Overview of anesthetic drugs: review, applications, contraindications (Proceedings)

Opioid analgesics

Opioids provide both analgesia and sedation. They are considered the gold standard for analgesia in veterinary patients. While opioids are generally considered very safe in a variety of patients, they can also have some undesirable side effects. Euphoria, dysphoria and excitement are sometimes seen after administration, particularly in feline patients. Simultaneous administration of an anxiolytic drug can help minimize these effects. Opioids work by binding to opioid receptors in the brain, spinal cord, and various other parts of the body. The specific effects of these drugs depend on the type of opioid analgesic used and what receptors it binds to. Opioids can act on several different receptors but the most familiar are the mu (m) and kappa (k) receptors. Drugs can either bind to these receptors and activate them (agonists) or bind to the receptors and block them, preventing activation (antagonists).

Opioid agonist drugs include morphine, hydrophone, oxymorphone and fentanyl. These drugs have a high potential for abuse and are therefore closely regulated and are labeled as DEA schedule II drugs. Their main features include the ability to provide analgesia for moderate to severe pain and the ability to be reversed if necessary. Side effects commonly seen include vomiting, bradycardia, respiratory depression, and excitement (especially in cats).

The most familiar agonist-antagonist drug is butorphanol (Torbugesic ®). This drug is an antagonist at the mu opioid receptor and an agonist at the kappa opioid receptor. Because of this feature, butorphanol can be used to partially reverse the effects of full agonist drugs. Butorphanol is a DEA schedule IV drug due to potential for abuse. Butorphanol is generally effective for mild pain relief, sedation, and cough suppression but its short duration of action can be a limiting factor in its use for analgesia.

Buprenorphine is a partial agonist at the mu receptor and an antagonist at the kappa receptor. This drug binds tightly to its receptors which gives it a relatively long duration (4-12 hrs in dogs) and also makes it very difficult to reverse. Generally this drug causes less sedation, excitement, and respiratory depression than full agonist drugs and provides mild to moderate analgesia.

Naloxone is an opioid antagonist than can be used to reverse the effects of other opioids. Naloxone is a non-scheduled drug and it does not provide analgesia or sedation. It has a rapid onset and can be used in emergencies to completely reverse the effects of other opioid drugs (respiratory depression, bradycardia, sedation). Excitement can be seen after administration and re-dosing is sometimes necessary as it has a short duration of action

Phenothiazine tranquilizers (Major tranquilizers)

Acepromazine is the most common phenothiazine used in small animals. This drug is an alpha adrenergic antagonist whose effects include sedation, anxiolysis, and vasodilation (resulting in hypotension and hypothermia). Acepromazine is also known to have anti-arrhythmic, anti-histaminic, and anti-emetic properties. This drug generally provides excellent sedation but provides no analgesia on its own. However, acepromazine can enhance the effects of analgesic drugs when co-administered. Acepromazine should be avoided in hypotensive, hypovolemic and geriatric patients as well as those with liver dysfunction. Acepromazine causes sequestration of red blood cells in the spleen and therefore can lower PCV. Certain breeds are known to be sensitive to the effects of acepromazine (Boxers, Greyhounds) so caution should be used if this drug is to be included in the anesthetic protocol.

Benzodiazepine tranquilizers (Minor tranquilizers)

Diazepam (Valium®) and midazolam (Versed®) are the most commonly used benzodiazepines. Effects of these drugs include anxiolysis, muscle relaxation, increased seizure threshold, decreased inhibitions, and excitement. Benzodiazepines have few cardiovascular effects and are reversible if necessary making them very safe in a variety of patients. They can be excellent as part of premedication in geriatric patients or those with systemic disease. Excitement, dysphoria, and impulse inhibition is often seen when benzodiazepines are administered to young or healthy patients and may not be the best choice as a sedative.

Anticholinergics (Parasympatholytics)

Anticholinergics are used during anesthesia to prevent and treat bradycardia from anesthetic drugs and/or vagal stimulation. Other effects of anticholinergics include decreased salivary secretions and decreased GI motility. Anticholinergic drugs should generally be avoided in patients that are tachycardic, have GI stasis, increased intracranial pressure, or cardiac disease. They are indicated for neonates or pediatric patients (who rely on HR to maintain CO), surgery involving the neck or airway (which can induce a vagal reflex), ocular procedures (which can induce a vagal reflex), brachycephalic patients (who generally have high vagal tone), vagally or opioid induced bradycardia.

