Chemistry:

Thiopental sodium (pentothal sodium, previously used name thiopentone sodium):

CNS effects:

Barbiturates are administered to produce anesthesia (short-acting barbiturates) or as anticonvulsants (long-acting barbiturates). However, they possess properties that are favorable to cerebral physiology. Barbiturates decrease cerebral blood flow (CBF) (Albrecht et al., 1977) and cause a dose-dependent depression of the electroencephalogram (EEG), eventually resulting in a flat EEG (Kiersey et al., 1951). They decrease cerebral oxygen consumption (CMRO₂) particularly in cortical areas by up to 55%, which parallels the depression of the neuronal activity. Metabolic needs of the brain remain constant; only hypothermia will decrease cerebral metabolic needs (Steen et al., 1983). Furthermore, they decrease intracranial pressure (Bedford et al., 1980) and similarly decrease intraocular pressure (Mirakhur and Shepherd, 1985). Since intracranial pressure (ICP) decreases more than mean arterial pressure (MAP), cerebral perfusion pressure is preserved. Thus barbiturates like thiopental are often chosen to anesthetize patients with CNS disease or trauma.

Methohexital, is an ultrashort-acting barbiturate, but is an exception to the cerebro-friendly status of barbiturates. Methohexital has been associated with generalized excitement and activation of epileptic foci (Stoelting, 1999) and is not recommended for patients with a seizure history.

Cardiovascular system:

Barbiturates cause changes in the cardiovascular system that is dependent on the dose and the physiological status of the patients. In healthy dogs, there is a decrease in stroke volume and contractility with an increase in heart rate (Turner and Ilkiw, 1990). In the healthy dogs, there is a minimal change to cardiac output as the reflex tachycardia compensates for the decrease in stroke volume, but mild hypotension is often seen.

Although unproved, anecdotal reports suggest that in compromised dogs, barbiturates result in an exaggerated cardiovascular depression. However, healthy dogs that suffered from acute blood loss did not show a depression in cardiovascular parameters (Ilkiw et al., 1991a). Dogs and pigs do, however, need a smaller induction dose following severe hemorrhage (Weiskopf and Bogetz, 1985). Caution should be used when administering barbiturates to patients with dehydration, hypovolemia, anemia, blood loss, or underlying cardiac disease.

Thiopental can precipitate ventricular arrhythmias, particularly bigeminy (Muir, 1977), as well as potentiate epinephrine-induced arrhythmias (Atlee and Malkinson, 1982). Lidocaine can be administered with thiopental. This allows for less thiopental to be administered (reduces cardiovascular depression) and protects against ventricular arrhythmias (Rawlings and Kolata, 1983). Caution should be used when administering thiopental to patients with high sympathetic tone or who are prone to arrhythmias.

There is a dose-dependent effect of the vasomotor center by barbiturates. Rapid IV injection of an induction dose of a thiobarbiturate causes a sharp but transitory fall in arterial pressure because of the high concentration briefly depressing the vasomotor center. Venodilation results in splenic sequestration of red blood cells (RBC) and a concomitant drop in packed cell volume. For this reason barbiturates are often avoided for anesthesia of patients scheduled for a splenectomy (Baldo et al., 2012). Furthermore, the vasodilation contributes to heat loss. With a decline in heat production during anesthesia and an increase in heat loss owing to peripheral vasodilation, anesthetized patients can quickly become hypothermic.

Barbiturates do not block the autonomic responses to pain or intubation and thus should be administered with drugs that will attenuate those responses (e.g., opioids).

Respiratory effects:

When used at anesthetic induction doses, barbiturates produce central respiratory depression. There is a decrease in respiratory rate and minute ventilation, with apnea in some patients (Quandt et al., 1998). In addition to causing respiratory depression, the barbiturates decrease the reflex responses to hypercapnia and hypoxemia (Hirshman et al., 1975). Following induction with a barbiturate, patients should be intubated and assisted with ventilation as necessary. The blood concentration inhibiting the respiratory center is considerably less than that arresting the heart, so patients that are apneic may be stable cardiovascularly. The occurrence of bigeminy appears to be decreased in well-oxygenated patients. Oral barbiturates used as anticonvulsants have minimal or no effect on respiratory function, probably due to lower plasma concentrations.

