Cough Suppressants and Sedation of the Cardiac Patient-Ettinger

Question 1

COUGH SUPPRESSANTS

Coughs can be stimulated by?

Answer 1

1. Central receptors in the brain or
2. Peripherally by receptors in the pharynx, larynx, trachea, bronchi, lungs, or pleural cavity.

Both chemical and mechanical stimuli can illicit a cough from any of these areas.

Question 2

Irritants can stimulate the cough receptors in the epithelium of the bronchi, causing a cough as well as causing bronchoconstriction.
……………….nerves conduct the cough impulse via the …………….. nerve to an area in the ……………. that is separate from the ……………. center. From there, ……………. fibers transmit the signal that results in a cough.

Answer 2

Afferent nerves conduct the cough impulse via the vagus nerve to an area in the medulla that is separate from the respiratory center. From there, efferent fibers transmit the signal that results in a cough.

Question 3

The cough …….. can be interrupted at different locations, depending on the mechanism of action of the drug.

………………………. may help to control coughing associated with bronchoconstriction.

Some drugs such as …………..depress the cough center in the medulla by a poorly understood mechanism.

Other drugs may have an effect on blocking coughs at the ………………..

The most effective drugs are?

Answer 3

Bronchodilators may help to control coughing associated with bronchoconstriction. S

ome drugs such as opioids depress the cough center in the medulla by a poorly understood mechanism.

Other drugs may have an effect on blocking coughs at the peripheral receptors.

The most effective drugs are those that work centrally.

Question 4

Diseases in the dog such as collapsing trachea, bronchitis, and canine upper respiratory infection complex or dry harsh, nonproductive coughs that do not respond to other therapy can be treated with cough suppressants. Also, when the chronic coughing is irritating to the owner, a cough suppressant can be used.

Answer 4

Diseases in the dog such as collapsing trachea, bronchitis, and canine upper respiratory infection complex or dry harsh, nonproductive coughs that do not respond to other therapy can be treated with cough suppressants. Also, when the chronic coughing is irritating to the owner, a cough suppressant can be used.

Question 5

In dogs, the only nonopioid antitussive available in the United States is …………………. hydrobromide. This is an over-the-counter preparation. It is a semisynthetic derivative of opium, but does not act on the opioid receptors in the medulla. Oral doses may not achieve effective levels, and intravenous doses may not last long in dogs.

Answer 5

In dogs, the only nonopioid antitussive available in the United States is dextromethorphan hydrobromide. This is an over-the-counter preparation. It is a semisynthetic derivative of opium, but does not act on the opioid receptors in the medulla. Oral doses may not achieve effective levels, and intravenous doses may not last long in dogs.Most formulations of dextromethorphan are in an alcohol base that is unpalatable to cats, which is why there are no studies of its effectiveness in that species. It can be tried in the dog to see if it will control the coughing. Owners need to be advised to buy a formulation that is not combined with an antihistamine, decongestant, ibuprofen, or acetaminophen, as these other medications may cause unwanted side effects.

Question 6

All of the other cough suppressants used in dogs and cats are opioids. Opioids act by affecting opioid receptors in the …………….., causing ……………, …………., and ……………suppression. Each opioid has varying effects on each of these centers, so some are more useful for analgesia and less useful for cough suppression. Also, their side effects may limit their use as antitussives.

Answer 6

All of the other cough suppressants used in dogs and cats are opioids. Opioids act by affecting opioid receptors in the brain, causing analgesia, sedation, and cough suppression. Each opioid has varying effects on each of these centers, so some are more useful for analgesia and less useful for cough suppression. Also, their side effects may limit their use as antitussives.

Question 7

Care must be taken when using opioids in animals with ………………, severe ………………., or —————disease, or in severely debilitated animals as these animals are easily ………………
Also, they should not be used in animals with head injuries, pulmonary edema, or severe respiratory diseases as unwanted sedation or respiratory depression may worsen these animals’ problems.

Answer 7

Care must be taken when using opioids in animals with hypothyroidism, severe renal insufficiency, or Addison’s disease, or in severely debilitated animals as these animals are easily overdosed. Also, they should not be used in animals with head injuries, pulmonary edema, or severe respiratory diseases as unwanted sedation or respiratory depression may worsen these animals’ problems.

Question 8

Overdosing of any opioid can result in profound central nervous system depression, cardiovascular collapse, hypothermia, or skeletal hypotonia. Fortunately, these severe side effects usually can be reversed with an opioid antagonist such as …………………..

Answer 8

Overdosing of any opioid can result in profound central nervous system depression, cardiovascular collapse, hypothermia, or skeletal hypotonia.[3] Fortunately, these severe side effects usually can be reversed with an opioid antagonist such as naloxone.

Question 9

Codeine phosphate has been used to suppress coughs in people and dogs. It has also been used for analgesia, coughing, and diarrhea in dogs and cats.

It is an effective antitussive in people, but no data is available as to its actual antitussive effects in dogs and cats.

It has a very …….. affinity for the …., ……, and ….. opioid receptors in the ………., so it has only 0.1 the potency of ……..

It may inhibit the release of some inflammatory mediators and has its ……….antitussive effects at special …………..receptors in the brain. Compared with other opioids, it has a ……………………first pass hepatic metabolism, so it lasts longer. In man about 10% of it is converted to …………. and more is converted to …….. in dogs.

Answer 9

It has a very low affinity for the mu, kappa, and delta opioid receptors in the brain, so it has only 0.1 the potency of morphine. It may inhibit the release of some inflammatory mediators and has its major antitussive effects at special codeine receptors in the brain. Compared with other opioids, it has a decreased first pass hepatic metabolism, so it lasts longer. In man about 10% of it is converted to morphine and more is converted to morphine in dogs. However, morphine has a short half-life in dogs, which may decrease codeine’s effectiveness. Its efficacy in animals as an antitussive or analgesic has not been established. Its oral absorption is low in animals.[2]

Question 10

The recommended antitussive dose of codeine in the dog is 0.1 to 0.3 mg/kg q4-6h[3] up to 1 to 2 mg/kg q6-12h. A low dose should be tried first and gradually increased to control the coughing. Side effects can include sedation, anorexia, and constipation with long-term use. Respiratory depression and decreased heart rates only occur with high doses.[2],[3] Several drug interactions can occur with codeine. Quinidine can inhibit codeine’s conversion to morphine in the liver which decreases its effectiveness. Anticholinergics combined with codeine can increase the likelihood of the dog developing constipation. Combining codeine and antidepressants will increase central nervous system depression. No information is available on its use in cats other than it can cause increased excitability and is used mainly for analgesia and not as an antitussive

Answer 10

The recommended antitussive dose of codeine in the dog is 0.1 to 0.3 mg/kg q4-6h[3] up to 1 to 2 mg/kg q6-12h. A low dose should be tried first and gradually increased to control the coughing. Side effects can include sedation, anorexia, and constipation with long-term use. Respiratory depression and decreased heart rates only occur with high doses.[2],[3] Several drug interactions can occur with codeine. Quinidine can inhibit codeine’s conversion to morphine in the liver which decreases its effectiveness. Anticholinergics combined with codeine can increase the likelihood of the dog developing constipation. Combining codeine and antidepressants will increase central nervous system depression. No information is available on its use in cats other than it can cause increased excitability and is used mainly for analgesia and not as an antitussive

Question 11

Hydrocodone bitartrate (Hycodan, Tussigon) is another opioid agonist which affects the …… and ……… opioid receptors in the brain, causing central ………. and ……….effects. Its use as a sedative or analgesic has not been studied in dogs or cats. It also directly suppresses the …………center of the medulla. This make it more effective than codeine and morphine at suppressing coughs.

Answer 11

Hydrocodone bitartrate (Hycodan, Tussigon) is another opioid agonist which affects the mu and kappa opioid receptors in the brain, causing central sedative and euphoric effects. Its use as a sedative or analgesic has not been studied in dogs or cats. It also directly suppresses the cough center of the medulla. This make it more effective than codeine and morphine at suppressing coughs.

No controlled studies have been done to show that it is an effective cough suppressant in dogs and cats. However, most veterinarians who have used it have found that it is effective in controlling coughing in dogs. It has not been used extensively in cats.

Question 12

There are many preparations of hydrocodone available. Sometimes it is combined with guaifenesin, acetaminophen, or atropine. The atropine is usually at a low level, and therefore it does not decrease the respiratory secretions. However, Hycodan itself can also dry secretions, so long-term use must be monitored for any respiratory problems.

Answer 12

There are many preparations of hydrocodone available. Sometimes it is combined with guaifenesin, acetaminophen, or atropine. The atropine is usually at a low level, and therefore it does not decrease the respiratory secretions. However, Hycodan itself can also dry secretions, so long-term use must be monitored for any respiratory problems.