There are two main choices of anticholinergics; atropine and glycopyrrolate. Atropine is most commonly used in emergency situations because of its rapid onset. Atropine is less commonly used as part of a standard premedication protocol due to its tendency to cause sinus tachycardia and tachyarrhythmias. Glycopyrrolate is less likely to cause severe tachycardia and is less arrhythmogenic than atropine. Because of this feature, glycopyrrolate may be a safer choice in cardiac patients that cannot tolerate significant increases in heart rate. After administration of an anticholinergic, it is common to see first or second degree AV block occur before the heart rate begins to increase. This is seen more commonly after administration of glycopyrrolate but can also be seen if low doses of atropine are used.

Alpha-2 agonists

This class of drugs can be used for sedation, analgesia, and muscle relaxation. Cardiovascular effects of alpha 2 drugs include bradycardia, hypertension, hypotension, peripheral vasoconstriction, and profound a profound decrease in cardiac output. Activation of alpha-2 receptors cause peripheral vasoconstriction resulting in an increase in blood pressure and reflexive decrease in heart rate. Heart rate generally remains low but hypotension can be seen about 20 minutes after administration. It is important to restrict the use of these drugs to young, healthy animals since cardiac output can decrease as much as 30-50%. This decrease is not tolerated well in geriatric animals or those with cardiac dysfunction. Besides the ability to provide sedation and analgesia, alpha-2 drugs have the desirable feature of reversibility. Yohimbine or atipamazole can be used to reverse the effects as needed.

Ketamine

Ketamine is the most commonly used dissociative agent. Dissociative drugs can provide amnesia, analgesia, and restraint. Palpebral and laryngeal reflexes generally remain after administration. Muscle rigidity is a side effect of ketamine so it is generally combined with a benzodiazepine to provide muscle relaxation. Dissociate anesthetics have many uses but are most commonly used for restraint of fractious patients, as part of anesthetic induction, or to provide adjunctive analgesia during surgery. More recently, ketamine has been used to help provide analgesia in patients whose pain may be refractory to more classical methods of pain control. This drug helps to provide analgesia by being an N-methyl-D-aspartate (NMDA) receptor antagonist. This property allows ketamine to augment intra and post operative analgesia and to prevent central sensitization. After administration of ketamine, an increase in heart rate and blood pressure are often seen. Ketamine can also increase the incidence of catecholamine induced arrhythmias. Care should be used with ketamine in patients with cardiac disease and avoided in cats with hypertrophic cardiomyopathy. Ketamine is metabolized by the liver so it should be avoided in patients with hepatic dysfunction. In cats, ketamine is excreted unchanged through the kidneys, so it should be avoided in these patients as well.

Thiopental

Thiopental is a short-acting barbiturate drug that is used as an induction agent. Thiopental causes a depression in CNS activity by interacting with inhibitory GABA receptors. After administration, a decrease intracranial pressure (ICP) and cerebral blood flow (CBF) occurs. This decrease in ICP and CBF can be desirable in patients with intracranial disease. Thiopental depresses respiratory centers in the medulla and apnea is commonly seen. Positive pressure ventilation should be provided as needed. Cardiovascular depression (low blood pressure, decreased contractility) and arrhythmias (particularly ventricular bigeminy) can also occur. Barbiturates depend on the liver for metabolism so these drugs should be avoided in patients with hepatic dysfunction. Since the introduction of propofol to the veterinary world, the use of thiopental has decreased significantly.

Propofol

Propofol is a non-barbiturate sedative, hypnotic agent that is used for anesthetic induction, maintenance of anesthesia, or sedation. It provides a rapid, excitement-free induction. Propofol is rapidly redistributed from the CNS which results in a rapid return to consciousness. It is considered a good choice in patients with hepatic dysfunction. Propofol causes a dose dependent respiratory depression and apnea is commonly seen. Though its effects a not long lasting, propofol will cause significant hypotension and has a negative inotropic effect. This is generally well tolerated by healthy patients. In feline patients, repeated doses or prolonged infusions of propofol (greater than 30 minutes) can result in prolonged recoveries. Heintz body anemia is also commonly seen in cats after repeated doses. Daily administration of propofol in cats is not recommended for these reasons.