Muscular effects:

Barbiturates produce good muscle relaxation and generally produce favorable intubating conditions. Laryngeal reflexes are preserved with barbiturate anesthesia (Jackson et al., 2004) facilitating better evaluation of laryngeal function. The increased sensitivity of laryngeal and bronchial reflexes can lead to laryngospasm (Barker et al., 1992). Although laryngeal reflexes are preserved, all patients induced with a barbiturate should be intubated to protect the airway and support ventilation.

Gastrointestinal (GI) tract:

There are no important effects such as diarrhea or intestinal stasis following routine use of thiobarbiturates.

Kidney:

The thiobarbiturates have no direct effect upon the kidney, but can decrease urine output because of decreased blood flow and glomerular filtration rate resulting from hypotension and decreased cardiac output. Patients with uremia have decreased plasma binding of barbiturates (more physiologically available drug) and thus need lower induction doses (Ghoneim and Pandya, 1975).

Fetus/neonates:

Most barbiturates easily cross the placenta and equilibrium between maternal and fetal circulations is established within a few minutes. While in utero, most fetuses are slightly acidemic when compared to the mother. Since barbiturates are less ionized in an acid environment, it is possible that the neonate will have a greater concentration of active drug. In humans, anesthesia with thiopental for cesarean sections resulted in neonates with depressed reflexes, altered acid–base status, and delayed suckling when compared to epidural anesthesia (Sener et al., 2003). Similarly, neurological function was depressed in puppies following cesarean sections where the dam was administered thiopental (Luna et al., 2004). Pentobarbital has been associated with slow neonatal recovery, delayed nursing, and increased morbidity (Thurmon et al., 1996). Phenobarbital is excreted in the milk, although the amounts are marginal. However, a suckling neonate can ingest the drug passed from the mother (Wong et al., 2008). Because neonates may have impaired clearance compared to an adult, this can potentially lead to adverse effects (sedation and decreased suckling activity).

Miscellaneous:

Doses of thiobarbiturates that produce surgical anesthesia depress basal metabolism so that less body heat is produced during anesthesia concurrently with excessive heat loss as a result of vasodilation. It is important that surgical patients anesthetized with barbiturates be kept warm.

The decrease in vasomotion associated with barbiturates also leads to splenic sequestration of RBCs. Since the spleen can become quite large and a significant amount of blood and be stored in the spleen, barbiturates are not recommended for patients having a splenectomy.

The “glucose effect” is a term used to describe a reanesthetizing action seen in animals recovering from barbiturate anesthesia that are administered glucose solutions. Glucose decreases microsomal metabolism and thus can decrease barbiturate metabolism (Peters and Strother, 1972). A similar event can occur with administration of epinephrine; however, little clinical effect is seen at routine barbiturate doses (Hatch, 1966).

Analgesia:

Barbiturates do not provide analgesia. While anesthetized, nociceptive input is not perceived by the brain, but the pain pathways are activated. In patients where pain will continue following anesthesia, alternative analgesics must be used. At subanesthetic doses, barbiturates may cause hyperalgesia (Ewen et al., 1995), but this effect is controversial and probably not clinically relevant when barbiturates are used as induction agents.

Thiopental:

Thiopental is highly protein bound (>70%) (Brandon and Baggot, 1981) and has a pKa near 7.6. After IV administration, thiobarbiturates are initially present in high concentrations in highly perfused tissues (e.g., the brain), resulting in rapid induction of general anesthesia. Thiobarbiturates then redistribute to the moderately perfused body tissues (e.g., muscle). This redistribution to moderately perfused tissues decreases the concentration in the plasma in brain tissues allowing the animal to regain consciousness. Further redistribution to adipose tissue from both highly and moderately perfused tissues results in the complete recovery from thiobarbiturate anesthesia. Animals with lower percentages of fat and/ or muscle tissue have a smaller percentage of area for the barbiturates to redistribute to. Thus normally lean patients (e.g., Sighthounds), neonates, or cachetic patients might have prolonged recoveries from thiobarbiturates. Similarly, since awakening depends of redistribution, repeated dosing is not recommended because of cumulative effects and prolongation of recovery.

Pharmacokinetics of thiopental in rabbits, sheep, and dogs showed an central volume of distribution of 38.6 ± 10 ml/kg, 44.5 ± 9.1 ml/kg, and 38.1 ± 18.4 ml/kg, respectively (Ilkiw et al., 1991b). Elimination half-life was longest in the sheep (251.9 ± 107.8 min), shorter in the dog (182.4 ± 57.9 min), and shortest in the rabbit (43.1 ± 3.4 min) (Ilkiw et al., 1991b).

