Overview of a General Anesthetic

Dalia Elmofty

Thomas Cutter

▪ EARLY HISTORY OF ANESTHESIA AGENTS

An anesthetic involves the administration of various intravenous and inhalational agents to produce a state in which a patient may safely and comfortably undergo a procedure. While the medical specialty of anesthesiology may be regarded as modern and “cutting edge,” many of the current medications have existed for centuries. The first known narcotic, opium, was found in a poppy plant, called the “joy plant” by the Sumerians, as far back as 3400 BC. In 1300 BC, the ancient Egyptians wrote about opium’s pain-relieving or analgesic properties. In 40 AD, the Greek physician Pedanius Dioscordes noted the effects of the plant Atropa mandragora, when it was used in combination with alcohol prior to surgery, and coined the term “anesthesia” to describe its effect. In 1803, Friedrich Wilhelm Serturner of Germany extracted the active ingredient from opium and named it morphine, after Morpheus, the Greek god of dreams.

The first inhalational anesthetic was described in 1800 by Sir Humphrey Davy as he personally experimented with nitrous oxide (“laughing gas”); he described it as producing a feeling of “well-being.” In 1818, Michael Faraday discovered that the volatile inhalational anesthetic ether could cause unconsciousness. In 1842, Crawford W. Long demonstrated ether’s effects on his colleagues during medical gatherings known as “ether frolics.” A dentist, William T. G. Morton, is credited with the use of the first inhalational anesthetic in a public demonstration at the Boston Massachusetts General Hospital in 1846 during a tooth extraction. The concept quickly spread and surgery flourished with the use of the new agents that could alleviate the pain and suffering of a surgical procedure (Figs. 20.1 and 20.2).

In Europe, chloroform was the preferred inhalational anesthetic. It was first described by Sir James Young Simpson, a Scottish obstetrician who administered it for labor pain. Dr. John Snow was recognized as the first professional anesthesiologist in England, when he provided a chloroform anesthetic to Queen Victoria during the birth of her children in 1853 and 1857.

Intravenous anesthesia using sedative/hypnotic medications was not possible until the syringe and hypodermic needle were invented by Alexander Wood of Edinburgh in 1855. Barbituric acid, the source of the barbiturate sodium pentothal, was discovered in 1864 by Adolph von Baeyer, but it was another six decades before the first short-acting intravenous barbiturate was used to induce unconsciousness by the German obstetrician Rudolph Bumm in 1927. Barbiturates have been largely replaced by propofol, which was introduced in the 1980s. Benzodiazepines, which at low doses relieve anxiety but at higher doses may cause unconsciousness, have been available since 1960. Midazolam, the most commonly used benzodiazepine in anesthetic medicine, has been available for over 20 years.

Curare was the first documented muscle relaxant, when, in 1800, Alexander von Humboldt wrote about a toxin from native plants by the Orinoco River that caused paralysis. It was not until the 1940s that curare was introduced into anesthesia as a muscle relaxant for surgery. Succinylcholine was introduced later by Bovet in 1949.

The local anesthetic cocaine is derived from the leaves of the coca plant and has been used by Peruvians for centuries as a stimulant. It was isolated in 1860 and first used as a local anesthetic by Carl Koller in 1884.

▪ FIGURE 20.1 Morton’s ether inhaler (1846) consisted of a glass bulb, an ether-soaked sponge, and a spout to be placed in patient’s mouth. (From Barash PG, Cullen BF, Stoelting RK. Clinical Anesthesia. Philadelphia, PA: Lippincott Williams & Wilkins; 2009, with permission.)

Inhalational gases, narcotics, local anesthetics, sedative hypnotics, and muscle relaxants are among the most commonly administered medications during anesthesia.

▪ FOUR GOALS OF AN ANESTHETIC

The four goals of an anesthetic are to provide a lack of awareness or amnesia, pain relief, immobility, and patient safety. Ideally, medications should have a fast onset, a predictable duration of action, and no side effects. Because no single medication can accomplish these four goals, an anesthesiologist often administers a “balanced anesthetic” with a small amount of a number of different drugs, thereby maximizing a drug’s positive effects while minimizing its side effects.

