Anesthesia and Analgesia:
Physiologic Effects of Pharmacologic Agents
G John Benson, DVM, MS, Dip ACVA
University of Illinois
Urbana, IL 61802
The word "anesthesia" was first used by the Greek
philosopher Dioscorides to describe the narcotic effects of mandragora. In 1771, the
Encyclopedia Britannica defined anesthesia as a "privation of the senses".
Oliver Wendell Holmes used the word to describe the ether-induced state which made surgery
possible.
The term anesthesia, as used by Holmes and as understood by many today, is the state in
which one is insensible to the trauma of surgery. If pain is the conscious perception of a
noxious stimulus, then anesthesia could be defined as the drug-induced state wherein the
patient neither perceives nor recalls noxious stimulation. This is consistent with Holmes'
original concept and with most of our present use of the word. Because loss of
consciousness is a threshold event, anesthesia must be an all or none phenomena which
cannot occur in degrees or in variable depths. Thus, hypnosis or narcosis could be viewed
as synonymous with anesthesia because it implies drug-induced sleep. Other attributes of
anesthetics, those drugs which induce the anesthetic state, can be classed as alternative
pharmacologic properties and not components of the anesthetic state.
Traditionally, our concept of anesthesia has been based upon the effects of available
general anesthetics. An alternative approach to understanding the anesthetic state is that
proposed by Prys-Roberts wherein the response of the patient to noxious stimuli and the
alteration of this response by drugs becomes the focus of consideration. Noxious stimuli
are those which cause actual or potential damage to tissue and can be produced by
mechanical, thermal, chemical or radiation injury. Surgery is a noxious stimulus of
varying intensity and character intraoperatively and for a variable period
postoperatively. Regardless of the nature of the noxious stimulus, nociceptor activation
leads to action potentials in A-delta and C nerve fibers. These action potentials may be
relayed centrally or may set up reflex responses at the spinal level. Ascending
nociceptive transmission results in the perception of pain in the conscious subject, and
evokes a number of somatic and autonomic reflexes. In addition, noxious stimuli induce
metabolic and endocrine responses. Perception of pain is dependent on a state of
consciousness. Suppression of both perception and recall of pain occurs with blood
concentrations of intravenous or inhalant anesthetics which do not suppress motor
responses. The motor response to somatic noxious stimulation is characterized by
withdrawal of the stimulated part. Suppression of this response is the basis for
quantitative indices of anesthetic potency, i.e., minimum alveolar concentration (MAC) for
inhalants and minimum infusion rate (MIR) for injectables. Human participants in such
studies who moved in response to noxious stimuli reported no recall of the procedure or
associated pain. The implication of these results is that the blood concentration
necessary to prevent gross purposeful movement, the somatic motor response, is greater
than that required to induce unconsciousness and by implication, perception of pain.
Purposeful movement is a sustained or patterned response that can be distinguished from a
simple flexor reflex; it does not imply volition or cognition. These responses arise from
pattern generators in the spinal cord and not from CNS structures subserving
consciousness. Isoflurane MAC is the same in intact and decerebrate rats. In the goat,
isoflurane MAC is higher if the gas only reaches the brain and not the spinal cord. As a
result of the forgoing, it becomes apparent that anesthetics are given in doses that
exceed those needed to induce unconsciousness (and therefore, analgesia). Rather, the
doses used in clinical practice are those which prevent induced somatic motor, autonomic
and endocrine responses. A patient that moves is not necessarily awake or perceiving pain,
but movement suggests that anesthesia is not sufficient to prevent nociception-induced
movement. Drugs that are not good hypnotics, i.e., opioids, can be extremely effective in
suppressing intraoperative movement.
Analgesia in the strictest sense is an absence of pain. Clinically, analgesia refers to
the reduction in the intensity of the pain perceived. The goal is not to completely
abolish or eliminate pain, but to make the pain as tolerable as possible without undue
depression of the patient. In the clinical setting, analgesia may be induced by obtunding
or interrupting the nociceptive process at one or more points between the peripheral
nociceptor and the cerebral cortex.
Perception of pain can be prevented by unconsciousness induced by general anesthetics.
In conscious patients perception is obtunded by systemic administration of analgesic
drugs, e.g., opioids.
Balanced analgesia results from the administration of analgesic drugs in combination
and at multiple sites to induce analgesia by altering more than one portion of the
nociceptive process.
The volatile inhalant general anesthetics currently available include halothane,
isoflurane, ethrane, desflurane and sevoflurane. Methoxyflurane, while a formerly popular
inhalant in veterinary medicine, is no longer being manufactured. Its use persists where
the drug was stockpiled for future use. Chemicophysical properties of inhalants are
important determinants of the type of apparatus necessary for their safe administration,
the rate at which induction and recovery and intraoperative alteration of depth of
anesthesia can be achieved, and the dose needed to maintain surgical anesthesia.