Question 13

The recommended dose of hydrocodone in dogs is 0.22 mg/kg q4-8h PO,[3] up to 0.45 to 0.9 mg/kg q6-12h.[1] There is no dose available in cats. Side effects in dogs include sedation, vomiting, mild bradycardias, and intestinal upsets such as borborygmus and diarrhea.[1] Constipation can occur with chronic usage. Respiratory depression will only occur at high doses. It has more sedative effects than codeine, but is less constipating then codeine. It should be used with caution in respiratory diseases with increased respiratory secretions and where liquids have been nebulized, as it inhibits the coughing reflex and slows clearing of these secretions. Also, it can mask the signs of underlying disease. It should only be used for coughs caused by collapsing trachea, bronchitis, or other problems with dry, harsh, nonproductive coughs.[3] Some authors feel that this is the best and safest antitussive for dogs.[1]

Answer 13

The recommended dose of hydrocodone in dogs is 0.22 mg/kg q4-8h PO,[3] up to 0.45 to 0.9 mg/kg q6-12h.[1] There is no dose available in cats. Side effects in dogs include sedation, vomiting, mild bradycardias, and intestinal upsets such as borborygmus and diarrhea.[1] Constipation can occur with chronic usage. Respiratory depression will only occur at high doses. It has more sedative effects than codeine, but is less constipating then codeine. It should be used with caution in respiratory diseases with increased respiratory secretions and where liquids have been nebulized, as it inhibits the coughing reflex and slows clearing of these secretions. Also, it can mask the signs of underlying disease. It should only be used for coughs caused by collapsing trachea, bronchitis, or other problems with dry, harsh, nonproductive coughs.[3] Some authors feel that this is the best and safest antitussive for dogs.[1]

Question 14

Hydrocodone can have an additive effect with acepromazine that results in hypotension in dogs with collapsing tracheas. It also will increase central nervous system depression when used with an antidepressant.[3]

Answer 14

Hydrocodone can have an additive effect with acepromazine that results in hypotension in dogs with collapsing tracheas. It also will increase central nervous system depression when used with an antidepressant.[3]

Question 15

Butorphanol tartrate (Torbutrol, Torbugesic) is an opioid agonist that has its main actions on the…………..receptors and weak effects on the ………… receptors which results in ……………… It affects the opioid cough receptors in the ……………. resulting in its antitussive effects.

When it is given subcutaneously, it is one hundred times as active as codeine and dextromethorphan and four times as active as morphine. Orally, it is 15 to 20 times more active than codeine or dextromethorphan. One study in dogs has shown that butorphanol has a good antitussive effect in dogs with pathologic coughs.[4] The antitussive dose for dogs is 0.055 to 0.11 mg/kg q6-12h SQ or 0.55 to 1.1 mg/kg q6-12h PO.[1] Another reference gives a dose of 0.22 mg/kg PO q6-12h to decrease coughing without causing sedation and 0.25 mg/kg PO BID to QID for coughing due to collapsing trachea.[3]

Answer 15

Butorphanol tartrate (Torbutrol, Torbugesic) is an opioid agonist that has its main actions on the kappa receptors and weak effects on the mu receptors which results in sedation. It affects the opioid cough receptors in the medulla, resulting in its antitussive effects.

When it is given subcutaneously, it is one hundred times as active as codeine and dextromethorphan and four times as active as morphine. Orally, it is 15 to 20 times more active than codeine or dextromethorphan. One study in dogs has shown that butorphanol has a good antitussive effect in dogs with pathologic coughs.[4] The antitussive dose for dogs is 0.055 to 0.11 mg/kg q6-12h SQ or 0.55 to 1.1 mg/kg q6-12h PO.[1] Another reference gives a dose of 0.22 mg/kg PO q6-12h to decrease coughing without causing sedation and 0.25 mg/kg PO BID to QID for coughing due to collapsing trachea.[3]

Question 16

Side effects of butorphanol in dogs include sedation and occasional diarrhea and/or anorexia. Long-term use can result in constipation. Butorphanol can increase the brain’s respiratory center’s threshold to carbon dioxide; however, this action does not suppress the respiratory center’s sensitivity, so respiratory depression………….a side effect of butorphanol. There have not been any studies done in cats, but the dose given for use as a preanesthetic is 0.2 to 0.4 mg/kg IM.[3] The side effects in cats are the same as in dogs, but also can include dysphoria.

Answer 16

Side effects of butorphanol in dogs include sedation and occasional diarrhea and/or anorexia. Long-term use can result in constipation. Butorphanol can increase the brain’s respiratory center’s threshold to carbon dioxide; however, this action does not suppress the respiratory center’s sensitivity, so respiratory depression is not a side effect of butorphanol. There have not been any studies done in cats, but the dose given for use as a preanesthetic is 0.2 to 0.4 mg/kg IM.[3] The side effects in cats are the same as in dogs, but also can include dysphoria.

Question 17

Diphenoxylate hydrochloride and atropine sulfate (Lomotil) is an opiate agonist combined with an anticholinergic that can be used as an antitussive, but is mainly used as an antidiarrheal in dogs. It should not be used in cats, as it causes hyperexcitability. It also should not be used in animals with hepatic encephalopathy, as it can promote the absorption of more toxins from the gastrointestinal tract because it can cause paralytic ileus. It also can cause constipation, bloating, and sedation. It will increase central nervous system and respiratory depression if it is used with barbiturates, antihistamines, tranquilizers (especially phenothiazines), or anesthesia.

Answer 17

Diphenoxylate hydrochloride and atropine sulfate (Lomotil) is an opiate agonist combined with an anticholinergic that can be used as an antitussive, but is mainly used as an antidiarrheal in dogs. It should not be used in cats, as it causes hyperexcitability. It also should not be used in animals with hepatic encephalopathy, as it can promote the absorption of more toxins from the gastrointestinal tract because it can cause paralytic ileus. It also can cause constipation, bloating, and sedation. It will increase central nervous system and respiratory depression if it is used with barbiturates, antihistamines, tranquilizers (especially phenothiazines), or anesthesia.

Question 18

The antitussive dose of diphenoxylate in dogs is 0.25 mg/kg PO q8-12h or 0.2 to 0.5 mg/kg PO BID. It can be used for extended periods of time, as stool softeners can be used to counteract any constipation that occurs.[3]

Answer 18

The antitussive dose of diphenoxylate in dogs is 0.25 mg/kg PO q8-12h or 0.2 to 0.5 mg/kg PO BID. It can be used for extended periods of time, as stool softeners can be used to counteract any constipation that occurs.[3]

Question 19

Morphine sulfate is another opiate agonist that has antitussive effects in the dog. It is used more frequently as a preanesthetic agent in dogs and for pain in dogs and cats. An antitussive dose is not available.

Answer 19

Morphine sulfate is another opiate agonist that has antitussive effects in the dog. It is used more frequently as a preanesthetic agent in dogs and for pain in dogs and cats. An antitussive dose is not available.

Question 20

Tramadol hydrochloride is an opiate agonist which has both analgesic and antitussive properties in the dog and cat. It acts on the opioid receptors in the ……………. to suppress coughs. It is well-tolerated in dogs and causes only mild sedation. When it is given orally in dogs, its bioavailability is very variable, and its half-life is 1.7 hours. In cats it is variably absorbed after an oral dose, and its half-life is 2.5 hours. Also, it will cause mydriasis and dysphoria in up to 25% of the cats, as well as being unpalatable in cats.[3]

Answer 20

Tramadol hydrochloride is an opiate agonist which has both analgesic and antitussive properties in the dog and cat. It acts on the opioid receptors in the medulla to suppress coughs. It is well-tolerated in dogs and causes only mild sedation. When it is given orally in dogs, its bioavailability is very variable, and its half-life is 1.7 hours. In cats it is variably absorbed after an oral dose, and its half-life is 2.5 hours. Also, it will cause mydriasis and dysphoria in up to 25% of the cats, as well as being unpalatable in cats.[3]

Because of its short half-life, tramadol is not used as an antitussive in dogs or cats. It also interacts with some drugs. It can cause digoxin toxicity when given with digoxin. Quinidine prolongs its blood concentrations, thereby prolonging its effects. In man and perhaps in animals, it may also prolong bleeding times if it is given with warfarin.[3]

Question 21

Trimeprazine tartrate with or without prednisolone (Temaril or Temaril-P) is listed as an antitussive for use in kennel cough, bronchitis, allergic bronchitis, and coughs of unknown origin. When it is combined with a steroid, it also has some antiinflammatory properties. No controlled studies have been done to prove its antitussive effects, and generally it is not recommended for use in most coughing dogs or cats.[1],[3]

Answer 21

Trimeprazine tartrate with or without prednisolone (Temaril or Temaril-P) is listed as an antitussive for use in kennel cough, bronchitis, allergic bronchitis, and coughs of unknown origin. When it is combined with a steroid, it also has some antiinflammatory properties. No controlled studies have been done to prove its antitussive effects, and generally it is not recommended for use in most coughing dogs or cats.[1],[3]

Question 22

SEDATION OF THE CARDIAC PATIENT:

Drugs used for sedation in dogs and cats can include tranquilizers which relieve anxiety without causing marked drowsiness and sedatives which cause drowsiness. A hypnotic agent will induce or facilitate sleep. Hypnotic agents are not used extensively in veterinary medicine, as animals are easily aroused by minor stimuli such as noise. Some drugs such as chloral hydrate or xylazine are both sedatives and hypnotics depending on the dose used. Tranquilizers have been further subdivided into antianxiety drugs (anxiolytics), antipsychotic drugs, and sedative/hypnotics. Antipsychotic drugs were previously called neuroleptics and reduce psychomotor agitation, curiosity, and aggressiveness in animals. They exert their effects by blocking dopamine-mediated central nervous system responses. Drugs in this class include butyrophenone and phenothiazines.