▪ FIGURE 20.2 Southworth and Hawes (1846) “Early operation using ether anesthesia.” The first public demonstration of inhalational anesthesia used during a tooth extraction by William T. G. Morton at Boston Massachusetts General Hospital. (Reproduced with permission from The J. Paul Getty Museum.)

The safe use of any anesthetic medication requires a thorough understanding of the drug’s pharmacology. Pharmacology can be divided into two parts: pharmacokinetics and pharmacodynamics (see Chapter 5). Pharmacodynamics is what the drug does to the body through interactions with receptors, cell membranes, enzymes and other proteins, and ion channels. The drug may either increase activity (agonist) or inhibit activity (antagonist). Pharmacokinetics is what the body does to the drug and includes the medication’s release from its formulation (liberation), its entry into the blood circulation (absorption), its spread through the fluids and tissues (redistribution), its breakdown (metabolism), and its elimination from the body (excretion).

Lack of Awareness

Lack of awareness is on a continuum, ranging from fully awake to moderate sedation to deep sedation to unconsciousness/general anesthesia (GA) (Fig. 20.3). The effects of various anesthetic agents on consciousness have been studied using the electroencephalogram (EEG), an instrument that measures electrical brain activity. Modified EEGs such as the BIS monitor are also occasionally used in the operating room to measure brain activity as an estimate of the depth of anesthesia. Total unconsciousness is associated with a marked decrease in EEG activity. Other techniques to measure brain activity include positron emission tomography (PET) and functional magnetic resonance imaging (fMRI).

By definition, a general anesthetic results in total unconsciousness, while other anesthetic techniques may result in only sedation or no reduction in consciousness at all. For example, a spinal anesthetic for a woman undergoing a cesarean section may not include any drugs to diminish awareness because of the concern for their effects on the baby. Medications that can cause unconsciousness include both inhalational gases and injectable medications.

Inhalational Gases

Nitrous oxide is a relatively weak inhalational anesthetic and does not typically produce total unconsciousness; thus, it is never used alone in a general anesthetic but instead supplements other medications. It works through both ion channel
and receptor activity and has a relatively benign side effect profile. Sevoflurane, desflurane, and isoflurane are common volatile inhalational agents and can be used as the sole agent for a general anesthetic.

▪ FIGURE 20.3 Excerpted from Continuum of Depth of Sedation: Definition of General Anesthesia and Levels of Sedation/Analgesia (Approved by the ASA House of Delegates on October 27, 2004, and amended on October 21, 2009) of the American Society of Anesthesiologists. A copy of the full text can be obtained from ASA, 520 N. Northwest Highway, Park Ridge, IL 60068-2573.

The exact mechanisms by which these volatile inhalational agents work are not entirely understood, but several theories have been proposed. On a molecular level, Meyer and Overton suggested that anesthetics work at the lipid portion of the nerve cell membrane. Later, Franks and Lieb determined that the site of action is at the protein layer of the cell membrane. The main receptor involved is the γ-aminobutyric acid (GABA) receptor, which is an inhibitory receptor. It is thought that certain anesthetic agents increase the inhibitory action of this receptor, thereby decreasing nerve cell activity and consciousness.

Volatile inhalational anesthetics must be vaporized from the liquid state and are administered from agent-specific vaporizers. A carrier gas
(e.g., oxygen) passes through the vaporizer and takes up the inhalational agent, just as a breeze will carry steam. The agent will then be carried to the patient through the breathing circuit to enter the lungs. Once in the lungs, it diffuses into the bloodstream where it is carried to the brain and elsewhere throughout the body. The inhalational agent’s speed of onset is inversely proportional to its solubility, which is indicated by the blood/gas coefficient (Table 20.1). The minimum alveolar concentration (MAC) is the concentration of the inhalational agent in the lungs that prevents movement in 50% of patients undergoing a surgical stimulus (e.g., being cut by a scalpel). Inhaled anesthetics are mainly eliminated from the body by exhalation, although there is some metabolism in the liver and excretion in the urine and through the skin.