The activity of a drug is dependent on the percentage of the drug that is unbound and unionized. Since thiopental is an acid it is nonionized in an acid environment. It is also highly protein bound. Many ill patients are both acidemic and hypoproteinemic and thus may have greater percentage of active drug available for pharmacological activity. Thus, the therapeutic index may be smaller in ill patients, making them easier to overdose.

Phenobarbital:

Phenobarbital is readily absorbed from the GI tract with bioavailability ∼90% in dogs (Pedersoli et al., 1987) and ∼99% in horses (Ravis et al., 1987). Pharmacokinetics of an IV bolus dose of phenobarbital in horses showed a volume of distribution at steady state of 0.803 ± 0.07 l/kg; terminal phase elimination of 18.3 ± 3.65 hours; and total body clearance 30.8 ± 6.2 ml/kg/h (Duran et al., 1987). In the dog, volume of distribution is ∼0.7 L/kg; the mean half-life was 92.6 ± 23.7 hours; mean total clearance 5.6 ± 2.31 ml/h/kg (Pedersoli et al., 1987). In the goat, the volume of distribution for pentobarbital (30 mg/kg) administered intravenously is 0.72 l/kg; the first-order disappearance rate kinetic constant is 0.76 hour and the half-life is 0.91 hour (Boulos et al., 1972).

Phenobarbital:

In dogs, the elimination phase half-life of pentobarbital is 8.2 ± 2.2 hours. The steady-state volume of distribution is 1.08 ± 0.21 liters/kg and the elimination clearance is 0.0013 ± 0.0004 liters/min (Frederiksen et al., 1983). It is 35–45% protein bound. Comparatively, ruminants, especially sheep and goats, metabolized pentobarbital much faster; elimination half-life in goats is ∼1 hour compared to ∼8.0 hours in dogs.

Dogs – sighthounds:

Since awakening from anesthesia is due to redistribution of barbiturates to fat and muscle, lean breeds with small fat stores (e.g., Whippet, Irish Wolfhounds) can show a prolonged effect to barbiturates. With little area to redistribute the drug, these breeds also have an increased risk of overdose.

Dogs – Greyhounds:

Greyhounds are classified as Sighthounds and are at risks as discussed above. In addition, Greyhounds are deficient in oxidative enzymes needed for metabolism of thiobarbiturates and thus can have extremely prolonged recoveries (Robinson et al., 1986). Although not toxic, the increased risk of overdose coupled with the prolonged recovery makes thiopental not recommended for use Greyhounds.

In Greyhounds, recovery from methohexital anesthesia is significantly faster than from thiopental (Sams et al., 1985). Currently, propofol is more commonly used in Greyhounds for anesthesia than barbiturates.

Ruminants:

Barbiturates can be successfully used for anesthesia in ruminants, but because of the propensity for ruminants to regurgitate, the airway needs to be protected by placement of a cuffed orotracheal tube.

In cattle, a congenital condition (“pink tooth”) that increases porphyrin concentrations can occur, which can lead to neurological disturbances from demyelination of peripheral and cranial nerves. In the liver, barbiturates stimulate production of an enzyme that increases porphyrin production potentially making the disease worse (Mees and Frederickson, 1975). Animals afflicted with a known or suspected disturbance in porphyrin metabolism should not be administered barbiturates.

Swine:

Many pigs may have prolonged recoveries from thiopental administration (∼1 hour) versus other animals (∼15 minutes). It is possible that redistribution of thiopental to the increased fat stores may contribute to the prolonged effect of the drug. Barbiturates do not trigger malignant hyperthermia.

Horses:

The administration of thiopental to horses without prior sedation is not recommended as there is significant excitement and incoordination. Rather, horses should be administered thiopental following sedation with an α₂-agonist (e.g., xylazine) and/or guaifenesin, and/or a benzodiazepine (e.g., diazepam). Induction of anesthesia with thiopental causes horses to become recumbent by the flexion of all four legs, as compared to ketamine where most horses will flex their hind legs first and assume a dog-sitting posture before complete recumbency. Care should be taken to prevent horses from injuring themselves during induction and recovery. Methohexital should not be used alone in horse because excitation during induction and/ or recovery.

Birds:

Thiopental has been successfully used in birds interosseously (Valverde et al., 1993), but because of prolonged recoveries and increased mortality it is not recommended.