Answer 22

SEDATION OF THE CARDIAC PATIENT:

Drugs used for sedation in dogs and cats can include tranquilizers which relieve anxiety without causing marked drowsiness and sedatives which cause drowsiness. A hypnotic agent will induce or facilitate sleep. Hypnotic agents are not used extensively in veterinary medicine, as animals are easily aroused by minor stimuli such as noise. Some drugs such as chloral hydrate or xylazine are both sedatives and hypnotics depending on the dose used. Tranquilizers have been further subdivided into antianxiety drugs (anxiolytics), antipsychotic drugs, and sedative/hypnotics. Antipsychotic drugs were previously called neuroleptics and reduce psychomotor agitation, curiosity, and aggressiveness in animals. They exert their effects by blocking dopamine-mediated central nervous system responses. Drugs in this class include butyrophenone and phenothiazines.

Question 23

This chapter will deal with drugs used to sedate dogs and cats.
There are five major classes of drugs used to sedate animals for examination and procedures. These classes include?

Answer 23

1. Phenothiazines,
2. Butyrophenones,
3. Benzodiazepines,
4. α-2 adrenergic agonists
5. Opioids.

Some of these can be combined.
There are two major types of veterinary cardiac patients that will need sedation. One type just needs sedation to relieve anxiety and to help it to hold still for the procedures. The other type is the aggressive animal who is a danger to both the veterinary staff and itself.

Question 24

Butyrophenones (Droperidol, Fluanisone)

Butyrophenones can be classified as ………., ……………, or …………..that are similar in action to phenothiazines. They act by blocking ……………… in the central nervous system and as a result cause ………………. The three drugs in this class are fluanisone, droperidol, and azaperone.

Butyrophenones are not available as single drugs and are combined with the opioid ………….for use in dogs. Droperidol with fentanyl is Innovar-Vet, and fluanisone with fentanyl is Hypnorm. These combinations result in sedation with profound analgesia. Also, the combination with fentanyl helps to prevent aggression or excitement in dogs that could occur if droperidol were used alone. However, the use of a butyrophenone alone or in combination with an opioid is still not recommended for use in cats because of possible central nervous stimulation, resulting in agitation and excitement.

Answer 24

Butyrophenones can be classified as tranquilizers, neuroleptics, or antipsychotics that are similar in action to phenothiazines. They act by blocking dopamine in the central nervous system and as a result cause sedation. The three drugs in this class are fluanisone, droperidol, and azaperone.

Butyrophenones are not available as single drugs and are combined with the opioid fentanyl for use in dogs. Droperidol with fentanyl is Innovar-Vet, and fluanisone with fentanyl is Hypnorm. These combinations result in sedation with profound analgesia. Also, the combination with fentanyl helps to prevent aggression or excitement in dogs that could occur if droperidol were used alone. However, the use of a butyrophenone alone or in combination with an opioid is still not recommended for use in cats because of possible central nervous stimulation, resulting in agitation and excitement.

Question 25

If butyrophenones are used in high doses in dogs, they can cause muscle tremors and muscle rigidity. Also, if they are given intravenously, they can cause excitement, so the intravenous route of administration should be avoided. Unexpected aggression and excitement in dogs given butyrophenones is avoided because these drugs are combined with opioids in the formulations available for use in dogs.[1] The butyrophenones have similar cardiovascular effects as the phenothiazines. They cause vasodilation by blocking the alpha-1 (α-1) adrenergic receptors on the vessels. Even though the degree of hypotension seems to be less than that of phenothiazines, butyrophenones should be avoided in patients who are hypovolemic or hypotensive or are taking vasodilators for their cardiac disease, as profound hypotension could result. When butyrophenones are combined with fentanyl, bradycardias can result because of the fentanyl. These bradycardias can be more severe in brachycephalic dogs and other dogs with increased vagal tone. The use of either atropine or glycopyrrolate may prevent sinus bradycardia, but may not be protective for dogs with advanced heart blocks. Butyrophenones supposedly are antiarrhythmic and help prevent ventricular arrhythmias. However, in people they will cause a long QT interval that can be prearrhythmic in some individuals. Currently there is no evidence that this occurs in dogs.[1] In high doses the butyrophenones will slow the respiratory rate, but at low to moderate doses they will increase the respiratory rate. However, when they are used in combination with the opioids, the respiratory rate decreases and the PCO2 increases due to the opioids.[1],[5] Butyrophenones plus fentanyl can cause some dogs to salivate and defecate. Also, these drugs should not be used with other analgesics or general anesthesia, as the combination will cause severe central nervous system depression and respiratory depression. The other drug to avoid using with butyrophenones is epinephrine, as arrhythmias can result.[1]

Answer 25

If butyrophenones are used in high doses in dogs, they can cause muscle tremors and muscle rigidity. Also, if they are given intravenously, they can cause excitement, so the intravenous route of administration should be avoided. Unexpected aggression and excitement in dogs given butyrophenones is avoided because these drugs are combined with opioids in the formulations available for use in dogs.[1] The butyrophenones have similar cardiovascular effects as the phenothiazines. They cause vasodilation by blocking the alpha-1 (α-1) adrenergic receptors on the vessels. Even though the degree of hypotension seems to be less than that of phenothiazines, butyrophenones should be avoided in patients who are hypovolemic or hypotensive or are taking vasodilators for their cardiac disease, as profound hypotension could result. When butyrophenones are combined with fentanyl, bradycardias can result because of the fentanyl. These bradycardias can be more severe in brachycephalic dogs and other dogs with increased vagal tone. The use of either atropine or glycopyrrolate may prevent sinus bradycardia, but may not be protective for dogs with advanced heart blocks. Butyrophenones supposedly are antiarrhythmic and help prevent ventricular arrhythmias. However, in people they will cause a long QT interval that can be prearrhythmic in some individuals. Currently there is no evidence that this occurs in dogs.[1] In high doses the butyrophenones will slow the respiratory rate, but at low to moderate doses they will increase the respiratory rate. However, when they are used in combination with the opioids, the respiratory rate decreases and the PCO2 increases due to the opioids.[1],[5] Butyrophenones plus fentanyl can cause some dogs to salivate and defecate. Also, these drugs should not be used with other analgesics or general anesthesia, as the combination will cause severe central nervous system depression and respiratory depression. The other drug to avoid using with butyrophenones is epinephrine, as arrhythmias can result.[1]

Question 26

The major advantages of butyrophenones in canine cardiac patients are that it provides good sedation and analgesia so that radiographs and echocardiograms can be done easily. Their disadvantages are that they cannot be used in patients on vasodilators, as they will potentiate the vasodilation and may result in profound hypotension which can be detrimental to these patients. Also, droperidol's effects last 6 to 8 hours, which makes it a poor choice for patients who may only be in the hospital for a couple of hours.[5] See Web Table 246-1 for advantages and disadvantages of their use in cardiac patients.

Answer 26

The major advantages of butyrophenones in canine cardiac patients are that it provides good sedation and analgesia so that radiographs and echocardiograms can be done easily. Their disadvantages are that they cannot be used in patients on vasodilators, as they will potentiate the vasodilation and may result in profound hypotension which can be detrimental to these patients. Also, droperidol's effects last 6 to 8 hours, which makes it a poor choice for patients who may only be in the hospital for a couple of hours.[5] See Web Table 246-1 for advantages and disadvantages of their use in cardiac patients.

Question 27

Phenothiazines Phenothiazines include ......................., chlorpromazine, promethazine, promazine, and prochlorperazine. They have been classified as ..............., ................, .............., and .................. The sedative and antiemetic effects of these drugs are caused by their ..........................of the central ................... receptors. Other effects of these drugs are because of their actions on the α-1 ...........receptors, ................. receptors, and .................... cholinergic receptors. Because phenothiazines inhibit the ................... receptors, they will calm an animal. However, some of these drugs such as acepromazine will cause more ......................... than the others. Prochlorperazine is used more as an ..................., whereas promethazine hydrochloride is used for its potent antihistamine effects. Chlorpromazine hydrochloride and promazine are not as potent as acepromazine maleate in inducing sedation and therefore are rarely used.[3] Acepromazine maleate is the phenothiazine used most in veterinary medicine. Acepromazine at low doses will sedate a dog. Increasing the dose may increase sedation to some extent in the dog, but not in the cat. Further increasing the dose in dogs only prolongs the length of sedation and increases side effects.

