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I commonly hear two questions from my patients: “How do anesthetics work?” and “How do the anesthetic drugs make me fall asleep?”
The short answer to both questions is, “We’re not sure.”
This column is designed as a brief tutorial for non-anesthesiologists who wish to better comprehend how anesthetic drugs work.
General anesthesia is the sum of hypnosis (sleep), amnesia, analgesia (pain relief), and the lack of any motion response to pain. Propofol and barbiturates cause hypnosis. Versed and other benzodiazepines cause amnesia. Narcotics such as morphine and fentanyl cause analgesia. Paralyzing drugs such as rocuronium, vecuronium and succinylcholine cause muscle relaxation and lack of motion.
The potent inhaled anesthetics sevoflurane, desflurane, and isoflurane produce all four of the effects of hypnosis, amnesia, analgesia, and lack of motion.
The molecules of anesthetic drugs have great diversity. Some are very small, such as nitrous oxide, while others such as propofol or barbiturates have complex formulas. Some are gases and some are injected liquids. This diversity leads investigators to postulate that there are multiple mechanisms of action for anesthetic drugs on the brain.
Drugs such as propofol and Versed are injected into the bloodstream and are circulated to the central nervous system, where they carry out their effect on brain cells. Inhaled anesthetics such as sevoflurane and desflurane traverse from the lungs into the bloodstream and are circulated to the central nervous system, where they carry out their effect on brain cells.
Once in the brain, it’s not clear how anesthetic drugs work. Most anesthetic drugs are hydrophobic, which literally translates to “water fearing.” This means their molecules are more soluble in fat than in water. Anesthetic drugs exhibit a correlation between their potency and how hydrophobic they are. The entry of any drug into a brain cell must be via the outer lining, or membrane, of that cell. Investigators believe anesthetics must move through, or bind to, the fat-soluble aspects of the membranes of brain cells. The drugs likely then bind to proteins within the cell membranes, and cause their anesthetic effect by changing the characteristics of ion channels within the cell membranes. There is no unifying theory as to how this occurs, but it is known that anesthetic agents have effects on brain cell membrane proteins, which depend on the hydrophobic, electrostatic, and size properties of the individual drug.
Specific examples in our understanding of anesthetic actions include:
(1) Barbiturate drugs, propofol, and inhalational anesthetics are known to act by potentiating a brain chemical called gamma-aminobutyric acid, or GABA. GABA is an inhibitory neurotransmitter, meaning it’s a brain chemical which inhibits other brain activity. This inhibition in some way promotes unconsciousness.
(2) The anesthetics nitrous oxide and ketamine are known to antagonize an excitatory N–methyl-d-aspartate (NMDA) subtype of neurotransmitter. By blunting this excitatory process, the drugs work to promote unconsciousness.
The takeaway message is that no specific premise exists to explain how all the different general anesthetic drugs work on the brain. A variety of mechanisms likely results in similar effects on the brain, each eliminating the transmission of sensory messages to the brain and initiating unconsciousness.
Anesthesiologists administer other types of drugs, including narcotics, paralyzing drugs, and local anesthetics. The mechanisms of action of these medications are better understood.
Narcotics such as morphine, fentanyl, Demerol, or Dilaudid cause pain relief by binding to opioid receptors in the brain (or the spinal cord). The most common narcotic side effects, e.g. sleepiness and nausea, also arise from the direct effect of the narcotics on the brain. Narcotics bind to three specific receptors in the central nervous system: the mu, delta, and kappa receptors. The mu receptor is primarily responsible for the pain-relieving and euphoria-inducing effects of narcotics. Investigators are searching for new narcotics to specifically target the mu receptor, with the aim of reducing side effects of sedation and nausea.
Muscle relaxants (muscle paralyzing drugs) such as rocuronium, vecuronium, and succinylcholine act on the body’s peripheral skeletal muscles. Muscles normally contract when a neurotransmitter molecule named acetylcholine travels from a nerve ending and binds to a receptor on the neuromuscular junction on the muscle. This binding causes the muscle to contract. Succinylcholine paralyzes muscles by binding to and activating the acetylcholine receptor, first by causing a muscle contraction and then by rendering the muscle flaccid. Rocuronium and vecuronium paralyze muscles by competitively binding to the receptor and blocking the normal access of acetylcholine, which renders the muscle flaccid.