Reptiles:

Barbiturates are metabolized very slowly in reptiles resulting in a prolonged recovery. The ultrashort-acting barbiturate, methohexital, has been used with varying duration of action in snakes (Preston et al., 2010).

Chemistry:

CNS effects:

Propofol induces CNS depression by enhancing the effects of GABA, an inhibitory neurotransmitter, providing a rapid, smooth induction of general anesthesia.

Propofol produces a favorable neurological status as it decreases ICP, decreases cerebral perfusion pressure, and decreases cerebral metabolic oxygen consumption (Pinaud et al., 1990). Since cerebral metabolic demands are decreased more than blood flow decreases, perfusion is adequate. Intracranial pressure is reduced in patients with both normal and elevated ICP. Propofol has also been shown to maintain cerebral autoregulation in pigs (Lagerkranser et al., 1997) and increase cerebral autoregulation in humans (Harrison et al., 2002).

Similar to its effects on intracranial pressure, propofol causes an acute decrease in intraocular pressure by 30–40% when administered at anesthetic doses (Neel et al., 1995).

Myoclonus has been reported following propofol administration and some have hypothesized that propofol might lower the seizure threshold. However, propofol has been shown to be anticonvulsant and does not produce seizure activity in patients with documented epilepsy (Cheng et al., 1996). Propofol has been used successfully in both dogs and humans for long-term control of status epilepticus (Brown and Levin, 1998).

Following propofol anesthesia, many human patients report a feeling of euphoria as well as having had amorous dreams (Canaday, 1993). Many domestic animals recover from propofol clear headed, coordinated, and seemingly feeling well.

The combination of good CNS perfusion, good quality recovery in patients with CNS disease (Caines et al., 2014), and anticonvulsant properties, makes propofol is a popular anesthetic for patients with CNS disease.

Cardiovascular effects:

Induction doses of propofol are associated with systemic hypotension (Reich et al., 2005). Although propofol causes negative inotropy, the decrease in blood pressure is primarily via a decrease in systemic vascular resistance (vasodilation); systemic vascular resistance decreased by 21% in dogs following an induction dose of propofol (5 mg/ml) (Wouters et al., 1995). The decrease in system vascular resistance likely contributes to splenic engorgement and this should be considered in patients anesthetized for splenectomy (Baldo et al., 2012). Following an induction dose of propofol, the heart rate is often decreased or unchanged, even with systemic hypotension (Whitwam et al., 2000). This is contrast to the barbiturates where there is often an increased heart rate in response to the decrease in blood pressure. Therefore a decrease in cardiac output should be expected.

Propofol can enhance the ability of epinephrine to induce cardiac arrhythmias but does not appear to be inherently arrhythmogenic (Kamibayashi et al., 1991).

Respiratory:

Apnea is a commonly seen following bolus administration of propofol. The apnea associated with propofol is increased as the rate of infusion is increased. That is, the faster the administration the more likely the incidence of apnea (Musk et al., 2005). Respiratory depression resulting in mild hypercapnia and acidosis are also seen in spontaneously breathing dogs following induction doses (Robertson et al., 1992) and in dogs administered propofol as a constant rate infusion. Patients given propofol should be monitored for hypoxemia and hypercapnia and if necessary the patient should be intubated and provided supplemental oxygen. Propofol should be cautiously in patients where securing an airway may be difficult (e.g., laryngeal masses, guinea pigs, etc.).

Muscular effects:

Propofol provides excellent muscle relaxation, but occasionally results in short and long-term myoclonic movements in humans and dogs (Nimmaanrat, 2005). Signs resolve spontaneously, but severity of movement can interfere with surgical procedures. Anecdotal treatment with ketamine at 1 mg/kg IV has resulted in the resolution of signs, whereas treating with benzodiazepines does not appear to affect the myoclonus (author’s personal experience). Laryngeal reflexes are decreased and result in a favorable intubating environment, but might increase the risk of aspiration in patients without a protected airway.

Miscellaneous:

Propofol crosses the placenta and enter the fetal circulation, but it appears to be readily removed from the fetal circulation after birth and produces minimal effects on healthy, newborn, human infants (Dailland et al., 1989) or puppies (Luna et al., 2004).

Propofol does not cause histamine release (Mitsuhata and Shimizu, 1993) and results in a diminished stress response compared with inhalant anesthetics (Ledowski et al., 2005).