Answer 27

Phenothiazines Phenothiazines include acepromazine, chlorpromazine, promethazine, promazine, and prochlorperazine. They have been classified as tranquilizers, neuroleptics, antipsychotics, and sedatives. The sedative and antiemetic effects of these drugs are caused by their inhibition of the central dopamine receptors. Other effects of these drugs are because of their actions on the α-1 adrenergic receptors, H1-histamine receptors, and muscarinic cholinergic receptors. Because phenothiazines inhibit the dopamine receptors, they will calm an animal. However, some of these drugs such as acepromazine will cause more sedation than the others. Prochlorperazine is used more as an antiemetic, whereas promethazine hydrochloride is used for its potent antihistamine effects. Chlorpromazine hydrochloride and promazine are not as potent as acepromazine maleate in inducing sedation and therefore are rarely used.[3] Acepromazine maleate is the phenothiazine used most in veterinary medicine. Acepromazine at low doses will sedate a dog. Increasing the dose may increase sedation to some extent in the dog, but not in the cat. Further increasing the dose in dogs only prolongs the length of sedation and increases side effects.[

Question 28

Side effects of acepromazine are excessive sedation and ataxia. Muscle twitching, especially involuntary muscle movements, are rare side effects. At very high doses, acepromazine can cause excitement.[5] Acepromazine can potentiate seizures if it is given with other drugs that lower the seizure threshold. Therefore, it should be avoided in animals with a history of seizures.[2] At lower doses, acepromazine has little effect on heart rate. However, some dogs especially brachycephalic breeds, given very high doses of acepromazine develop signs of excessive vagal tone which results in marked bradycardia including sinus arrest.[1],[2] A few dogs, especially Boxers, have had episodes of vasovagal syncope following the use of acepromazine. The vasovagal syncope is probably a combination of the bradycardia caused by decreasing sympathetic stimulation and the vasodilation causing hypotension that occurs with acepromazine. The vasovagal syncope can be treated with sympatholytics and fluids. The vasovagal syncope might be avoided by using acepromazine with atropine in brachycephalic dogs and boxers.[1] Acepromazine can protect against arrhythmias caused by ultrashort barbiturates and protects against ventricular tachycardia caused by halothane or epinephrine. Acepromazine can cause hypotension mainly as a result of its blocking of the alpha-adrenergic receptors resulting in peripheral vasodilation. The hypotension is mild and does not cause any problems except in patients with shock or hypovolemia.[2] However, care must also be taken in animals receiving vasodilators, as the two drugs together might cause a more marked hypotension. Because most cardiac patients are receiving vasodilators, acepromazine must be used at very low doses or not used at all in those patients. Also, many fearful dogs receiving acepromazine have developed a marked hypotension which may be a form of orthostatic hypotension.[1] An additional side effect of acepromazine is hypothermia. The hypothermia is a combination of peripheral vasodilation which allows more blood to pool peripherally and the central effects in the thermoregulatory center in the brain. The hypothermia is more severe in smaller animals with large surface areas, which allows more blood to be in surface vessels where heat is lost. The respiratory system is only mildly affected by acepromazine. Although the respiratory rate may decrease slightly, the minute respiratory volume is normal. So animals with respiratory problems are not adversely affected by the use of acepromazine, and it is particularly effective in calming dogs with collapsing tracheas. However, acepromazine does impair the movement of the arytenoid cartilage and should not be used in animals with laryngeal paralysis.[1] Acepromazine has a spasmolytic action on the gastrointestinal tract of the dog which results in decreased motility. Also, even though acepromazine has little antihistamine effects, it might interfere with the results of intradermal allergy testing and so should not be used to sedate dogs having these tests. Acepromazine can also sequester red blood cells in the spleen, causing a decreased hematocrit, and it can also transiently reduce platelet numbers and platelet aggregation. Acepromazine is well absorbed after intramuscular injection, but it is not as well absorbed after subcutaneous injection even though it still effective when given subcutaneously. After acepromazine has been given intravenously, the sedation is seen within five minutes, but it may not be optimal for 20 minutes.[5] Maximum sedative effects are usually seen 30 to 45 minutes after IM or subcutaneous injection. Oral doses have variable absorption and must be given at higher doses to be effective. Acepromazine's effects and duration of action depend on the dose and route of administration. In most dogs, acepromazine's effects last 3 to 4 hours, but it can last 7 hours or longer. Owners of giant breeds of dogs and sight hounds have complained about excessive sedation that lasts over 12 to 24 hours in these dogs. Collies and Australian Shepherds are also reported to be sensitive to acepromazine's effects. No studies have been done to document prolonged effects of acepromazine in these breeds.[5] Acepromazine is tightly protein bound and has a wide distribution throughout the animal's body because it is highly lipophilic. It is metabolized in the liver, and its metabolites are excreted in the urine. In severe liver disease, its actions are prolonged because of decreased metabolism.[1] Opioids will enhance hypotension caused by acepromazine when they are used in combination. Propranolol will increase blood levels of acepromazine, and quinidine will cause additive central nervous system depression when used with acepromazine.[3] Occasionally acepromazine can cause central nervous system stimulation and aggression. Also, in an animal that is already aggressive, it may not work to sedate them and may make them more prone to be startled and therefore more aggressive.[3] See Web Table 246-1 for the doses of acepromazine and Web Table 246-2 for its advantages and disadvantages in cardiac patients

Answer 28

Side effects of acepromazine are excessive sedation and ataxia. Muscle twitching, especially involuntary muscle movements, are rare side effects. At very high doses, acepromazine can cause excitement.[5] Acepromazine can potentiate seizures if it is given with other drugs that lower the seizure threshold. Therefore, it should be avoided in animals with a history of seizures.[2] At lower doses, acepromazine has little effect on heart rate. However, some dogs especially brachycephalic breeds, given very high doses of acepromazine develop signs of excessive vagal tone which results in marked bradycardia including sinus arrest.[1],[2] A few dogs, especially Boxers, have had episodes of vasovagal syncope following the use of acepromazine. The vasovagal syncope is probably a combination of the bradycardia caused by decreasing sympathetic stimulation and the vasodilation causing hypotension that occurs with acepromazine. The vasovagal syncope can be treated with sympatholytics and fluids. The vasovagal syncope might be avoided by using acepromazine with atropine in brachycephalic dogs and boxers.[1] Acepromazine can protect against arrhythmias caused by ultrashort barbiturates and protects against ventricular tachycardia caused by halothane or epinephrine. Acepromazine can cause hypotension mainly as a result of its blocking of the alpha-adrenergic receptors resulting in peripheral vasodilation. The hypotension is mild and does not cause any problems except in patients with shock or hypovolemia.[2] However, care must also be taken in animals receiving vasodilators, as the two drugs together might cause a more marked hypotension. Because most cardiac patients are receiving vasodilators, acepromazine must be used at very low doses or not used at all in those patients. Also, many fearful dogs receiving acepromazine have developed a marked hypotension which may be a form of orthostatic hypotension.[1] An additional side effect of acepromazine is hypothermia. The hypothermia is a combination of peripheral vasodilation which allows more blood to pool peripherally and the central effects in the thermoregulatory center in the brain. The hypothermia is more severe in smaller animals with large surface areas, which allows more blood to be in surface vessels where heat is lost. The respiratory system is only mildly affected by acepromazine. Although the respiratory rate may decrease slightly, the minute respiratory volume is normal. So animals with respiratory problems are not adversely affected by the use of acepromazine, and it is particularly effective in calming dogs with collapsing tracheas. However, acepromazine does impair the movement of the arytenoid cartilage and should not be used in animals with laryngeal paralysis.[1] Acepromazine has a spasmolytic action on the gastrointestinal tract of the dog which results in decreased motility. Also, even though acepromazine has little antihistamine effects, it might interfere with the results of intradermal allergy testing and so should not be used to sedate dogs having these tests. Acepromazine can also sequester red blood cells in the spleen, causing a decreased hematocrit, and it can also transiently reduce platelet numbers and platelet aggregation. Acepromazine is well absorbed after intramuscular injection, but it is not as well absorbed after subcutaneous injection even though it still effective when given subcutaneously. After acepromazine has been given intravenously, the sedation is seen within five minutes, but it may not be optimal for 20 minutes.[5] Maximum sedative effects are usually seen 30 to 45 minutes after IM or subcutaneous injection. Oral doses have variable absorption and must be given at higher doses to be effective. Acepromazine's effects and duration of action depend on the dose and route of administration. In most dogs, acepromazine's effects last 3 to 4 hours, but it can last 7 hours or longer. Owners of giant breeds of dogs and sight hounds have complained about excessive sedation that lasts over 12 to 24 hours in these dogs. Collies and Australian Shepherds are also reported to be sensitive to acepromazine's effects. No studies have been done to document prolonged effects of acepromazine in these breeds.[5] Acepromazine is tightly protein bound and has a wide distribution throughout the animal's body because it is highly lipophilic. It is metabolized in the liver, and its metabolites are excreted in the urine. In severe liver disease, its actions are prolonged because of decreased metabolism.[1] Opioids will enhance hypotension caused by acepromazine when they are used in combination. Propranolol will increase blood levels of acepromazine, and quinidine will cause additive central nervous system depression when used with acepromazine.[3] Occasionally acepromazine can cause central nervous system stimulation and aggression. Also, in an animal that is already aggressive, it may not work to sedate them and may make them more prone to be startled and therefore more aggressive.[3] See Web Table 246-1 for the doses of acepromazine and Web Table 246-2 for its advantages and disadvantages in cardiac patients

Question 29

Benzodiazepines (Diazepam, Midazolam, Zolazepam with Tilamine) Benzodiazepines are primarily .................. drugs, but at higher doses they can cause sedation by depressing the ..........................,....................,and........................ systems in the brain. Also, their sedative and anticonvulsant effects in people are caused by their .....................................of GABA on the GABAA receptors in the brain. GABAA receptors are linked to chloride channels which open and result in hyperpolarization, thereby decreasing membrane excitability. Therefore, when benzodiazepines interact with a regulatory site on the GABA receptor, GABA will more readily attach to the receptor and decrease excitability.[1] These may be the same mechanisms by which they work in animals, but studies have not been done to show this.

Answer 29

Benzodiazepines (Diazepam, Midazolam, Zolazepam with Tilamine) Benzodiazepines are primarily anxiolytic drugs, but at higher doses they can cause sedation by depressing the limbic, thalamus, and hypothalamic systems in the brain. Also, their sedative and anticonvulsant effects in people are caused by their enhancing the effects of GABA on the GABAA receptors in the brain. GABAA receptors are linked to chloride channels which open and result in hyperpolarization, thereby decreasing membrane excitability. Therefore, when benzodiazepines interact with a regulatory site on the GABA receptor, GABA will more readily attach to the receptor and decrease excitability.[1] These may be the same mechanisms by which they work in animals, but studies have not been done to show this.

