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Chapter 3 Agents and Adjuncts

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Propofol, , and are used only in small animals, small ruminants, and neonates of any species, but not in adult large animals because of the high expense of these agents. The ultra-short injectable are no longer used in general practice in the US due to recent changes in anesthetic practice and limited availability.

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Since its introduction to the veterinary market almost two decades ago, its popularity has gradually increased, and now it is the most commonly used ultra– short-acting injectable agent in small animals for brief procedures or for anesthetic induction before intubation and maintenance with inhalant agents.

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The macroemulsion contains propofol at a concentration of 10 mg/mL as well as egg lecithin, glycerin, and soybean oil. It has a milky appearance but is given by the IV route and consequently is the sole exception to the general rule that milky liquids should never be given intravenously.

Although the mode of action is not completely understood, propofol appears to affect GABA receptors in a similar manner to other . Propofol has a rapid onset and short duration of action because it is highly fat-soluble. Propofol is rapidly taken up by vessel-rich tissues such as the brain, heart, , and kidneys but is very quickly redistributed to muscle and fat and is subsequently rapidly metabolized. This accounts for the rapid recovery and minimal residual effects seen even after repeated injections.

The onset of action is about 30 to 60 seconds, and the duration of action is 2 to 5 minutes after a single bolus, with complete recovery in 20 minutes () and 30 minutes ().

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95% to 99% of propofol travels in the blood bound to plasma proteins and 1% to 5% freely circulates. Only the free (unbound) molecules of propofol are able to enter the brain to induce because the molecules bound to proteins are unable to cross cell membranes. In hypoproteinemic animals (that is, those with total plasma protein less than 3 g/dL) there is less plasma protein to bind propofol molecules and more propofol in the active, unbound form.

The tendency of a drug to dissolve in fats, oils, or lipids is referred to as lipid solubility (also called partition coefficient) and is related to the ability to penetrate the fatty layer of the cell membranes. Propofol is highly lipid-soluble and therefore passes into the brain cells quickly, causing a faster onset of action as compared with other drugs with low lipid solubility.

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Tissue redistribution is a phenomenon that occurs because of the way in which this drug is distributed to various tissues based on blood flow. After IV administration, absorption is most rapid in tissues with very high blood flow, known as the vessel-rich group (the CNS, heart, liver, , and endocrine tissues), which make up only about 10% of total body weight but receive about 75% of the total blood flow. Absorption is less rapid in muscle, which makes up about 50% of the body weight but receives only 20% of the blood flow, and slowest in fat, which makes up about 20% of body weight but receives a meager 5% of the blood flow.

Propofol is highly lipid-soluble, and its entry into brain tissue is enhanced by the high lipid content of the brain. The rapid absorption of propofol into the brain causes the animal to lose consciousness within 30 to 60 seconds of .

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TECHNICIAN NOTE Major effects and adverse effects of propofol are as follows: • CNS depression ranging from sedation to general anesthesia • Transient excitement, muscle tremors, and seizure-like activity during induction • Bradycardia, decreased cardiac output, and that can be significant and prolonged in some patients • Respiratory depression including especially after rapid injection or high doses • Prolonged apnea, decreased oxygen saturation, and cyanosis • Muscle twitching during induction • Muscle relaxation • Antiemetic effect • Decreased intracranial and intraocular pressure • Pain on IV injection

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A longer recovery time is needed if multiple injections were used. In dogs, recovery from propofol anesthesia is rapid and smooth, even after multiple injections. Because of the rapid recovery seen with this agent, it is useful for patients that need to be released immediately after surgery. Dogs that have received propofol may appear completely recovered within 20 minutes of the final dose. Cats recover within about 30 minutes after a single injection but may experience longer recoveries after multiple injections owing to the fact that they metabolize propofol more slowly. Chapter 3 Anesthetic Agents and Adjuncts

TECHNICIAN NOTE Propofol should be handled in a strictly aseptic manner. The manufacturer recommends that unused propofol macroemulsion that contains no preservative should be discarded within 6 hours of opening to avoid contamination. Unused portions of PropoFlo™28 and propofol microemulsions can be stored at room temperature for up to 28 days after opening.

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This agent was originally marketed in the 1970s, but was ultimately taken off the market in most countries due to adverse effects caused by the solubilizing agent in the formulation. The currently available formulation contains a different solubilizing agent that does not cause these undesirable effects.