Propofol has antioxidant effects in humans, dogs, and pigs (Aldemir et al., 2001; Allaouchiche et al., 2001; Lee, 2012). The clinical relevance of this activity is unclear.

Propofol has been shown to decrease postanesthetic nausea and vomiting in people at both anesthetic and subanesthetic doses (Apfel et al., 2004); however, this effect has not been documented in domestic animals.

Subanesthetic IV doses of propofol have been shown to decrease the pruritus seen following spinally administered opioids in humans (Horta et al., 2006).

Propofol does not provide any analgesia or produce hyperalgesia as has been reported with barbiturate anesthesia (Wilder-Smith et al., 1995).

Dogs:

Propofol can be used for short or long-term sedation, induction of general anesthesia, and continuous rate infusions. The induction dose required for Greyhounds is not different from that required for mixed-breed dogs; however, the recovery time was longer for Greyhounds (see Section Metabolism).

Cats:

Propofol can induce oxidative injuries to feline red blood cells when administered as an induction dose followed by a 30 minutes constant rate infusion. This can result in Heinz body formation, anorexia, diarrhea, and malaise (Andress et al., 1995). However, cats administered induction doses of propofol twice daily for 5 days did not show adverse hematological changes (Bley et al., 2007).

Equine:

Propofol should not be used as a sole induction agent in horses as it is associated with excitement. The excitement is likely caused by the long time required to administer the large volume of drug, resulting in the display of stage II anesthesia (excitement stage). Following sedation with an α_2-agonist many horses still showed excitement at induction with propofol (Mama et al., 1996). Heavy sedation with guaifenesin has been shown to mitigate the excitement at induction (Brosnan et al., 2011).

The quality of recovery from propofol anesthesia horses is good (Mama et al., 1996; Posner et al., 2013). Although good recovery characteristics are important for horses, the presence of excitement during induction and the prohibitive cost for large patients make it unlikely that propofol will be routinely used in equine patients.

Pigs:

Propofol does not trigger malignant hyperthermia in susceptible animals (Fruen et al., 1995). However, good sedation is necessary to provide reasonable venous access. Respiratory depression and apnea have been reported with propofol administration in pigs (Tendillo et al., 1996); thus, propofol should be used with caution unless intubation can be readily accomplished.

Bird:

Propofol produces significant respiratory depression in red tailed hawks and great horned owls (Hawkins et al., 2003). It is reasonable to presume that all birds may need ventilatory assistance when anesthesia is maintained with propofol. CNS excitement has been noted at recovery (Hawkins et al., 2003).

Fish:

Propofol has been used to produce anesthesia in fish both intravenously and via immersion (Fleming et al., 2003; Oda et al., 2014).

Controlled drug status:

Propofol is a nonscheduled (controlled) drug, but has been proposed to be placed in Schedule IV.

Withdrawal times:

Withdrawal times have not been established for animals that produce food. However, FARAD recommends at least 72 hours for meat (Lin and Walz, 2014), but could not offer recommendations for milk due to lack of data.

Chemistry:

CNS effects:

Based on EEG findings, the antagonism of NMDA receptors produces a dissociation of the thalamocortical and limbic systems (Reich et al., 2005). This produces an altered consciousness or catalepsy, where the patient does not appear asleep, but does not react to noxious or nonnoxious stimuli. Although patient may not look asleep, NMDA antagonists are effective at producing amnesia (Haas and Harper, 1992). When used alone, the dissociative anesthetics rarely produce a surgical depth of anesthesia, but when combined with other CNS depressants produce adequate relaxation and immobility.

The CNS effects of dissociatives are different than most other anesthetics. They increase CBF which is coupled with an increase in cerebral glucose metabolism and oxygen demand (CMRO₂) (Dawson et al., 1970). The increased CBF is caused by vasodilation of cerebral vessels and an increase in blood pressure, which results in an increase in ICP. Hypercapnia contributes to the rise in ICP and controlling ventilation can attenuate the rise in ICP. Thus, these drugs should be used with caution in any patient having or suspected of having elevated ICP, or where cerebral metabolic demands may not be being met. The effects on ICP are also associated with increased intraocular pressure. Ordinarily, this is not a problem, but these agents should not be used in patients with glaucoma.

Ketamine causes the development of EEG patterns that are epileptiform (Kayama, 1982) and is used to elicit more robust seizures during electroconvulsive therapy (Krystal et al., 2003). Interestingly, there is also evidence that ketamine is anticonvulsive (Reder et al., 1980) as well as neuroprotective (Himmelseher and Durieux, 2005). However, most anesthesiologists recommend avoiding ketamine in patients with a seizure history and it should not be used in patients with elevated intracranial pressure.