Question 30

In normal animals, benzodiazepines will rarely sedate an animal enough to do diagnostic or other procedures. Also, they may cause hyperexcitability, making the animal hard to handle, and a vicious animal more difficult to handle. So they are combined with other drugs such as opioids to achieve sedation and avoid excitement in these animals. In animals that are at high risk such as the neonates, aged animals, or critically ill patients, benzodiazepines may produce sedation with few side effects. Benzodiazepines can be used orally as they have high oral availability and can also be used intravenously and intramuscularly. For sedation of cardiac patients the route of administration, either intravenous or intramuscular, depends on the drug selected. Diazepam is insoluble in water and is combined with propylene glycol, sodium benzoate in benzoic acid, and ethanol. These substances are irritating and cannot be given IM because of the pain they cause. Care also must be taken with IV injections to avoid thrombophlebitis, pain, and arrhythmias. Midazolam is water-soluble and therefore can be given IM and IV without pain and is highly bioavailable.[1] Benzodiazepines are highly protein bound. They also are lipophilic drugs and therefore are distributed throughout the body. They also readily cross the blood-brain barrier and the placenta. Their effect on the fetus is variable and hard to measure.[1] Metabolism of benzodiazepines is in the liver by several mechanisms including demethylation, hydroxylation, and glucuronide conjugation. Some of the metabolites of diazepam are also active which accounts for its longer duration of action in the dog and sometimes resedation 6 to 8 hours after the initial dose. Midazolam does not have any active metabolites. Diazepam's elimination half-life is 3.2 hours, and midazolam's elimination half-life is 77 minutes.[1] Benzodiazepines have few effects on the cardiac or respiratory systems, even in cardiac patients on other medications. At very high doses, there could be a slight reduction in blood pressure and cardiac output. Arrhythmias have been reported if diazepam is injected too rapidly IV because of its propylene glycol base. Benzodiazepines can increase the respiratory depression and central nervous system depression caused by other drugs such as opioids. Also, the central nervous system depression of barbiturates and propofol can be enhanced by benzodiazepines. Drugs that extend the actions of benzodiazepines include those that impair their eliminations by inhibiting microsomal enzymes. Drugs such as erythromycin prolong midazolam's sedation, and cimetidine prolongs diazepam's effects.[1] Benzodiazepines have been reported to contribute to development of hepatic encephalopathy. So they should be avoided in animals with liver diseases, especially those with hepatic shunts. Also, in cats chronic use of oral diazepam has been reported to cause hepatic failure.[1] Diazepam (Valium) is the benzodiazepine that has been used most frequently in dogs and cats for sedatives and control of seizures. Its antiseizure qualities are excellent, but it rarely will sedate healthy animals. It may sedate animals with advanced cardiovascular diseases, but usually it has to be used with another agent in order to achieve enough sedation for diagnostic procedures. Diazepam has rapid oral absorption which peaks in 30 minutes and lasts 2.5 to 3.2 hours in the dog. About 80% of it is bioavailable after it is absorbed. It would be given to a nervous dog by the owner prior to coming to the office in an attempt to partially sedate and calm the animal. However, it can make aggressive animals worse, as it removes their inhibition; so, its use should be avoided in these dogs. Nervous cats do not respond well to oral Valium even though it lasts up to 5.5 hours.[3] Cats can become irritable, depressed, or have an aberrant demeanor; so it is not a good sedative by itself in cats.[3] Because it is in a propylene glycol base, diazepam can cause fatal arrhythmias if given too rapidly IV. The rest of its effects are discussed above. Midazolam hydrochloride (Versed) by itself does not give predictable sedation in dogs or cats. Cats especially tend to become excited if this is used as a sole agent for sedation. Usually midazolam is combined with either opioids or ketamine to get more predictable sedation. In people, midazolam reverses the hypertension and tachycardia caused by ketamine.[3] Studies need to be done in cats to prove whether or not this is the case, as this combination would then be ideal to use in cats with cardiac disease, especially hypertrophic cardiomyopathy. Midazolam is three times as potent as diazepam and has a faster onset of action, but a shorter duration of action. Because it is water-soluble, it can be used both IM and IV. Midazolam given alone has little effect on the cardiovascular or respiratory systems. It is eliminated more slowly by animals with congestive heart failure because of poor cardiac output and possible hepatic congestion. When it is combined with an opioid, it has less cardiac depression, but more respiratory depression than the use of an opioid plus acepromazine.[3] Calcium channel blockers will increase midazolam blood levels and thereby increase its effects. Dogs with atrial fibrillation and cats with hypertrophic cardiomyopathy may be on calcium channel blockers which could potentiate midazolam effects. Cimetidine also increases midazolam blood levels. Central nervous system depressants increase the respiratory depression with midazolam. Opiates will increase the hypnotic effects of midazolam, but these are generally good drugs to use in combination for sedation. Phenobarbital will decrease the peak levels of midazolam. Climagolam is another benzodiazepine that has been used in combination with fentanyl for anesthesia, but not sedation in the dog. Zolazepam is a benzodiazepine combined with tiletamine (Telazol) for anesthesia and tranquilization in dogs. Telazol is similar to the combination of ketamine and Valium. It should not be used in animals with severe cardiac or pulmonary disease, as it causes respiratory depression. It also causes tachycardia, especially in dogs. Some patients given Telazol have developed pulmonary edema, and both hypertension or hypotension have also been reported. Its dose has to be decreased in geriatric or debilitated patients and in those with renal dysfunction. Some dogs will have excessive salivation, increased bronchial or tracheal secretions, and transient apnea with its use. Dogs also may have erratic and prolonged recovery with involuntary muscle twitching, hypertonia, cyanosis, and hyperexcitability.[3] In cats, Telazol will decrease heart rate and blood pressure after an IM injection. The IM injection is painful. Its effects on respiration are unknown. Its onset of action in cats is 1 to 7 minutes, and it lasts 0.33 to 1 hour. Most cats recover within 1 to 5.5 hours, and they have a smooth recovery. If an overdose of a benzodiazepine occurs, it can be reversed with flumazenil, a benzodiazepine antagonist. Flumazenil's use in veterinary medicine has been limited, but it potentially could be used to reverse the effects of benzodiazepines in animals that remain only a short time in the hospital. The advantages of using diazepam or midazolam in cardiac patients is that they have minimal cardiovascular and respiratory effects. The disadvantage is that they do not consistently sedate patients for diagnostic procedures and may actually increase aggression in aggressive animals.