Local anesthetic drugs such as lidocaine, bupivicaine (Marcaine), and ropivicaine temporarily block the function of nerves outside the central nervous system. These local anesthetic drugs block the peripheral nerve from conducting of the feeling of pain to the brain. Nerve conduction is dependent on the opening of sodium channels in nerve cell membranes, allowing an influx of sodium ions into the nerve. The blocking of sodium transport renders the nerve incapable of transmitting the pain message.
Modern anesthetic care can involve all the drugs discussed above. For example, in a general anesthetic for an abdominal surgery, the anesthesiologist may inject Versed into the IV as a premedication to reduce anxiety, then inject propofol into the IV to initiate sleep, and inject rocuronium into the IV to induce muscle relaxation/paralysis prior to inserting an endotracheal breathing tube. General anesthesia is then maintained by the administration of a potent inhaled anesthetic gas such as sevoflurane, supplemented by the intravenous injection of a narcotic such as fentanyl to assure post-operative pain relief.
Physician anesthesiologists must master the diverse anesthetic drug repertoire of injectable hypnotics, narcotics, muscle relaxants, as well as the inhaled general anesthetics. The selection of the proper anesthetic drugs and doses for each individual patient makes anesthesiology both fun and fascinating.
Reference: Mantilla CB, Wong GY, Molecular and cellular mechanisms of anesthesia, Faust’s Anesthesiology Review, Elsevier, 2013, Chapter 60, 139-41.
Published in September 2017: The second edition of THE DOCTOR AND MR. DYLAN, Dr. Novak’s debut novel, a medical-legal mystery which blends the science and practice of anesthesiology with unforgettable characters, a page-turning plot, and the legacy of Nobel Prize winner Bob Dylan.
In this debut thriller, tragedies strike an anesthesiologist as he tries to start a new life with his son.
Dr. Nico Antone, an anesthesiologist at Stanford University, is married to Alexandra, a high-powered real estate agent obsessed with money. Their son, Johnny, an 11th-grader with immense potential, struggles to get the grades he’ll need to attend an Ivy League college. After a screaming match with Alexandra, Nico moves himself and Johnny from Palo Alto, California, to his frozen childhood home of Hibbing, Minnesota. The move should help Johnny improve his grades and thus seem more attractive to universities, but Nico loves the freedom from his wife, too.
Hibbing also happens to be the hometown of music icon Bob Dylan. Joining the hospital staff, Nico runs afoul of a grouchy nurse anesthetist calling himself Bobby Dylan, who plays Dylan songs twice a week in a bar called Heaven’s Door. As Nico and Johnny settle in, their lives turn around; they even start dating the gorgeous mother/daughter pair of Lena and Echo Johnson. However, when Johnny accidentally impregnates Echo, the lives of the Hibbing transplants start to implode. In true page-turner fashion, first-time novelist Novak gets started by killing soulless Alexandra, which accelerates the downfall of his underdog protagonist now accused of murder. Dialogue is pitch-perfect, and the insults hurled between Nico and his wife are as hilarious as they are hurtful: “Are you my husband, Nico? Or my dependent?”
The author’s medical expertise proves central to the plot, and there are a few grisly moments, as when “dark blood percolated” from a patient’s nostrils “like coffee grounds.” Bob Dylan details add quirkiness to what might otherwise be a chilly revenge tale; we’re told, for instance, that Dylan taught “every singer with a less-than-perfect voice…how to sneer and twist off syllables.” Courtroom scenes toward the end crackle with energy, though one scene involving a snowmobile ties up a certain plot thread too neatly. By the end, Nico has rolled with a great many punches.
Nuanced characterization and crafty details help this debut soar.
Click on the image below to reach the Amazon link to The Doctor and Mr. Dylan:
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