Dissociative anesthetics cause an increase in norepinephrine via central adrenergic stimulation and a decreased reuptake of norepinephrine, resulting in an increase in sympathetic tone (Stoelting, 1999). The increase in norepinephrine affects all systems under adrenergic control (e.g., cardiovascular, respiratory, endocrine, etc.).

Emergence delirium (e.g., anxiousness, vocalization, thrashing) is a concern whenever dissociative anesthetics are used. Delirium may be merely unpleasant in smaller animals, but can be dangerous when used in larger animals (e.g., horses). Emergence delirium can be attenuated or prevented by administering dissociative anesthetics with sedatives or tranquilizers (e.g., xylazine, diazepam, acepromazine). The R (+) isomer of ketamine is associated with more delirious effects (Stoelting and Hillier, 2012).

Awakening from ketamine is primarily due to redistribution of drug, although some effects are from metabolism.

Cardiovascular system:

Ketamine has direct myocardial depressant effects (Diaz et al., 1976) but its administration is generally associated with increase in cardiac output, mean aortic pressure, pulmonary arterial pressure, central venous pressure, and heart rate (Haskins et al., 1985). The stimulatory effects are due to directly stimulating the central adrenergic centers (i.e., increased sympathetic tone) and by inhibiting the neuronal uptake of catecholamines, especially norepinephrine (Annetta et al., 2005). The cardiovascular stimulation is associated with an increase in myocardial work and myocardial oxygen demands (Haskins et al., 1985), thus ketamine should be used with caution in patients with cardiovascular disease that cannot tolerate increased metabolic needs. Although the sympathetic stimulation overrides the direct cardiovascular depressant effects of ketamine (Adams, 1997), patients that are catecholamine depleted (i.e., critically ill) may show more of the cardiodepressive effects (Waxman et al., 1980).

The increased sympathetic tone also may cause tachycardia. Caution should be used with patients that are already tachycardic or dysrhythmic.

Ketamine preserves cardiovascular function and oxygen balance during experimentally produced septic shock (Van der Linden et al., 1990). This cardiovascular sparing effect may be due to the ability of ketamine to block the inflammatory cascade caused by endotoxins that depress cardiovascular function (Taniguchi and Yamamoto, 2005) as well as by increasing levels of norepinephrine that may attenuate the inappropriate peripheral vasodilation seen in septic patients.

Respiratory:

Dissociative anesthetics generally have a mild effect on minute ventilation and therefore usually cause a moderate increase in carbon dioxide concentrations. This is in contrast to many other anesthetics that are potent respiratory depressants. However, when other CNS depressants are administered with ketamine, significant respiratory depression can be observed. Ketamine also can cause an apneustic pattern of breathing, which is characterized by a rapid sequence of breaths followed by breath holding on inspiration. This occurs more commonly with rapid IV administration of ketamine. Although apneustic breathing is unusual to watch, minute ventilation and carbon dioxide levels are generally within normal limits.

Ketamine has bronchodilating properties and decreases airway resistance (Durieux, 1995). This makes it useful as an induction drug for patients with clinical asthma as well as patients with obstructive airway disease (e.g., chronic obstructive pulmonary disease).

When ketamine is used as a sole anesthetic, pharyngeal and laryngeal reflexes remain active (Robinson et al., 1986). Preservation of these reflexes, however, leads to an increase risk of laryngospasm and coughing secondary to secretions or manipulation in the oropharynx. These complications make ketamine alone a poor drug for use in endoscopy or oropharyngeal surgery. Although laryngeal reflexes are preserved they can be uncoordinated, and thus aspiration is possible. Endotracheal intubation should be used to maintain and protect the airway.

Additionally, ketamine stimulates salivation, which can be copious at times. The administration of an anticholinergic agent (e.g., glycopyrrolate) for its antisialagogue properties can attenuate the amount of salivation. Caution should be exercised when using anticholinergics in patients with small airways as the antisialagogue properties can make for viscous secretions that can occlude the airways or endotracheal tube.

Upper airway muscle tone and reflexes are preserved when dissociatives are used alone. However, since these drugs are generally administered with muscle relaxants, laryngeal control is then diminished or absent. Endotracheal intubation is recommended for all anesthetized patients to maintain and protect the airway.