Answer 30

In normal animals, benzodiazepines will rarely sedate an animal enough to do diagnostic or other procedures. Also, they may cause hyperexcitability, making the animal hard to handle, and a vicious animal more difficult to handle. So they are combined with other drugs such as opioids to achieve sedation and avoid excitement in these animals. In animals that are at high risk such as the neonates, aged animals, or critically ill patients, benzodiazepines may produce sedation with few side effects. Benzodiazepines can be used orally as they have high oral availability and can also be used intravenously and intramuscularly. For sedation of cardiac patients the route of administration, either intravenous or intramuscular, depends on the drug selected. Diazepam is insoluble in water and is combined with propylene glycol, sodium benzoate in benzoic acid, and ethanol. These substances are irritating and cannot be given IM because of the pain they cause. Care also must be taken with IV injections to avoid thrombophlebitis, pain, and arrhythmias. Midazolam is water-soluble and therefore can be given IM and IV without pain and is highly bioavailable.[1] Benzodiazepines are highly protein bound. They also are lipophilic drugs and therefore are distributed throughout the body. They also readily cross the blood-brain barrier and the placenta. Their effect on the fetus is variable and hard to measure.[1] Metabolism of benzodiazepines is in the liver by several mechanisms including demethylation, hydroxylation, and glucuronide conjugation. Some of the metabolites of diazepam are also active which accounts for its longer duration of action in the dog and sometimes resedation 6 to 8 hours after the initial dose. Midazolam does not have any active metabolites. Diazepam's elimination half-life is 3.2 hours, and midazolam's elimination half-life is 77 minutes.[1] Benzodiazepines have few effects on the cardiac or respiratory systems, even in cardiac patients on other medications. At very high doses, there could be a slight reduction in blood pressure and cardiac output. Arrhythmias have been reported if diazepam is injected too rapidly IV because of its propylene glycol base. Benzodiazepines can increase the respiratory depression and central nervous system depression caused by other drugs such as opioids. Also, the central nervous system depression of barbiturates and propofol can be enhanced by benzodiazepines. Drugs that extend the actions of benzodiazepines include those that impair their eliminations by inhibiting microsomal enzymes. Drugs such as erythromycin prolong midazolam's sedation, and cimetidine prolongs diazepam's effects.[1] Benzodiazepines have been reported to contribute to development of hepatic encephalopathy. So they should be avoided in animals with liver diseases, especially those with hepatic shunts. Also, in cats chronic use of oral diazepam has been reported to cause hepatic failure.[1] Diazepam (Valium) is the benzodiazepine that has been used most frequently in dogs and cats for sedatives and control of seizures. Its antiseizure qualities are excellent, but it rarely will sedate healthy animals. It may sedate animals with advanced cardiovascular diseases, but usually it has to be used with another agent in order to achieve enough sedation for diagnostic procedures. Diazepam has rapid oral absorption which peaks in 30 minutes and lasts 2.5 to 3.2 hours in the dog. About 80% of it is bioavailable after it is absorbed. It would be given to a nervous dog by the owner prior to coming to the office in an attempt to partially sedate and calm the animal. However, it can make aggressive animals worse, as it removes their inhibition; so, its use should be avoided in these dogs. Nervous cats do not respond well to oral Valium even though it lasts up to 5.5 hours.[3] Cats can become irritable, depressed, or have an aberrant demeanor; so it is not a good sedative by itself in cats.[3] Because it is in a propylene glycol base, diazepam can cause fatal arrhythmias if given too rapidly IV. The rest of its effects are discussed above. Midazolam hydrochloride (Versed) by itself does not give predictable sedation in dogs or cats. Cats especially tend to become excited if this is used as a sole agent for sedation. Usually midazolam is combined with either opioids or ketamine to get more predictable sedation. In people, midazolam reverses the hypertension and tachycardia caused by ketamine.[3] Studies need to be done in cats to prove whether or not this is the case, as this combination would then be ideal to use in cats with cardiac disease, especially hypertrophic cardiomyopathy. Midazolam is three times as potent as diazepam and has a faster onset of action, but a shorter duration of action. Because it is water-soluble, it can be used both IM and IV. Midazolam given alone has little effect on the cardiovascular or respiratory systems. It is eliminated more slowly by animals with congestive heart failure because of poor cardiac output and possible hepatic congestion. When it is combined with an opioid, it has less cardiac depression, but more respiratory depression than the use of an opioid plus acepromazine.[3] Calcium channel blockers will increase midazolam blood levels and thereby increase its effects. Dogs with atrial fibrillation and cats with hypertrophic cardiomyopathy may be on calcium channel blockers which could potentiate midazolam effects. Cimetidine also increases midazolam blood levels. Central nervous system depressants increase the respiratory depression with midazolam. Opiates will increase the hypnotic effects of midazolam, but these are generally good drugs to use in combination for sedation. Phenobarbital will decrease the peak levels of midazolam. Climagolam is another benzodiazepine that has been used in combination with fentanyl for anesthesia, but not sedation in the dog. Zolazepam is a benzodiazepine combined with tiletamine (Telazol) for anesthesia and tranquilization in dogs. Telazol is similar to the combination of ketamine and Valium. It should not be used in animals with severe cardiac or pulmonary disease, as it causes respiratory depression. It also causes tachycardia, especially in dogs. Some patients given Telazol have developed pulmonary edema, and both hypertension or hypotension have also been reported. Its dose has to be decreased in geriatric or debilitated patients and in those with renal dysfunction. Some dogs will have excessive salivation, increased bronchial or tracheal secretions, and transient apnea with its use. Dogs also may have erratic and prolonged recovery with involuntary muscle twitching, hypertonia, cyanosis, and hyperexcitability.[3] In cats, Telazol will decrease heart rate and blood pressure after an IM injection. The IM injection is painful. Its effects on respiration are unknown. Its onset of action in cats is 1 to 7 minutes, and it lasts 0.33 to 1 hour. Most cats recover within 1 to 5.5 hours, and they have a smooth recovery. If an overdose of a benzodiazepine occurs, it can be reversed with flumazenil, a benzodiazepine antagonist. Flumazenil's use in veterinary medicine has been limited, but it potentially could be used to reverse the effects of benzodiazepines in animals that remain only a short time in the hospital. The advantages of using diazepam or midazolam in cardiac patients is that they have minimal cardiovascular and respiratory effects. The disadvantage is that they do not consistently sedate patients for diagnostic procedures and may actually increase aggression in aggressive animals.

Question 31

Alpha-2 (α-2) Adrenergic Agonists (Xylazine, Detomidine, Ranitidine, Medetomidine) Alpha-2 (α-2) agonists exert their sedative, analgesic, and muscle-relaxant effects on the ............... α-2 receptors and on the ....................... α-2 receptors. The α-2 agonists used in veterinary medicine also have some α-.....effects, as well. Even though α-2 adrenergic agonists are very good sedatives, they have marked effects on the cardiovascular and respiratory systems which makes them risky to use in patients with moderate to severe cardiac disease. The α-2 agonists cause profound cardiac effects even at low doses. Decreased sympathetic tone allows .......... tone to produce profound bradycardias at sedative doses of these drugs. A baroreceptor response to hypertension may also contribute to the bradycardias. ECGs run on animals given α-2 agonists can show heart rates that drop by as much as 50%, marked sinus arrhythmia, sinoatrial block, and profound first degree heart block that can progress to second-degree and even complete heart block. These bradycardias can be prevented by using atropine or glycopyrrolate first, but these drugs can cause tachycardias which extend the hypertensive phase of the drugs, decreasing cardiac output further. α-2 Agonists have variable effects on blood pressure. The agonists activate peripheral α-2 and α-1 postsynaptic receptors which cause vasoconstriction and therefore hypertension. The agonists also reduce norepinephrine release and decreases sympathetic tone centrally which causes vasodilation. The end result is that the blood pressure goes up initially followed by hypotension which persists longer. The length of time that the animal is hypertensive is determined by the drug used and the route of administration. High doses given IV prolong the hypertensive phase. α-2 Agonists also cause a marked decrease in cardiac output although they have no direct cardiac depression. The decreased cardiac output is a result of the profound bradycardia and vasoconstriction which causes an increased afterload. If atropine or glycopyrrolate are used to counteract the bradycardias, a sinus tachycardia results which also can decrease the cardiac output and extend the hypertensive phase of the α-2 agonist. α-2 Agonists may or may not potentiate catecholamine-induced arrhythmias. An early study showed that the threshold for arrhythmias was reduced in anesthetized dogs. However, a later study of xylazine and medetomidine failed to show any antiarrhythmic effects.[2] Dexmedetomidine has been shown to have an antiarrhythmic effect.[1] α-2 Agonists have other side effects in other systems. However, because of their adverse effects on heart rate, producing severe bradycardias and hypertension followed by hypotension, they should not be used in dogs or cats with moderate to severe cardiac diseases. Medetomidine hydrochloride (Domitor) is a synthetic α-2 adrenergic agonist that is used for sedation, analgesia, and muscle relaxation in dogs and cats. Its effects are reversible with atipamizole. Because of its side effects of hypertension and profound bradycardias, it is not recommended for use in dogs with significant heart disease. However, it can be used in some cats with hypertrophic cardiomyopathy. A study using medetomidine to sedate cats with hypertrophic obstructive cardiomyopathy (HOCM) showed that these cats actually benefited from its use.[6] In HOCM the hypertrophy of the intraventricular septum combined with systolic anterior motion (SAM) of the mitral valve results in dynamic obstruction of blood flow out the left ventricular outflow tract (LVOT). This obstruction can be documented by continuous wave Doppler as an increased velocity of blood in the LVOT. In this study, cats with HOCM were given medetomidine (20 mg/kg IM) and allowed to rest for 15 minutes. All cats had adequate sedation to allow echocardiography to be done, but could still be stimulated. Two cats did vomit after being given the medetomidine, but there were no other adverse side effects seen. The cats had a smooth recovery and were able to go home one hour after being sedated. None of the cats needed to have the medetomidine reversed with atipamizole.[6] The medetomidine decreased the heart rate in all the cats, but all of them remained in a sinus rhythm and none had any heart blocks or other adverse bradycardias. The cats’ blood pressures did not change. There was a significant decrease in LVOT outflow velocity, and SAM was totally eliminated in these cats. These changes were caused by the decrease in heart rate and increased systemic vascular resistance which decreased the outflow obstruction and decreased the effects of drag forces in the mitral valve apparatus which decreased SAM.[6] The only change in the echocardiographic values was a mild increase in left atrial systolic size. This was felt to be caused by increases in cardiac afterload coupled with decreased heart rate. So, if medetomidine was used to sedate a cat with HCOM before an echocardiogram, it would make it impossible to document the presence of outflow obstruction, but the other echocardiogram parameters would be the same as in a nonsedated cat. So, medetomidine is safe to use in cats with HOCM.[6]