Etomidate

Etomidate is another drug that can be used for anesthetic induction. In some ways, etomidate appears to be an ideal anesthetic agent. Unlike many other drugs, it produces a loss of consciousness without significant changes in heart rate, blood pressure and cardiac output. This feature makes it an excellent choice for patients with severe cardiac dysfunction. Etomidate also minimally depresses the respiratory system and has wide safety margin (therapeutic index). Despite these advantages, etomidate has some drawbacks. It is metabolized by the liver in humans and should be used cautiously in veterinary patients with liver disease. Etomidate has been associated with pain upon injection as well as intravascular hemolysis due to its propylene glycol carrier. This hemolysis is usually most significant in patients that receive repeat boluses or a constant rate infusion. Etomidate has also been shown to cause a decrease in cortisol production. This decrease has been associated with increased morbidity and mortality in human patients sedated long term with etomidate. Because it causes a suppression of adrenocortical function, etomidate should not be used in patients with adrenocortical disease (Addison's) and used with care in severely ill patients since it can alter their ability to respond to stress. When administering this drug, premedication with a benzodiazepine is recommended since un-premedicated patients are prone to myoclonus, retching, and excitement. The high cost of etomidate compared to many other induction agents also limits is usefulness at many veterinary practices.

Non-steroidal anti-inflammatory drugs (NSAIDs)

NSAIDs are a commonly used class of drugs in veterinary medicine. These drugs provide analgesia by modification of the inflammatory response, specifically by inhibiting prostaglandin synthesis. Prostaglandins are inflammatory mediators that also have a role in protecting renal, platelet, and gastrointestinal function. When using NSAIDs for animals undergoing anesthesia it is important to monitor and maintain blood pressure in order to preserve renal blood flow. NSAIDs can provide excellent analgesia alone or in combination with other analgesics but their use should be limited to patients with normal renal and hepatic function and patients that are normovolemic. Patients should not received steroids and NSAIDs at the same time as it significantly increases the likelihood of side effects. Side effects of these drugs can include vomiting, gastrointestinal ulceration, and hepatic or renal toxicity.

Local anesthetics

Local anesthetics have many possible uses in anesthesia. These drugs work to disrupt nerve impulse transmission by blocking sodium channels and causing a temporary loss of sensation. Complete anesthesia/ analgesia of the affected area can be achieved with minimal systemic side effects. Muscle relaxation occurs from blockade of motor impulses so temporary muscle weakness may occur. Local anesthetics are very versatile and can be used a variety of ways to provide analgesia. They can be "splashed" onto a surgical site before closure, applied to mm, infiltrated around a nerve or group of nerves, or even used intravenously (lidocaine) as a CRI. When using local anesthetics it is important to calculate appropriate doses, especially in cats, to avoid local anesthetic toxicity.

Inhalant anesthetics

Inhalant anesthetics are very useful for maintenance of general anesthesia as they provide the anesthetist with excellent control of anesthetic depth, provide rapid inductions, do not rely heavily on metabolism by the liver, and are safely used in a variety of species. Disadvantages of most inhalant anesthetics include dose dependent reduction in cardiac output, reduction in systemic vascular resistance, and respiratory depression. Inhalant anesthetics are often compared in terms of MAC and solubility (blood gas partition coefficient). The MAC, or minimum alveolar concentration, of an inhalant is a measure of its potency. The MAC is the concentration of inhalant anesthetic in the alveoli that prevents a response to surgical stimulus in 50% of test subjects. The solubility of an inhalant reflects the speed at which the gas reaches therapeutic concentrations in the brain and produces unconsciousness. Very soluble gases, like halothane, have a longer induction times. This occurs because very soluble gases produce a slow rise in blood concentration as they cross from the alveoli to the pulmonary circulation. The slow rise in blood concentration of anesthetic results in a slow rise in brain concentration and therefore a longer induction time. Insoluble gases, like sevoflurane, have a short induction time and recovery time for this reason.

References

Keegan, R.D. "Inhalants Used in Veterinary Anesthesia" Recent Advances in Veterinary Anesthesia and Analgesia: Companion Animals, Gleed R. R. and Ludders J.W. International Veterinary Information Service, Ithaca, NY. Nov 4 2005.

Posner, L.P. "Etomidate in the Critically Ill Patient: Pros and Cons". NAVC Proceeding 2007. North American Veterinary Conference. Jan 13 2007.

Carrol, Gwendolyn DVM, DACVA. Small Animal Pain Management. AAHA Press, 1998.

Muir et al. Handbook of Veterinary Anesthesia. Mosby, 2000.