Muscular effects:

Dissociative anesthetics provide little muscle relaxation and may cause muscle rigidity, myoclonus, and/ or uncoordinated muscle movements. Muscle relaxation is generally provided by the coadministration of sedatives or tranquilizers (e.g., benzodiazepine, α₂-agonists).

Miscellaneous:

The appearance of patients anesthetized with dissociative anesthetics is different than with most other anesthetics. Many patients do not close their eyes, can have muscle tone and muscle movement, and often do not look “asleep”. It is important to protect the corneas of patients with adequate lubrication and prevent objects from rubbing on the cornea. Coadministration of sedatives or tranquilizers can attenuate these signs.

Analgesia:

As described in the Mechanism of Action section, NMDA antagonists such as ketamine produce analgesia. For many years the dogma has been that ketamine provided greater somatic compared with visceral analgesia. However, this view is too simplistic to explain the varied analgesic effects and should be discarded. The mechanism for antinociception is complex and likely involves interactions at more than one type of receptor. Ketamine provides a use-dependent (i.e., works better when the nerves are stimulated) blockade of the NMDA receptor as well as inhibiting neurotransmitter release, both of which has been shown to mediate nociception (Annetta et al., 2005). Analgesia is also likely mediated by the action of ketamine on mu and kappa opioids receptors (Annetta et al., 2005). Opioid receptors extend beyond the CNS and spinal cord and occur in many peripheral tissues. Ketamine produces analgesia at subanesthetic doses for acute surgical pain and have opioid-sparing effects (Annetta et al., 2005).

Additionally, NMDA antagonists at subanesthetic doses are effective at treating chronic pain associated with central sensitization (wind-up pain), neuropathic pain (Guirimand et al., 2000), and likely other types of inflammatory pain. Ketamine by constant rate infusion has been successful in interrupting central sensitization. The duration of the infusion needs to be at least 24 hours, but at times, administration was continued for days to weeks before signs abated (Correll et al., 2004; Sigtermans et al., 2009). When ketamine is used at subanesthetic doses, behavioral changes are rarely seen.

Ketamine:

In most species, ketamine is biotransformed by the liver by N-demethylation to norketamine which then undergoes hydroxylation to form a water-soluble glucuronide derivative that is eliminated in urine (White et al., 1982; Stoelting and Hillier, 2012). Norketamine is an active metabolite of ketamine and has 10–30% activity of the parent drug (Leung and Baillie, 1986; Hanna et al., 1988). In the cat, because of deficiencies in some glucuronidation pathways, ketamine only undergoes transformation to norketamine which is excreted largely unchanged in the urine (Hanna et al., 1988). Since the active metabolites are excreted by the kidneys, decreased renal excretion may prolong the effects of the drug.

Telazol:

Telazol is an equal mixture of tiletamine and zolazepam (a benzodiazepine), so the metabolism of this drug needs to be discussed in terms of the two drugs. In cats, the duration of effect of zolazepam exceeds that of tiletamine so that, with time, the pharmacodynamic effect is that of the benzodiazepine tranquilization (Telazol Product-Literature, 2017). In dogs, the duration of effect of tiletamine exceeds that of zolazepam so that, with time, the pharmacodynamic effects reflect the dissociative anesthetic, including muscle rigidity, sympathetic stimulation, and emergence delirium (Telazol Product-Literature, 2017). Other species have similar disparities in metabolism and recoveries from Telazol. Pigs awaken slowly and calmly, whereas horses can have an agitated recovery if not provided with additional sedation. Reversal of the zolazepam in animals with a benzodiazepine antagonist can lead to an anxious recovery if sufficient plasma levels of tiletamine are still present.

CNS disease:

Ketamine/ tiletamine should not be used in animals with elevated intracranial pressure.

Pain from injection:

Ketamine is a hydrochloride salt, which must be kept at a low pH to maintain solubility. The pH of ketamine is 3.5 which can cause some irritation and pain during IM injections (Hanna et al., 1988).

Cardiovascular disease:

Ketamine/ tiletamine should be used with caution in patients with coronary artery disease, uncontrolled arterial hypertension, cardiomyopathy, or heart failure.

Emergence delirium:

Caution should be used in patients where emergence delirium could be injurious to the patient or to medical personnel (e.g., horse). Emergence delirium can be prevented or attenuated by coadministration of sedatives or tranquilizers. In general, dissociative anesthetics should not be administered as sole agents.