Answer 31

Alpha-2 (α-2) Adrenergic Agonists (Xylazine, Detomidine, Ranitidine, Medetomidine) Alpha-2 (α-2) agonists exert their sedative, analgesic, and muscle-relaxant effects on the central α-2 receptors and on the peripheral α-2 receptors. The α-2 agonists used in veterinary medicine also have some α-1 effects, as well. Even though α-2 adrenergic agonists are very good sedatives, they have marked effects on the cardiovascular and respiratory systems which makes them risky to use in patients with moderate to severe cardiac disease. The α-2 agonists cause profound cardiac effects even at low doses. Decreased sympathetic tone allows vagal tone to produce profound bradycardias at sedative doses of these drugs. A baroreceptor response to hypertension may also contribute to the bradycardias. ECGs run on animals given α-2 agonists can show heart rates that drop by as much as 50%, marked sinus arrhythmia, sinoatrial block, and profound first degree heart block that can progress to second-degree and even complete heart block. These bradycardias can be prevented by using atropine or glycopyrrolate first, but these drugs can cause tachycardias which extend the hypertensive phase of the drugs, decreasing cardiac output further. α-2 Agonists have variable effects on blood pressure. The agonists activate peripheral α-2 and α-1 postsynaptic receptors which cause vasoconstriction and therefore hypertension. The agonists also reduce norepinephrine release and decreases sympathetic tone centrally which causes vasodilation. The end result is that the blood pressure goes up initially followed by hypotension which persists longer. The length of time that the animal is hypertensive is determined by the drug used and the route of administration. High doses given IV prolong the hypertensive phase. α-2 Agonists also cause a marked decrease in cardiac output although they have no direct cardiac depression. The decreased cardiac output is a result of the profound bradycardia and vasoconstriction which causes an increased afterload. If atropine or glycopyrrolate are used to counteract the bradycardias, a sinus tachycardia results which also can decrease the cardiac output and extend the hypertensive phase of the α-2 agonist. α-2 Agonists may or may not potentiate catecholamine-induced arrhythmias. An early study showed that the threshold for arrhythmias was reduced in anesthetized dogs. However, a later study of xylazine and medetomidine failed to show any antiarrhythmic effects.[2] Dexmedetomidine has been shown to have an antiarrhythmic effect.[1] α-2 Agonists have other side effects in other systems. However, because of their adverse effects on heart rate, producing severe bradycardias and hypertension followed by hypotension, they should not be used in dogs or cats with moderate to severe cardiac diseases. Medetomidine hydrochloride (Domitor) is a synthetic α-2 adrenergic agonist that is used for sedation, analgesia, and muscle relaxation in dogs and cats. Its effects are reversible with atipamizole. Because of its side effects of hypertension and profound bradycardias, it is not recommended for use in dogs with significant heart disease. However, it can be used in some cats with hypertrophic cardiomyopathy. A study using medetomidine to sedate cats with hypertrophic obstructive cardiomyopathy (HOCM) showed that these cats actually benefited from its use.[6] In HOCM the hypertrophy of the intraventricular septum combined with systolic anterior motion (SAM) of the mitral valve results in dynamic obstruction of blood flow out the left ventricular outflow tract (LVOT). This obstruction can be documented by continuous wave Doppler as an increased velocity of blood in the LVOT. In this study, cats with HOCM were given medetomidine (20 mg/kg IM) and allowed to rest for 15 minutes. All cats had adequate sedation to allow echocardiography to be done, but could still be stimulated. Two cats did vomit after being given the medetomidine, but there were no other adverse side effects seen. The cats had a smooth recovery and were able to go home one hour after being sedated. None of the cats needed to have the medetomidine reversed with atipamizole.[6] The medetomidine decreased the heart rate in all the cats, but all of them remained in a sinus rhythm and none had any heart blocks or other adverse bradycardias. The cats’ blood pressures did not change. There was a significant decrease in LVOT outflow velocity, and SAM was totally eliminated in these cats. These changes were caused by the decrease in heart rate and increased systemic vascular resistance which decreased the outflow obstruction and decreased the effects of drag forces in the mitral valve apparatus which decreased SAM.[6] The only change in the echocardiographic values was a mild increase in left atrial systolic size. This was felt to be caused by increases in cardiac afterload coupled with decreased heart rate. So, if medetomidine was used to sedate a cat with HCOM before an echocardiogram, it would make it impossible to document the presence of outflow obstruction, but the other echocardiogram parameters would be the same as in a nonsedated cat. So, medetomidine is safe to use in cats with HOCM.[6]

Question 32

Opioids (Buprenorphine, Butorphanol, Codeine, Diprenorphine, Fentanyl, Methadone, Morphine, Naloxone, Nalbuphine, Pentazocine, Pethidine, Remifentanil, Sufentanil, Tramadol) Opioids are usually used for their analgesic properties. However, they also have antitussive and sedative properties. They also have multiple side effects which include respiratory depression, emesis, defecation or constipation, dysphoria, and pruritus. There are many different naturally occurring opioids. Those that are derived directly from the ......................... such as morphine, codeine, and papaverine are called ..........., whereas any substances, mostly ...................., that interact with the opioid receptors are called .................

Answer 32

Opioids are usually used for their analgesic properties. However, they also have antitussive and sedative properties. They also have multiple side effects which include respiratory depression, emesis, defecation or constipation, dysphoria, and pruritis. There are many different naturally occurring opioids. Those that are derived directly from the poppy seed such as morphine, codeine, and papaverine are called opiates, whereas any substances, mostly synthetic, that interact with the opioid receptors are called opioids.

Question 33

Opioid receptors in the brain are distinct and have common characteristics. The three types of opioid receptors in the brain are the mu (µ) or MOP, kappa (κ) or KOP, and delta (δ) or DOP. There is a fourth receptor that is an opioid-like receptor (NOP) that reacts with opioid-like drugs, but not with opioids.

Answer 33

Opioid receptors in the brain are distinct and have common characteristics. The three types of opioid receptors in the brain are the mu (µ) or MOP, kappa (κ) or KOP, and delta (δ) or DOP. There is a fourth receptor that is an opioid-like receptor (NOP) that reacts with opioid-like drugs, but not with opioids. It has been postulated, but not proven, that other opioid receptors may exist.

Question 34

Opioids act in the brain by mimicking the action of ................. which are produced in the ............. and ........... systems and stimulate opioid ................. Different opioids bind to different receptors and therefore have different actions. When stimulated, the ........receptor will cause analgesia (strong), cough suppression, respiratory depression, constipation, hypotension, euphoria, nausea and vomiting, spinal and supraspinal analgesia, miosis, addiction (in man), and sedation. Activation of the ............ receptor causes spinal analgesia, sedation, mild addiction (man), diuresis, miosis, dysphoria, and psychomimetic effects. Stimulation of the ............. receptor causes analgesia (moderate) and motor excitation.

Answer 34

Opioids act in the brain by mimicking the action of endorphins which are produced in the nervous and endocrine systems and stimulate opioid receptors. Different opioids bind to different receptors and therefore have different actions. When stimulated, the mu receptor will cause analgesia (strong), cough suppression, respiratory depression, constipation, hypotension, euphoria, nausea and vomiting, spinal and supraspinal analgesia, miosis, addiction (in man), and sedation. Activation of the kappa receptor causes spinal analgesia, sedation, mild addiction (man), diuresis, miosis, dysphoria, and psychomimetic effects. Stimulation of the delta receptor causes analgesia (moderate) and motor excitation.

Question 35

Different opioids bind to different receptors and some only bind partially to some receptors and strongly to others. Also, one opioid can have multiple effects and be an agonist, partial agonist, or antagonist of each type of opioid receptor. The effects of each opioid will depend on how much of it reaches each receptor, which is mediated by its route of administration, dose, absorption, distribution, duration of effect, metabolism, and excretion. Ideally an opioid can be selected for its desired effects and few side effects. More synthetic opioids are being developed to achieve the beneficial effects without the side effects. Full opioid agonists have strong effects on one opioid receptor type and weak effects in other receptors. Some opioids are partial agonists in that they have their major activity at only one receptor type and little to no effects on other opioid receptors. Others are mixed agonist-antagonists which means they will activate one receptor and inhibit another one.

Answer 35

Different opioids bind to different receptors and some only bind partially to some receptors and strongly to others. Also, one opioid can have multiple effects and be an agonist, partial agonist, or antagonist of each type of opioid receptor. The effects of each opioid will depend on how much of it reaches each receptor, which is mediated by its route of administration, dose, absorption, distribution, duration of effect, metabolism, and excretion. Ideally an opioid can be selected for its desired effects and few side effects. More synthetic opioids are being developed to achieve the beneficial effects without the side effects. Full opioid agonists have strong effects on one opioid receptor type and weak effects in other receptors. Some opioids are partial agonists in that they have their major activity at only one receptor type and little to no effects on other opioid receptors. Others are mixed agonist-antagonists which means they will activate one receptor and inhibit another one.

Question 36

Most opioids are well absorbed from all routes of administration. However, high first pass removal by the liver limits their use orally. Some agents can be given rectally and be absorbed without first pass removal. The protein binding and distribution vary greatly between drugs, but most are well distributed and will cross the placenta. So they should not be used in pregnant animals. Metabolism and length of activity also vary among the drugs. Side effects of each opioid will vary depending on which opioid receptors they activate. However, some general side effects will be discussed and then each individual agent will be discussed.

Answer 36

Most opioids are well absorbed from all routes of administration. However, high first pass removal by the liver limits their use orally. Some agents can be given rectally and be absorbed without first pass removal. The protein binding and distribution vary greatly between drugs, but most are well distributed and will cross the placenta. So they should not be used in pregnant animals. Metabolism and length of activity also vary among the drugs. Side effects of each opioid will vary depending on which opioid receptors they activate. However, some general side effects will be discussed and then each individual agent will be discussed.

Question 37

Respiratory depression is a common and unwanted side effect of opioid agonists of the ............. receptors such as morphine. The degree of respiratory depression increases as the dose of the opioid agonist increases. The opioid agonist affects the respiratory center in the ................ causing respiratory depression especially in response to ................... This will also suppress the ..................... Partial mu receptor agonists such as .............. and mixed agonists-antagonists such as ....................... cause less respiratory depression. Many of these partial and mixed agonists have a limited respiratory depression which does not increase as the dose increases. However, if any of these full or partial or mixed agonist opioids are used with other drugs that suppress the respiratory centers such as sedatives, profound respiratory depression can result. Also, opioids should be avoided in patients with severe respiratory disease.