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Major effects and adverse effects of alfaxalone are as follows: • CNS depression ranging from sedation to general anesthesia • Minimal cardiovascular depression • Tachycardia • Hypotension especially when used with inhalant anesthetics • Respiratory depression including apnea especially after rapid injection or high doses • Muscle relaxation • Excitement during recovery may occur

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TECHNICIAN NOTE Uses for are as follows: The ultra–short-acting barbiturates thiopental sodium and were used for many years to induce anesthesia primarily in dogs, cats, and horses, although in recent years, these agents have been unavailable or difficult to obtain. The short-acting barbiturate is used to induce and maintain general anesthesia in laboratory animals and to treat status epilepticus in small animals. The long-acting barbiturate is used as a sedative and anticonvulsant.

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Phencyclidine has a high potential for abuse so it not used in veterinary medicine. may be given orally to restrain feral cats. Ketamine is a controlled substance. Chapter 3 Anesthetic Agents and Adjuncts

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The unusual combination of actions result in a distinctive trancelike state termed anesthesia (so called because it dissociates various regions of the brain), in which the animal appears awake but immobile and unaware of its surroundings (Figure 3-7). Dissociative anesthesia is described in the section on effects on the central nervous system. The effects of dissociative agents on the cardiovascular and pulmonary systems are also unique and different than effects produced by most other anesthetic agents.

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TECHNICIAN NOTE Major effects and adverse effects of are as follows: Cataleptoid state Intact reflexes Eyes open, pupils central and dilated Normal or increased muscle tone Analgesia (primarily somatic) Sensitivity to sound, light, or other sensory stimuli, seizure-like activity, or bizarre behavior especially during recovery Nystagmus Increased heart rate, cardiac output, and mean arterial pressure (MAP) secondary to SNS stimulation Decreased inotropy Apneustic respiration at higher doses Increased salivary and respiratory tract secretions Pain after IM injection

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• Dissociative anesthetics do not affect the in the same way as most other anesthetics. and tidal volume may change, but respiratory depression is usually insignificant at usual doses. At higher doses, animals exhibit apneustic respiration, a breathing pattern in which there is a pause for several seconds at the end of the inspiratory phase, followed by a short, quick expiratory phase. These animals appear to hold their breath. • Although not usually a problem at conventional doses, overdoses may cause severe respiratory depression or respiratory arrest. • Dissociatives also significantly increase salivation and respiratory tract secretions. Care must be taken to ensure that the airway is protected to prevent aspiration. Anticholinergics can be used to control these signs but may further predispose the patient to cardiac .

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TECHNICIAN NOTE Major effects and adverse effects of guaifenesin are as follows: • Skeletal muscle relaxation • Minimal cardiopulmonary effects • Few adverse effects at therapeutic doses • Thrombophlebitis after IV injection • Tissue reaction after perivascular injection

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Use 5% to 10% solution in dextrose to minimize hemolysis. Chapter 3 Anesthetic Agents and Adjuncts

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The first inhalant anesthetics are no longer used because they have been gradually replaced by the halogenated agents, which continue to be among the safest and most commonly used anesthetics. In fact, their use is so commonplace for such a wide variety of routine veterinary procedures that it is difficult to imagine caring for patients without them.

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Also , , , and . Oxygen-anesthetic mixture delivered to patient through a breathing circuit. Chapter 3 Anesthetic Agents and Adjuncts

Mechanism of action is not fully understood. Chapter 3 Anesthetic Agents and Adjuncts

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TECHNICIAN NOTE Halogenated anesthetics are considered safe for most patients relative to other anesthetics. However, safety depends to a large degree on the care with which these agents are administered and the vigilance of the anesthetist in monitoring their effect on the patient.

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Not all inhalant anesthetic agents are the same. Inhalation anesthetic agents also differ in how they affect the cardiovascular, respiratory, and other vital systems. Table 3-3 summarizes the physical properties and pharmacology of commonly used anesthetic agents. Chapter 3 Anesthetic Agents and Adjuncts

TECHNICIAN NOTE Vapor pressure is a measure of the tendency of a liquid anesthetic to evaporate and is significant to the anesthetist because it determines whether a precision or nonprecision vaporizer is used to deliver the agent.

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Vapor pressure is measured at 20°C (68°F). can be delivered with a nonprecision vaporizer if carefully monitored. A 5% mixture is the concentration needed for anesthesia. The concentration level can easily rise about that level because of the high vapor pressure of isoflurane. Most precision vaporizers have a maximum 5% concentration delivery level. A nonprecision vaporizer could be a glass jar with a wick. Methoxyflurane is no longer available in the United States. Chapter 3 Anesthetic Agents and Adjuncts

A low blood-gas partition coefficient means the agent will enter and leave the blood rapidly. has a low blood-gas partition coefficient so it is characterized by very rapid induction and recovery rates.