Ocular disease:

Ketamine/ tiletamine should not be used animals with elevated intraocular pressure or with an open globe injury due to the rise in intraocular pressure following administration.

Increased sympathetic tone:

Ketamine/ tiletamine should be avoided in patients with high sympathetic tone such as hyperthyroidism or pheochromocytoma since administration of these drugs can increase norepinephrine levels and exacerbate the side effects of these diseases.

Urethral obstruction or renal insufficiency:

Caution should be used in patients where excretion of the active metabolites may be decreased, such as cats with urethral obstruction or anuric renal failure.

Horse:

Horses should not be administered dissociative anesthetics as single agents due to the lack of muscle relaxation and recovery delirium. Telazol in particular can be associated with rough anesthetic recoveries and should be balanced with the use of additional sedatives or tranquilizers, before induction and before recovery.

Tigers:

Great controversy occurs over the use of Telazol in the large cats and in tigers specifically. Although there is little published evidence, many anesthesiologists and zoo medicine specialists caution against the use of Telazol in the large cats (Tilson, 1994; Muir et al., 2000; Morris, 2001). Reported complications have ranged from slow ataxic recoveries to delayed (2–4 days after anesthesia) neurological dysfunction, including hind limb weakness, drowsiness, hyperreflexia, hyperresponsive behavior, twitches, seizures, and death (Tilson, 1994; Klein, 2007; Lewis, 2007).

Rabbits:

At clinical doses, tiletamine (the dissociative part of Telazol) causes lethal renal tubular necrosis in New Zealand White rabbits (Doerning et al., 1992). Other rabbit species appear unaffected.

Pigs:

A combination known as TKX (Telazol, ketamine, xylazine) is commonly used to anesthetize pigs. The mixture is composed of 500 mg (as powder) Telazol, 250 mg ketamine, and 250 mg xylazine. Due to slow zolazepam metabolism, pigs can have prolonged recoveries after TKX.

Use of ketamine in animals susceptible to malignant hyperthermia has been controversial; however, ketamine did not induce malignant hyperthermia in 76 susceptible pigs (Dershwitz et al., 1989).

Withdrawal time:

Ketamine extra label use: at least 3 days for meat and 48 hours for milk.

Controlled drug schedule:

• Ketamine is a Schedule III Controlled Drug.
  
• Telazol is a Schedule III Controlled Drug.

Chemistry:

CNS effects:

Etomidate is considered cerebral friendly because it results in decreased ICP, decreased CBF, and decreased cerebral metabolic rate for O₂ (CMRO₂). Since the MAP is essentially unchanged, this results in a favorable metabolic state for the CNS; the cerebral perfusion pressure is increased as is the cerebral oxygen supply : demand ratio. The EEG quiets (similar to the barbiturates), but there can be increased EEG activity at epileptogenic foci. Grand mal seizure have been reported, and some anesthetists argue against its use in patients with a known seizure history (Bergen and Smith, 1997).

Due to similar mechanisms, the intraocular pressure is also decreased. Intraocular pressure can decrease by up to 60% but the effect lasts for only for ∼5 minutes.

Cardiovascular system:

Etomidate is unique amongst most intravenous general anesthetics in that it causes minimal hemodynamic changes and thus maintains cardiovascular function. At routine induction doses, etomidate causes minimal changes in stroke volume (SV), MAP, cardiac index (CI), pulmonary artery pressure (PAP), pulmonary arterial wedge pressure (PAWP), central venous pressure (CVP), or systemic vascular resistance (SVR) (De Hert et al., 1990). In addition to causing minimal CV derangements, the baroreceptor and sympathetic nervous system reflexes remain intact, which also contributes to hemodynamic stability. Etomidate is not arrhythmogenic, does not sensitize the heart to catecholamine, and it does not cause histamine release. It is the most commonly used induction agent in dogs having pacemaker implantation (Sanchis-Mora et al., 2014).

Respiratory:

Etomidate can cause respiratory depression. Induction doses can result in brief periods of apnea, but generally arterial carbon dioxide partial pressure (PaCO₂) is only slightly increased if affected at all. Arterial oxygen (PaO₂) is generally unaffected. However, when etomidate is administered with other drugs that can affect CNS function, more respiratory depression can be seen. Since etomidate has limited effect on muscle relaxation, airway reflexes are generally maintained. Intubation, however, is highly recommended.

Endocrine system: