. The higher the tidal volume and the faster the ventilation rate, the more rapid the anesthetic concentration is going to rise in the blood.
In addition to these two parameters, the anesthetic effects of the different inhaled anesthetics also depend on their solubility. Anesthetics with low solubility such as nitrous oxide are going to have rapid onset and rapid recovery of the effect while anesthetics with good blood solubility such as halothane are expected to have a slower rate for onset and recovery.
Cardiac output is another important parameter that impacts anesthetic uptake but not induction. While increased cardiac output can allow for faster uptake of the inhaled anesthetic from the alveoli, the brain is well protected from rapid changes in blood concentrations of these compounds by a well-regulated blood brain barrier. Therefore, high cardiac output may result in peripheral distribution of the anesthetic without increasing the brain concentrations.
Elimination of the inhaled anesthetic is also dependent on the solubility of the compound. Similar to induction rate, the higher the solubility of the inhaled anesthetic in the blood the slower it will be eliminated. Newer inhaled anesthetics are mainly dependent on ventilation for their elimination and are little metabolized. This property of the newer inhaled drugs such as desflurane or sevoflurane make them safe in patients with liver or kidney disease.
Pharmacodynamics of Inhaled Anesthetics
While the anesthetic effect of the inhaled anesthetics is due to the direct action of the compounds on the central nervous system, inhaled anesthetics also affect the cardiovascular system, the respiratory system, the renal system, the liver and the smooth muscle cells of the uterus.
The main anesthetic effect can be explained by the suppression effect on brain metabolism and cerebral blood flow that is observed with inhaled anesthetics. While inhaled anesthetics decrease the cerebral blood flow similar to intravenous anesthetics, they also cause vasodilation in the brain. The central nervous system effects of inhaled anesthetics can be divided into four stages.
First, analgesia is achieved, followed by excitement, surgical anesthesia and finally medullary depression. The anesthesiologist aims to achieve either stage III or IV depending on his or her goals and the type of the procedure to be performed.
The surgical anesthesia stage can be achieved by the minimal alveolar concentration which is different for each inhaled anesthetic. At the medullary suppression stage, the patient would die if respiratory and cardiac support is not provided because the respiratory and cardiac control centers in the brain stem will be affected by the anesthetic.
The effects of the different inhaled anesthetics on the brain can also be appreciated by doing a simultaneous electroencephalogram (EEG) during anesthetic induction.
While this procedure is usually done for research purposes it also gave us some insights about the epileptogenic effects of sevoflurane and enflurane. While sevoflurane can cause epileptic spikes and slow wave complexes on the EEG, only enflurane was associated with the induction of clinical seizures. Hence, the use of enflurane for epilepsy surgery is not recommended.
Inhaled anesthetics also have an effect on the cardiovascular system. They decrease cardiac contractility, mean arterial blood pressure and induce vasodilation. Vasodilation decreases peripheral vascular resistance which in turn also contributes to the reduction in the mean arterial blood pressure.
Isoflurane, desflurane and sevoflurane have a lower impact on the cardiac output compared to halothane or enflurane, hence they are recommended in patients with heart failure. Halothane might induce arrhythmias in selected patients.
Inhaled anesthetics also have an impact on the respiratory function due to their effects on the central nervous system. They decrease ventilation, sensitivity to hypoxia, and might induce bronchospasm.
While newer inhaled anesthetics are not metabolized for elimination, they can still have an impact on the liver. Patients who are in hypovolemic shock are at an increased risk of inhaled anesthetic induced hepatitis. Patients who inhale nitrous oxide for long periods of time might develop megaloblastic anemia due to methionine deficiency.
Malignant hyperthermia is currently believed to be a heritable condition. In addition to volatile anesthetics, succinylcholine, a depolarizing muscle relaxant, can also cause malignant hyperthermia.
Patients develop muscle rigidity, hyperthermia, tachycardia, hypercapnia, hyperkalemia and metabolic acidosis. Patients develop these symptoms due to a sudden increase in the free cytosolic calcium concentration in skeletal muscles after exposure to one of the triggering agents.
Management of malignant hyperthermia includes appropriate fluid and electrolytes replacement therapy and the administration of dantrolene. Dantrolene prevents calcium release from the sarcoplasmic reticulum.
Patients who are known to be at risk, i.e. family history of malignant hyperthermia, should undergo the caffeine-halothane contracture test. A skeletal muscle biopsy is taken from the patient and caffeine-halothane mixture is injected. If the test is positive, then the patient should not be administered a volatile anesthetic.
Barbiturates such as thiopental and methohexital induce anesthesia by a mechanism of action that involves the GABAA receptors.
Thiopental is also recommended in traumatic brain injuries patients to induce coma or for urgent surgical intervention for example for an epidural hematoma because it decreases the intracranial pressure by decreasing the cerebral blood flow without inducing vasodilation. Inhaled anesthetics might also decrease cerebral blood flow but they cause vasodilation.
Diazepam can be used rectally for seizure’s abortion but is unlikely to be of benefit in patients undergoing surgery because it does not have an anesthetic or an analgesic effect. It can, however, decrease anxiety presurgically. Midazolam on the other hand can be used to induce anesthesia. Benzodiazepines also act on GABA receptors.
Ketamine is a dissociate analgesic. It does not induce loss of consciousness but causes analgesia and amnesia. The patients can undergo day-care procedures with ketamine. They will be awake during the procedure but the procedure will be painless and they will not remember the procedure afterwards.
Ketamine acts by inhibiting the NMDA glutamate receptors. Ketamine should not be used in patients with brain tumors or traumatic brain injuries because it can increase the intracranial pressure. Additionally, ketamine should be used with caution in patients with cardiovascular disease because it can elevate the blood pressure.
Propofol induces anesthesia very rapidly and the effects wears off very quickly. It is currently being used in the intensive care unit, in surgeries and during laparoscopic surgeries.
Additionally, Propofol has been previously used in patients undergoing therapeutic endoscopy. Propofol can cause hypotension which might complicate cases who are at an increased risk of peripheral vascular injury, i.e. hypovolemic patients.