Answer 37

Respiratory depression is a common and unwanted side effect of opioid agonists of the mu receptors such as morphine. The degree of respiratory depression increases as the dose of the opioid agonist increases. The opioid agonist affects the respiratory center in the medulla causing respiratory depression especially in response to hypercapnia. This will also suppress the cough centers. Partial mu receptor agonists such as buprenorphine and mixed agonists-antagonists such as butorphanol cause less respiratory depression. Many of these partial and mixed agonists have a limited respiratory depression which does not increase as the dose increases. However, if any of these full or partial or mixed agonist opioids are used with other drugs that suppress the respiratory centers such as sedatives, profound respiratory depression can result.[1] Also, opioids should be avoided in patients with severe respiratory disease.

Question 38

Opioids have very variable effects on the cardiovascular system. At high doses they produce a ................. caused by depression of the .................... cardiovascular control center. This results in increased ...............tone, which slows the heart. This effect is commonly seen in dogs and can be treated or prevented by the use of ................ or ...............

Answer 38

Opioids have very variable effects on the cardiovascular system. At high doses they produce a bradycardia caused by depression of the brainstem cardiovascular control center. This results in increased parasympathetic tone, which slows the heart. This effect is commonly seen in dogs and can be treated or prevented by the use of atropine or glycopyrrolate.[1]

Question 39

At routine doses, opioids have no effects on .............. or ................ A few of the opioids at higher doses can cause peripheral vasodilation by depressing the ....-adrenergic receptors and inhibiting ................... Most opioids can be safely used in most patients with cardiac diseases. However, they may reduce the effectiveness of ................. in some patients.

Answer 39

At routine doses, opioids have no effects on contractility or blood pressure. A few of the opioids at higher doses can cause peripheral vasodilation by depressing the α-adrenergic receptors and inhibiting baroreceptors. Most opioids can be safely used in most patients with cardiac diseases. However, they may reduce the effectiveness of diuretics in some patients.

Question 40

Other side effects of opioids can include nausea and vomiting because of their effect on the...........................in the brain. If an animal is debilitated or otherwise incapacitated, care must be taken that it does not develop aspiration pneumonia after vomiting as cough reflexes are also depressed by the opioids.

Answer 40

Other side effects of opioids can include nausea and vomiting because of their effect on the chemoreceptor trigger zone in the brain. If an animal is debilitated or otherwise incapacitated, care must be taken that it does not develop aspiration pneumonia after vomiting as cough reflexes are also depressed by the opioids.

Question 41

Some opioids will cause dogs to defecate when they are first given. However, with chronic use the opioids will cause constipation. The constipation can be managed with stool softeners. In animals that ingest toxins or have intestinal obstructions or acute abdominal problems, opioids should be avoided as they will further enhance these problems by slowing gastrointestinal motility. Other side effects of opioids can include urinary retention caused by increased sphincter tone. Also, diuresis can result from those opioids that activate the kappa receptors. Two of the opioids, pethidine and morphine, can cause a release of histamine when they are injected intravenously. So care must be taken when morphine is used IV and pethidine is not administered via this route. Cats are very susceptible to the motor excitation effect of opioids, and care must be taken to use opioids at lower doses in order to avoid this problem.

Answer 41

Some opioids will cause dogs to defecate when they are first given. However, with chronic use the opioids will cause constipation. The constipation can be managed with stool softeners. In animals that ingest toxins or have intestinal obstructions or acute abdominal problems, opioids should be avoided as they will further enhance these problems by slowing gastrointestinal motility. Other side effects of opioids can include urinary retention caused by increased sphincter tone. Also, diuresis can result from those opioids that activate the kappa receptors. Two of the opioids, pethidine and morphine, can cause a release of histamine when they are injected intravenously. So care must be taken when morphine is used IV and pethidine is not administered via this route. Cats are very susceptible to the motor excitation effect of opioids, and care must be taken to use opioids at lower doses in order to avoid this problem.

Question 42

Addiction or tolerance to opioids can occur in animals if the drugs are given over long periods of time. The usual manifestation is a requirement for a higher and higher dose to achieve the same effects. However, because sedation should only be necessary for diagnostic procedures in cardiac patients, this is not a problem that is encountered. Neonates, debilitated, and geriatric patients are more susceptible to opioids. Therefore, opioids should be used at lower doses in these patients and monitored closely.

Answer 42

Addiction or tolerance to opioids can occur in animals if the drugs are given over long periods of time. The usual manifestation is a requirement for a higher and higher dose to achieve the same effects. However, because sedation should only be necessary for diagnostic procedures in cardiac patients, this is not a problem that is encountered. Neonates, debilitated, and geriatric patients are more susceptible to opioids. Therefore, opioids should be used at lower doses in these patients and monitored closely.

Question 43

Patients with liver disease may have a prolonged action of the opioids because of delayed metabolism. Other contraindications for the use of opioids include animals with central nervous system problems, especially those with head trauma, coma, or increased intracranial pressure. The opioids increase central depression in these patients, as well as increasing intracranial pressures. None of the opioids should be used in animals with hypothyroidism, severe renal insufficiency, or Addison's disease because of adverse side effects which could occur.

Answer 43

Patients with liver disease may have a prolonged action of the opioids because of delayed metabolism. Other contraindications for the use of opioids include animals with central nervous system problems, especially those with head trauma, coma, or increased intracranial pressure. The opioids increase central depression in these patients, as well as increasing intracranial pressures. None of the opioids should be used in animals with hypothyroidism, severe renal insufficiency, or Addison's disease because of adverse side effects which could occur.

Question 44

The actions of pure opioid agonists can be reversed with ................. However, ................. is less effective at reversing the effects of the ...............agonists. ................'s effects are of short duration, so it may have to be given frequently to counteract the opioid agonist's effects.

Answer 44

The actions of pure opioid agonists can be reversed with naloxone. However, naloxone is less effective at reversing the effects of the partial agonists. Naloxone's effects are of short duration, so it may have to be given frequently to counteract the opioid agonist's effects. Because opioids can be reversed by naloxone if an animal has an adverse reaction, it makes the use of the opioid more attractive for use in cardiac patients.

Question 45

......................agonists include morphine, papaveretum, pethidine, methadone, fentanyl, alfentanil, remifentanil, and etorphine. .....................agonists include buprenorphine, butorphanol, pentazocine, and nalbuphine

Answer 45

Opioid agonists include morphine, papaveretum, pethidine, methadone, fentanyl, alfentanil, remifentanil, and etorphine. Partial opioid agonists include buprenorphine, butorphanol, pentazocine, and nalbuphine

Question 46

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Answer 46

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Question 47

Central Venous Pressure Continuous monitoring of central venous pressure (CVP) is beneficial as it provides a measure of .................preload and guides fluid therapy during surgery. A large bore triple lumen ......................... catheter is ideal for measurement of CVP, as the additional ports allow for fluid and drug administration.

Answer 47

Central Venous Pressure Continuous monitoring of central venous pressure (CVP) is beneficial as it provides a measure of right ventricular preload and guides fluid therapy during surgery. A large bore triple lumen jugular catheter is ideal for measurement of CVP, as the additional ports allow for fluid and drug administration.

Question 48

Urine Output This is a useful indicator of the adequacy of fluid therapy, CO and blood pressure. However, since renal blood flow is preserved in low CO states, urine output is a relatively insensitive and late indicator of low CO. This has been demonstrated experimentally, where renal blood flow was shown to correlate poorly with cardiac index during acute manipulations of CO

Answer 48

Urine Output This is a useful indicator of the adequacy of fluid therapy, CO and blood pressure. However, since renal blood flow is preserved in low CO states, urine output is a relatively insensitive and late indicator of low CO. This has been demonstrated experimentally, where renal blood flow was shown to correlate poorly with cardiac index during acute manipulations of CO

Question 49

Pulse Oximetry This provides an indirect continuous assessment of patient oxygenation, in terms of percent saturation of arterial hemoglobin. It is important to remember that because of the shape of the hemoglobin oxygen dissociation curve, hemoglobin is 100% saturated at a Pao2 of around ..........mm Hg. Since anesthetized patients are generally provided with 100% inspired O2 concentration, significant lung pathology can exist with no change in pulse oximetry reading. Consequently pulse oximetry should not be considered a replacement for blood gas analysis, but is rather an adjunct monitoring device.

Answer 49

Pulse Oximetry This provides an indirect continuous assessment of patient oxygenation, in terms of percent saturation of arterial hemoglobin. It is important to remember that because of the shape of the hemoglobin oxygen dissociation curve, hemoglobin is 100% saturated at a Pao2 of around 100 mm Hg. Since anesthetized patients are generally provided with 100% inspired O2 concentration, significant lung pathology can exist with no change in pulse oximetry reading. Consequently pulse oximetry should not be considered a replacement for blood gas analysis, but is rather an adjunct monitoring device.

Question 50

Capnography Capnography is an important tool for monitoring CO2 in the respiratory gasses during general anesthesia. Capnography provides assessment of adequacy of ventilation. Capnography also has application during cardiopulmonary resuscitation, as absence of CO2 in expiratory gases indicates ........................... during cardiac compressions.

Answer 50

Capnography Capnography is an important tool for monitoring CO2 in the respiratory gasses during general anesthesia. Capnography provides assessment of adequacy of ventilation. Capnography also has application during cardiopulmonary resuscitation, as absence of CO2 in expiratory gases indicates absence of blood flow during cardiac compressions.