As with all medications, gases have side effects. In the brain, they increase cerebral blood flow and intracranial pressure while decreasing cerebral metabolic oxygen consumption. Their effect on the ventilatory system (airway and lungs) is to depress respiration and bronchodilate. The pungent nature of desflurane can cause airway irritation. They also can decrease systemic vascular resistance and the heart’s contractility, thereby lowering blood pressure (hypotension). Isoflurane and desflurane can cause increased heart rate, which can cause ischemia (inadequate blood flow) in a patient with coronary artery disease.

Injectable Medications

Common intravenous sedative hypnotic agents that produce unconsciousness include propofol, etomidate, benzodiazepines (e.g., midazolam), and barbiturates (e.g., sodium pentothal) (Table 20.2). These work by depressing the reticular activating system, an area in the brain responsible for regulating arousal/wakefulness, and by increasing GABA action, inducing a loss of consciousness. Ketamine is an N-methyl D-aspartate (NMDA) antagonist that induces a state known as “dissociative anesthesia.” All of these agents are typically injected intravenously, although some can be injected intramuscularly or absorbed through moist surfaces (mucosa) such as those found in the nasal passages, the rectum, and the mouth. Their high lipid solubility in the brain results in a rapid onset of action. In many cases, their duration of action is primarily determined by redistribution (dilution) throughout the body rather than by metabolism or excretion. Thus, they accumulate when large doses are given and are more often used to start (induce) a general anesthetic than to maintain it.

Propofol’s side effects include pain at the site of injection, so it is often preceded by or administered along with the local anesthetic lidocaine. It also produces a dose-dependent hypotension as a result of decreasing the heart’s contractility and lowering the systemic vascular resistance and causes significant ventilatory depression (i.e., the patient can stop breathing). Sodium pentothal’s clinical profile is similar to propofol’s, but it does not hurt when injected and it does not lower the blood pressure quite as much. Its disadvantage is that its sedating effects persist longer than those of propofol. Etomidate causes less hypotension than either propofol or sodium pentothal, but it can suppress hormone (steroid) production and is relatively expensive. Midazolam is noted to have less adverse cardiovascular and ventilatory effects than any of the preceding drugs, but the doses required to cause unconsciousness require a long time to wear off. Ketamine also maintains hemodynamic and
ventilatory stability, but it has some significant psychological effects, such as hallucinations and nightmares, that may persist for days or weeks after administration.

TABLE 20.1 BLOOD/GAS COEFFICIENT, MAC, AND SIDE EFFECTS OF INHALATIONAL AGENTS

INHALATIONAL AGENT	BLOOD/GAS COEFFICIENT	MAC (%)	SIDE EFFECTS
INHALATIONAL AGENT	BLOOD/GAS COEFFICIENT	MAC (%)	HEART RATE	BLOOD PRESSURE
Desflurane	0.42	6.6	0-↑	↓
Sevoflurane	0.65	1.8	0	↓
Isoflurane	1.46	1.17	↑	↓
MAC, minimal alveolar concentration; ↓, decrease; ↑, increase; 0, no change.
Adapted from Barash PG, Cullen BF, Stoelting RK. Clinical Anesthesia. Philadelphia, PA: Lippincott Williams & Wilkins; 2009:420.

TABLE 20.2 COMMONLY USED INTRAVENOUS ANESTHETIC AGENTS

INTRAVENOUS ANESTHETIC AGENT	DOSE (mg/kg)	ONSET (s)	DURATION (min)	SIDE EFFECTS
INTRAVENOUS ANESTHETIC AGENT	DOSE (mg/kg)	ONSET (s)	DURATION (min)	HEART RATE	BLOOD PRESSURE
Propofol	1-2	15-45	5-10	0-↓	↓
Thiopental	3-6	<30	5-10	↑	↓
Etomidate	0.2-0.3	15-45	3-12	0	0
Ketamine	1-2	45-60	10-20	↑	↑
↓, decrease; ↑, increase; 0, no change.
Adapted from Barash PG, Cullen BF, Stoelting RK. Clinical Anesthesia. Philadelphia, PA: Lippincott Williams & Wilkins; 2009: 457.