TECHNICIAN NOTE The blood-gas partition coefficient is a measure of the solubility of an inhalant anesthetic in blood as compared with alveolar gas. It is significant because it indicates the speed of induction and recovery one should expect for a given inhalant anesthetic. The lower the blood-gas partition coefficient, the faster the expected induction and recovery Chapter 3 Anesthetic Agents and Adjuncts

A high blood-gas partition coefficient means a low concentration gradient will be created and the agent will enter the blood slowly. It will also leave tissues more slowly. Methoxyflurane has a high blood-gas partition coefficient. Chapter 3 Anesthetic Agents and Adjuncts

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MAC is measured as the lowest concentration of the agent at which 50% of patients show no response to painful stimulus. A vaporizer setting of 1 × MAC will maintain light surgical anesthesia, 1.5 × MAC will maintain moderate surgical anesthesia, and 2 × MAC will maintain deep surgical anesthesia in most patients.

TECHNICIAN NOTE The MAC of an anesthetic agent is the lowest concentration at which 50% of patients show no response to a painful stimulus. It is significant because it is a measure of the potency of the agent and is used to determine the average setting that must be used to produce surgical anesthesia. Chapter 3 Anesthetic Agents and Adjuncts

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Isoflurane vapors are irritating to some animals so they will resist induction with a mask. Must be careful not to turn off the vaporizer too soon as animals recover quickly. Animals respond quickly to changes in the vaporizer setting during anesthesia. A low rubber solubility means that little anesthetic agent will be lost by absorption into the rubber components of the anesthetic machine and breathing circuit. The lack of preservatives means that there will be no preservative residue that accumulates in the vaporizer.

TECHNICIAN NOTE Of the volatile anesthetics commonly used in veterinary anesthesia, isoflurane is considered to have the fewest adverse cardiovascular effects and is therefore considered to be the inhalation agent of choice for patients with cardiac disease. Chapter 3 Anesthetic Agents and Adjuncts

Because of its minimal cardiovascular effects, isoflurane is the agent of choice in patients with cardiac disease. Isoflurane is used in patients with head trauma or brain tumors because it maintains cerebral blood flow. There is little retention of isoflurane in body fat because it is almost completely eliminated from the body through the after the vaporizer has been turned off. This also makes it the agent of choice for patients with liver or kidney disease, neonatal patients, and geriatric patients. Unless given an after anesthesia, the patient may show signs of pain and excitement during recovery. Carbon monoxide poisoning is characterized by cherry-red blood and mucous membranes and must be treated immediately. Chapter 3 Anesthetic Agents and Adjuncts

Sevoflurane is nonirritating so it is the agent of choice for mask or chamber induction. High controllability of depth of anesthesia is desirable for equine patients. Sevoflurane is less potent than isoflurane and therefore higher concentrations are needed to induce and maintain anesthesia.

TECHNICIAN NOTE Sevoflurane is the inhalant agent best suited to mask and chamber inductions. The high controllability of anesthetic depth associated with sevoflurane has made this agent popular in equine anesthesia, despite its relatively high cost. Chapter 3 Anesthetic Agents and Adjuncts

Being the least potent agent means that the highest concentration of the agent must be used to induce and maintain anesthesia. Known as the “one breath anesthesia” because of the rapid recovery (one breath).

Halogenated Organic Compounds Chapter 3 Anesthetic Agents and Adjuncts

Appendix B contains detailed information on the use of . Chapter 3 Anesthetic Agents and Adjuncts

TECHNICIAN NOTE The advantages of nitrous oxide were significant when older agents such as methoxyflurane and halothane were in use. These advantages are much less important with the advent of newer agents such as isoflurane and sevoflurane. Consequently, nitrous oxide is now seldom used in general practice. There are unique characteristics of nitrous oxide, including adverse effects and other cautions, with which the anesthetist must be familiar if using this agent. The reader is directed to Appendix C for detailed information about its use.

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Doxapram stimulates the respiratory centers in the brainstem. Most anesthetic agents and many adjuncts are respiratory system , so respiratory depression is commonly seen during anesthesia. This complication is usually managed by precise control of anesthetic depth and, if needed, manual or mechanical-assisted or mechanical-controlled ventilation. In emergency situations, severe respiratory depression associated with and alpha2- agonists can be treated with reversal agents, but the beneficial effects of the corresponding agonist, including sedation, analgesia, and hypnosis, will also be lost. When complete reversal is not desirable or when agents that cannot be reversed are used, the anesthetist may need to use other methods to manage respiratory depression. The pharmacologic agent most commonly used for this purpose is doxapram. Doxapram stimulates the respiratory centers in the brainstem. Chapter 3 Anesthetic Agents and Adjuncts

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TECHNICIAN NOTE One drop of doxapram solution contains approximately 1 mg of doxapram. To stimulate respirations, 1 to 5 drops can be dripped under a neonatal puppy’s tongue, and 1 to 2 drops under a kitten’s tongue, depending on patient size and degree of depression.

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