Chapter 3 Agents and Adjuncts

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Anesthetic agents and adjuncts may be classified a number of ways. First, they may be classified based on the route of administration. Inhalant agents are administered from an anesthetic machine into the lower respiratory tree via an endotracheal tube or mask. Injectable agents are injected intravenously, intramuscularly, subcutaneously, intraperitoneally, intralesionally, or into a number of other locations. Oral agents are given by mouth, and topical agents are applied to a body surface such as the skin or mucous membranes. Another way these agents may be classified is based on the time period at which they are given during the course of an anesthetic procedure. given before general anesthesia are referred to as preanesthetic medications. Drugs used to induce general anesthesia are referred to as induction agents, and those used to maintain general anesthesia are referred to as maintenance agents. A third way anesthetic agents and adjuncts may be classified is according to the principal effect. Local induce a loss of sensation in a localized area of the body. In contrast, general anesthetics induce a loss of sensation over the entire body, accompanied by unconsciousness. Sedatives and tranquilizers are agents that cause sedation and tranquilization, respectively. Analgesics prevent and control pain. Muscle relaxants decrease muscle tone. Chapter 3 Anesthetic Agents and Adjuncts

Neuromuscular blockers, although infrequently used in general practice, are used to relax or paralyze skeletal muscles during ophthalmic, orthopedic, or other surgeries. Anticholinergic agents are used to decrease effects of parasympathetic nervous system (PNS) stimulation such as bradycardia and excessive salivation. Finally, reversal agents lessen or abolish the effects of other anesthetic agents and are therefore used to “wake” the patient after sedation or anesthesia. Many of the agents used in anesthesia cause two or more of these effects, depending on the dose and the circumstances under which they are used. For instance, morphine causes sedation and is an excellent analgesic. The injectable dexmedetomidine causes moderate to profound sedation, analgesia, and good muscle relaxation when given alone but can be used in combination with other agents to induce general anesthesia. The intravenous (IV) anesthetic propofol induces general anesthesia at higher doses but can be used as a sedative when given as a low-dose constant rate infusion (CRI). As a consequence, classification of these agents based on the principal effect is somewhat arbitrary.

The final way anesthetic agents and adjuncts may be classified is based on their chemistry. For the student, this is perhaps the most useful method of classification because the agents within a given class tend to have similar properties and effects. For this reason, the anesthetic agents and adjuncts Chapter 3 Anesthetic Agents and Adjuncts

discussed herein will be presented this way. Tables 3-1 to 3-4 summarize the principal effects and adverse effects of the anesthetic agents and adjuncts.

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Before embarking on a study of anesthetic agents and adjuncts, a general knowledge of pharmacokinetics (the effect the body has on a drug) and pharmacodynamics (the effects a drug has on the body) is necessary.

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Anesthetic agents and adjuncts differ according to the degree to which they stimulate target tissue receptors. Agonists bind to and stimulate tissue receptors. Most anesthetics and adjuncts are classified as agonists.

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Some drug classes such as the alpha2-adrenergics and include drugs that are classified as antagonists. Antagonists bind to but do not stimulate receptors. Antagonists competitively bind to target tissues preventing the corresponding agonist from causing more stimulation. Must use the proper antagonist when “waking” a patient from anesthesia. Chapter 3 Anesthetic Agents and Adjuncts

The class also includes some partial agonists and agonist-antagonists. Partial agonists bind to and partially stimulate receptors. Agonist-antagonists bind to more than one receptor type and simultaneously stimulate at least one and block at least one. Both partial agonists and agonist-antagonists are sometimes used to partially block the effects of pure agonists.

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Most anesthesia protocols use a combination of drugs to provide adequate analgesia and anesthesia.

TECHNICIAN NOTE Many commonly used general anesthetics are not analgesics but indirectly provide pain control during the anesthetic period by producing a state of unconsciousness. Therefore when these agents are used, analgesia in the peri- operative period must be provided by the use of true analgesics such as the opioids. Chapter 3 Anesthetic Agents and Adjuncts

Two or more anesthetic agents and/or adjuncts are often used in combination. Some drugs can be safely mixed in the same syringe, whereas others cannot. Incompatible mixtures can produce a variety of harmful or even fatal adverse effects because of loss of potency, change in chemistry, precipitation of one or more of the drugs, or other untoward interactions. For this reason, the anesthetist must observe some general guidelines when faced with a decision to mix two or more drugs.

TECHNICIAN NOTE With the exception of diazepam, most anesthetic agents and adjuncts are water- soluble. In general, two or more water-soluble drugs can be safely mixed, but a water-soluble drug and a non–water-soluble drug cannot. For this reason, when using two or more drugs in the same patient, do not mix them unless you are sure that it is safe to do so.

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Any use of a controlled substances necessitates compliance with strict handling and storage requirements as well as detailed record-keeping requirements owing to the potential for abuse or theft. Specifically, these agents are subject to diversion by people for illicit purposes, and, when used in this manner, have the potential to induce psychological and/or physical dependency. Theft, illegal use, or diversion of a controlled substance is a criminal act that is punishable by imprisonment and/or fines, and may affect eligibility for professional licensure.

In the United States, the Controlled Substances Act assigns each drug to one of five drug schedules (I, II, III, IV, or V) according to its potential for abuse. In a similar way, Canadian legislation has classified each agent as a narcotic, controlled, or prescription drug. Agents classified as narcotics in Canada or as Schedule II substances in the United States cannot be dispensed or drawn into a syringe except under the direct supervision of a licensed veterinarian.

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The inventory must include: • the date the inventory was taken including whether or not it was taken at the beginning or end of the day • the finished form of the drug (e.g. injectable, tablets, oral liquid) • the amount of each drug on hand (e.g. volume for liquid drugs, number of tablets) • the drug concentration (e.g. 10 mg/ml, 100 mg tablets) • the number of containers of each drug (e.g. five 10 ml bottles, two 500 tablet bottles) It should also include the name, address, and DEA registration number of the registrant and the signature of the person that took the inventory

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Schedule II controlled substances may be ordered only by using DEA From 222, which must be filled out in triplicate. Two copies are forwarded to the supplier, and one is retained by the purchaser. No special order form is necessary for Schedule III and IV agents, however the supplier must verify that the purchaser is registered.

In June 2010, electronic prescription writing was approved by the DEA, but in order to participate in this program, only software that meets DEA requirements can be used.

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Carfentanil and etorphine hydrochloride (highly potent opioid agonists used to immobilize wild animals) and diprenorphine (a highly potent opioid antagonist used to reverse effects of carfentanil and etorphine in wild animals) must be stored in a safe or steel cabinet. These substances are highly dangerous to humans, and therefore must be used with great caution.

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(See Box 3-1 for DEA prescription writing requirements.)

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These are the principal reasons for giving commonly used preanesthetic medications follow. Table 3-6 summarizes these benefits.

TECHNICIAN NOTE Patients given sedatives by the IM or SC route should be left undisturbed until peak action is reached because excitement or stimulation can sometimes cause the patient to override the effects. Drugs given intravenously should be administered slowly and cautiously because potency and the potential for adverse effects are increased when drugs are given by this route.

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Give either drug IM 20-30 minutes before anesthetic induction. Chapter 3 Anesthetic Agents and Adjuncts

Also known as parasympatholytics, anticholinergics are noncontrolled drugs that are most commonly used to prevent and treat bradycardia and to decrease salivary secretions arising from parasympathetic stimulation. The two anticholinergic agents commonly used in veterinary medicine are and glycopyrrolate. Secretions from the respiratory system, gastrointestinal system, salivary glands, and eye will be decreased. Ophthalmic lubricating ointment will prevent corneal drying. Chapter 3 Anesthetic Agents and Adjuncts

TECHNICIAN NOTE Major effects and adverse effects of anticholinergics are as follows: • Prevention of bradycardia • Increased heart rate • Cardiac arrhythmias • Reduction and thickening of respiratory secretions • Bronchodilatation • Mydriasis • Reduction of GI, salivary, and lacrimal secretions. • Inhibition of peristalsis

TECHNICIAN NOTE Atropine is available in two strengths that vary in concentration by a factor of nearly 30. When drawing up the drug, remember to check the concentration on the bottle so that you do not mix the two up!

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These two terms are often used interchangeably even though they are not the same. Tranquilizer—reduces anxiety but not awareness or wakefulness. Sedative—reduces mental activity and causes sleepiness. Most veterinarians use the terms sedative and tranquilizer interchangeably, however. This is because the effects of these drugs often overlap, as most of these drugs produce both effects to some.

Three classes of tranquilizers or sedatives are commonly used in veterinary medicine: phenothiazines, benzodiazepines, and alpha2-adrenoceptor agonists (alpha2-agonists). In addition to tranquilization and sedation, some also cause other effects including ataxia and prolapse of the nictitating membrane (also called the third eyelid) (Figure 3-3). Chapter 3 Anesthetic Agents and Adjuncts

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TECHNICIAN NOTE Major effects and adverse effects of phenothiazines are as follows: Calming, sedation, reluctance to move Reduction of the seizure threshold Tachycardia or bradycardia Antiarrhythmic effects Peripheral vasodilatation Hypotension Antiemetic effects Penile prolapse in horses and other large animals Decreased PCV

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Patients should be placed in a quiet location free from stimulation between administration and peak effect, because the sedative effects can be overridden if the patient is stimulated to a sufficient degree. Make sure needle is in a vein, not in an artery. Overdoses are treated with phenylephrine or norepinephrine.

Responses to this drug are also species- and breed-dependent. Doses should be reduced 25% in collies and Australian shepherds to minimize the possibility of exaggerated or prolonged sedation. Giant breed dogs, greyhounds, and boxers can be very sensitive to this drug and may experience severe bradycardia and hypotension. Terriers and cats are more resistant to its effects. Severe hypotension and bradycardia are treated with IV fluid therapy and anticholinergics. In horses, care must be taken to ensure that acepromazine is injected into a vein. Inadvertent injection into the carotid artery can cause severe CNS excitement or depression, seizures, and death.

TECHNICIAN NOTE The commonly used dose of acepromazine (about 0.05 to 0.1 mg/kg in small animals with a maximum dose of 3 mg in dogs and 1 mg in cats; 0.03 to 0.05 mg/kg in horses) is significantly less than the labeled dose. Higher doses will increase hypotension but not sedation. Chapter 3 Anesthetic Agents and Adjuncts

The benzodiazepines, also referred to as minor tranquilizers, are a group of DEA Schedule IV controlled, reversible drugs (with the exception of zolazepam, a component of the combination drug Telazol®, which is a schedule III product) most often used in combination with other agents for their muscle relaxant, anticonvulsant, and appetite-stimulating properties. These drugs produce unreliable sedative effects and in dogs, cats, and horses may instead produce dysphoria, excitement, and ataxia, especially when administered to young, healthy animals. Diazepam is the active ingredient in Valium. Only zolazepam (as a component of Telazol®) is approved for use in animals in the United States and Canada. Diazepam and midazolam are commonly used off-label in animals. Chapter 3 Anesthetic Agents and Adjuncts

TECHNICIAN NOTE Diazepam should not be mixed in a single syringe with water-soluble drugs (except ketamine) because a precipitate may form. Diazepam should not be stored in syringes, IV bags, or other plastic containers because it is absorbed.

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If a water-insoluble and water-soluble drug are mixed in a syringe, a precipitate may form. Diazepam can also be administered concurrently with opioids, thiopental, and propofol. Diazepam is light sensitive. Chapter 3 Anesthetic Agents and Adjuncts

Water solubility means midazolam can be mixed with other commonly used water-soluble drugs without a precipitate forming. Diazepam and midazolam are both commonly used in combination with other agents to induce anesthesia. Although it is not possible to induce anesthesia in a healthy animal through the use of these drugs alone, they are an effective supplement to other agents. In particular, the combination of ketamine and diazepam has gained wide acceptance as a safe and effective IV induction agent in small animals, horses, and ruminants. When this combination is used in small animals, midazolam may be substituted for diazepam. Diazepam may also be administered concurrently with opioids, propofol, or etomidate (provided separate syringes are used) to achieve safe, smooth induction of high-risk patients. If diazepam is given in combination with opioids, propofol, or etomidate, an IV catheter should be used and a saline flush given after each drug. Chapter 3 Anesthetic Agents and Adjuncts

Telazol ® is discussed further with dissociative anesthetics.

TECHNICIAN NOTE Major effects and adverse effects of benzodiazepines are as follows: Antianxiety and calming only in old or ill patients Anticonvulsant activity Disorientation and excitement in young, healthy dogs Dysphoria and aggression in cats Muscle fasciculations in horses Ataxia or recumbency in large animals Few cardiopulmonary effects Skeletal muscle relaxation Pain on IM injection of diazepam Chapter 3 Anesthetic Agents and Adjuncts

Minor procedures include radiography, wound treatment, and bandaging. Easy reversal means patients wake up quickly and can go home the same day. Chapter 3 Anesthetic Agents and Adjuncts

Xylazine (Rompun, AnaSed), dexmedetomidine (Dexdomitor), detomidine (Dormosedan), and romifidine (Sedivet) are members of this class of drugs. Medetomidine (Domitor), a predecessor to dexmedetomidine, was discontinued in the United States several years ago. These drugs are most often administered intramuscularly or intravenously. SC injection is less reliable and not recommended. Alpha2-agonists have considerable potential for adverse effects. These are reported most commonly when the drugs are given by the IV route. Chapter 3 Anesthetic Agents and Adjuncts

Alpha2-agonists can be reversed with the proper antagonist. Without reversal, complete recovery can take 2-4 hours. Chapter 3 Anesthetic Agents and Adjuncts

The early phase cardiovascular effects are more pronounced if the drug is given IV. Chapter 3 Anesthetic Agents and Adjuncts

By increasing the effect of other anesthetic agents, the amount necessary can be decreased. Chapter 3 Anesthetic Agents and Adjuncts

Adverse effects are more severe when drugs are administered IV. Don’t administer drug to an animal with any respiratory disease. Chapter 3 Anesthetic Agents and Adjuncts

Small amounts of alpha2-agonists can cause effects in humans and animals if absorbed through skin abrasions or mucous membranes. Chapter 3 Anesthetic Agents and Adjuncts

TECHNICIAN NOTE

Major effects and adverse effects of alpha2-adrenoceptor agonists are as follows: Dose-dependent sedation that can be profound Analgesia Agitation or aggression when touched Reaction to loud noises Muscle tremors in horses Cattle often lie down Initial hypertension, bradycardia, and pale mucous membranes followed by hypotension, decreased cardiac output and a further decrease in the heart rate Severe decrease in heart rate, blood pressure, cardiac output and tissue perfusion especially when high doses are given Respiratory depression that can be severe Muscle relaxation Vomiting in dogs and cats GI effects including bloat and colic Hyperglycemia Hypothermia

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Increased urination Permature parturition in cattle Horses may sweat

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Xylazine has been available for several decades and is the first widely used alpha2-agonist in both large and small animal species. It is supplied as a 2% solution (20 mg/mL) for small animal use and as a 10% solution (100 mg/mL) for equine use. Therefore to avoid a serious overdose, it is very important to look carefully at the label before drawing up a dose.

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The agonist and antagonist are marketed together as a package. doses are recommended for “sedation/analgesia in dogs” and “preanesthesia in dogs” Painful when given IM. Keep animal in a quiet environment 10-15 minutes after administration. Chapter 3 Anesthetic Agents and Adjuncts

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Alpha2-antagonists compete for binding sites on receptors with alpha2-agonists and will eventually replace the alpha2-agonists.

Yohimbine, tolazoline, and atipamezole are alpha 2-antagonists that can be used to reverse the effects of alpha2-agonists. Because of the adverse cardiovascular effects and long duration of sedation that can occur after administration of alpha2- agonists, use of an antagonist is often desirable. Yohimbine and tolazoline are used to reverse the effects of xylazine in dogs, cats, ruminants, horses and exotic species. Atipamezole is used to reverse the effects of dexmedetomidine in dogs, cats, and exotic species.

TECHNICIAN NOTE

Alpha2-antagonists have few adverse effects at clinical doses but can have significant adverse effects if too much is given. Doses should be based on the amount of the agonist that was given and the length of time since agonist administration and should be reduced if more than 30 minutes have elapsed. When given intravenously, these agents should be given slowly! Chapter 3 Anesthetic Agents and Adjuncts

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Opioids are derivatives of opium, an extract of a species of poppy called Papaverum somniferum. Opioids include both naturally derived compounds called opiates and synthesized compounds. Classification depends on the predominant effect of the derivative. This is a versatile class of drugs used for analgesia, sedation, and, when combined with other agents, anesthetic induction. Opioids are classified as agonists, partial agonists, agonist-antagonists, or antagonists, depending on their predominant effects. Chapter 3 Anesthetic Agents and Adjuncts

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Specific opioids and their uses in anesthesia are discussed later. Chapter 3 Anesthetic Agents and Adjuncts

Endogenous opioid peptides are chemicals that are naturally present in the body. Three major types of opioid receptors have been identified: mu (μ), kappa (κ), and delta (δ), each of which has two or more subtypes. This variety of receptors produces a wide spectrum of effects because each opioid agent differs in its action at each of these sites and therefore in its overall effects on the body. Chapter 3 Anesthetic Agents and Adjuncts

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The effect of an opioid depends on the dose, route of administration, agent used, species of patient, temperament, and pain status. Narcosis is a sleep-like state induced by high doses of an opioid. Most general anesthetics have limited analgesic properties. Chapter 3 Anesthetic Agents and Adjuncts

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Major effects and adverse effects of opioids are as follows: • CNS depression or excitement depending on the dose, route, agent used, species, patient temperament, and pain status. • CNS depression in dogs (except for those not in pain) • CNS excitement (excitement, dysphoria, and increased motor activity) in cats and large animals • Excellent somatic and visceral analgesia • Dose-dependent bradycardia and respiratory depression that can be pronounced • Panting in dogs • Hypothermia in dogs and hyperthermia in cats • Salivation and vomiting in small animals • Initial vomiting, diarrhea and flatulence, then ileus and constipation • Colic and sweating in horses • Increased responsiveness to noise • Miosis in dogs and mydriasis in cats and large animals • Decreased urine production and urine retention

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The ceiling effect occurs when there is no greater respiratory depression with high doses than with low doses. Chapter 3 Anesthetic Agents and Adjuncts

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Opioid agonists, partial agonists, and agonist-antagonists are used in many ways in veterinary anesthesia. They are a common component of preanesthetic protocols. For high-risk patients, some anesthetists prefer to use an opioid such as morphine or hydromorphone as the sole preanesthetic agent. More commonly, however, opioids are mixed with a tranquilizer (such as acepromazine, diazepam, or dexmedetomidine) and/or an anticholinergic (atropine or glycopyrrolate) and given during the preanesthetic period. Many combinations are used; see Protocols 9-1 and 9-2 in Chapter 9 for common combinations used in small animals. Ideally, these combinations should be chosen on the basis of individual patient need and drawn up into a syringe immediately before use. Some practices prepare these mixtures in advance and administer a set dose by IM or SC injection according to patient weight. This is more convenient than individual preparation, but there is some risk of inappropriate treatment, particularly if the patient is geriatric or debilitated or has significant organ dysfunction (e.g., liver disease). Opioids are also used to prevent and treat postoperative pain (see Chapter 7 for a complete discussion of analgesia) and are often used in combination with a tranquilizer to achieve a state of profound sedation and analgesia termed neuroleptanalgesia.

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Animals given neuroleptanalgesics generally lie quietly in lateral or sternal recumbency (adult horses stand quietly) but can be aroused by sufficient noise or surgical stimulation. Therefore, neuroleptanalgesia is commonly used for procedures that require significant CNS depression and analgesia but not general anesthesia.

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Any combination of opioid and tranquilizer is acceptable. Veterinarian’s preference. Administer IM or slowly IV to prevent excitation. Chapter 3 Anesthetic Agents and Adjuncts

TECHNICIAN NOTE Neuroleptanalgesics must be administered intravenously slowly, because if rapidly injected, CNS stimulation may occur. The anesthetist must also be prepared to intubate and ventilate the patient if necessary, as respiratory depression may be profound.

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An agonist-antagonist (butorphanol) can be used to partially reverse the effects of a pure agonist. Opioid antagonists reverse the effects of opioids only. Chapter 3 Anesthetic Agents and Adjuncts

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The primary effect of naloxone is reversal of both the desirable and undesirable effects of an agonist, partial agonist, or agonist-antagonist, including sedation, dysphoria, panting, respiratory depression, hypotension, bradycardia, GI effects, and analgesia. The action of opioid antagonists is often dramatic, causing the patient to appear nearly unaffected shortly after administration. The respiratory depression caused by buprenorphine may be unresponsive, however, because this agent tightly binds to the mu receptors and is not easily displaced.

TECHNICIAN NOTE Opioid antagonists should be administered by IM or slow IV injection. They reverse both the desirable and undesirable effects of an agonist, partial agonist, or agonist-antagonist, including sedation and analgesia. The action of opioid antagonists is often dramatic, causing the patient to appear nearly unaffected shortly after administration.

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Reversal is not necessary following routine anesthesia. However, the technique is extremely useful in emergencies, after an overdose, or to reverse opioid effects after neuroleptanalgesia for nonpainful procedures. Chapter 3 Anesthetic Agents and Adjuncts

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