Pain Relief (Analgesia)

Analgesia is defined as decreased pain sensation. Opioids are commonly used to produce analgesia and may be used alone or in conjunction with other analgesics such as local anesthetics, ketamine, dexmedetomidine, or clonidine. The administration of analgesic medications may reduce the reflex response to a painful stimulus that is often apparent as an increase in heart rate and blood pressure, each of which can endanger a patient if the increases are too great. Opioids act as agonists on receptors in the brain and the spinal cord and are therefore regarded as “centrally acting,” although there are also some effects throughout the body (“peripherally acting”) (Table 20.3). They have some sedativelike properties, but they cannot provide GA on their own. They are typically included as part of a balanced anesthetic to provide some sedation along with analgesia. They are associated with hemodynamic stability but have the significant side effect of ventilatory depression, especially when used with other drugs that cause sedation. Other centrally acting analgesics include dexmedetomidine and clonidine, which are agonists for α-receptors, and ketamine, which acts as an antagonist on NMDA receptors. Local anesthetics provide analgesia by blocking nerve cells’ ion channels, thereby preventing nerve signal transmission when they block the ion channels of the nerve cells.

TABLE 20.3 COMMONLY USED PARENTERAL NARCOTICS

NAME	DOSE	MECHANISM OF ACTION	ACTIVE METABOLITES	SIDE EFFECTS
Morphine	Intraoperative 0.1-1 mg/kg Postoperative 0.03-0.15 mg/kg	Prototypical µ-opioid receptor agonist	Morphine 6-glucuronide (analgesic property) Morphine 3-glucuronide (lacks analgesic property, neuroexcitatory side effects)	Nausea, vomiting, pruritis, sedation, respiratory depression, neuroexcitatory (CNS irritability, seizure, myoclonus)
Dilaudid	Intraoperative 1-2 mg Postoperative 0.2-1 mg	Hydrogenated ketone analogue of morphine	Hydromorphone 3-glucuronide (lacks analgesic property, neuroexcitatory side effects)	Nausea, vomiting, pruritis, sedation, respiratory depression, neuroexcitatory (CNS irritability, seizure, myoclonus)
Fentanyl	Intraoperative 2-150 µg/kg Postoperative 0.5-1.5 µg/kg	µ-opioid receptor agonist		Nausea, vomiting, pruritis, sedation, respiratory depression
Adapted from Morgan GE, Mikhail MS, Murray MJ. Clinical Anesthesia. The McGraw-Hill Companies, Inc.; 2006:196.

Immobility

A still, nonmoving patient is essential for a successful operation. Movement is a result of muscle contractions that occur when a signal originates in the brain, travels down the spinal cord, and then out to a peripheral nerve to the neuromuscular junction, which is where the nerve comes into close contact with the muscle (Fig. 20.4). A substance known as acetylcholine (ACh) is released from the nerve and attaches to receptors on the muscle, where it causes a change in the muscle’s electrical properties (depolarization). This results in an exchange of sodium into the muscle cell and potassium out of the cell and triggers a muscle contraction. The contraction ends when ACh leaves the receptor and is metabolized by the enzyme acetylcholinesterase. The muscle repolarizes (relaxes) and is ready to depolarize (contract) again.

For some procedures, an awake or sedated patient who can cooperate is all that is needed. Other procedures require the patient to be unconscious and unable to create the motor nerve signal, or paralyzed and unable to transmit the signal. Local anesthetics block the nerves themselves that carry the signals, while neuromuscular blocking agents, also called muscle relaxants, block at the neuromuscular junction (see Chapter 16).

Depolarizing Muscle Relaxants

Succinylcholine is a depolarizing muscle relaxant and has a structure similar to that of ACh. It binds to the receptors on the muscles and causes prolonged depolarization, resulting in a sustained and uncoordinated total body muscle contraction (fasciculations) followed by relaxation. The muscles cannot contract again until the succinylcholine leaves the receptor and is metabolized by an enzyme called pseudocholinesterase. Succinylcholine has a rapid onset of action (30-60 seconds) and is clinically inactive in approximately 10 minutes.

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