Halothane, a halogenated alkane derivative was
introduced in 1956. Because of its intermediate solubility in blood and high potency,
induction and recovery from anesthesia are rapid. Halothane enhances the arrhythmogenic
effects of epinephrine. In addition, halothane has been associated with postoperative
hepatitis. Nevertheless, it still has a place in veterinary, and to a lesser extent in
human, medicine.
Methoxyflurane, the first in a series of
methyl-ethyl ethers was introduced in 1960. It did not enhance myocardial sensitivity to
the arrhythmogenic effects of catecholamines nearly as much as halothane. It also appeared
to provide more muscle relaxation than did halothane. An interesting property of
methoxyflurane is that at subanesthetic concentrations it induces analgesia.
Methoxyflurane is extremely soluble in blood and tissues resulting in slow induction and
prolonged recovery. In addition, it undergoes extensive hepatic metabolism resulting in
plasma fluoride concentrations sufficient to induce severe nephrotoxicity in some human
patients. As a result, methoxyflurane lost its place in human medicine. Nevertheless, it
is still used as an inhaled analgesic by emergency medics in Australia.
Enflurane, was introduced in 1973. Ethrane
offered several advantages over halothane and methoxyflurane. It was not arrhythmogenic,
resisted metabolism reducing the risk of potential hepatic and renal toxicity and was of
intermediate solubility allowing rapid induction and recovery from anesthesia. Its use in
veterinary medicine was limited because it is a potent respiratory depressant, especially
at doses sufficient to induce surgical anesthesia; and it induces seizure-like activity in
the EEG with rigidity and myoclonus at deep levels of surgical anesthesia.
Isoflurane is an isomer of ethrane introduced
in 1981. Isoflurane retained the advantages of ethrane without the respiratory depression,
EEG effects and poor muscle relaxation during surgical anesthesia.
Desflurane differs from isoflurane by the
substitution of a chloride atom with a fluoride atom at the alpha-ethyl component of the
molecule. Desflurane is extremely insoluble resulting in rapid induction and recovery. It
is the most resistant to metabolism making the possibility for hepatic or renal toxicity
remote. Desflurane is extremely volatile, a characteristic that necessitated the
development of a new vaporizer for its use.
Sevoflurane is nearly as insoluble as
desflurane allowing for rapid induction and recovery. However, because its vapor pressure
is similar to existing agents (ethrane), it can be administered with conventionally
designed vaporizers for use. A major advantage of sevoflurane is that it is nonirritating
to airways and is well accepted by patients, lending itself to mask or chamber inductions.
Desflurane is more irritating and pungent resulting in breathholding and struggling.
Sevoflurane undergoes greater hepatic metabolism than desflurane; 2-5% vs 0.02-0.2%
respectively.
The mechanism by which inhalants produce CNS depression is not known. Most evidence is
consistent with the hypothesis that synaptic transmission is inhibited through multineural
polysynaptic pathways, particularly in the reticular system. Peripheral neural function is
relatively normal and unaffected. The exact site of action is not as yet identified but
evidence suggests that an inhibitory G-protein receptor may be involved as well as an
effect on GABA receptors. Thus inhalant anesthesia may be the result of increased
potassium and chloride conductance with resulting hyperpolarization of the cell membrane.
Inhalant anesthetics induce dose-dependent depression of the central nervous,
cardiovascular and respiratory systems. However, the pharmacologic effects at equivalent
MAC concentrations demonstrate that the dose-response curves for the various anesthetics
are not necessarily parallel.
EEG
At less than 0.4 MAC, volatile inhalants increase the frequency and voltage of the EEG.
At approximately 0.4 MAC, there is an abrupt shift of high voltage activity from the
posterior regions to the forebrain; cerebral metabolic oxygen requirements decrease
abruptly reflecting a transition from the conscious to unconscious state; and amnesia in
people is induced. As 1 MAC is approached, maximum voltage is achieved and frequency
decreases. At 1.5 MAC isoflurane, burst suppression occurs and at 2 MAC, electrical
silence predominates. Electrical silence does not occur with enflurane and only at 3.5 MAC
with halothane. Enflurane induces seizure-like spike activity that may be accompanied by
tonic-clonic twitching and increased tone at deep surgical planes of anesthesia.
During normocapnia, administration of greater than 0.6 MAC causes cerebral blood flow
to increase even though cerebral oxygen requirements are reduced. This effect is due to
vasodilation and is greatest with halothane and least with isoflurane and desflurane.
Autoregulation of cerebral blood flow in response to changes in arterial pressure is
retained during 1 MAC isoflurane but not halothane. Inhalants induce a dose-dependent
decrease in cerebral metabolic oxygen requirements. Oxygen requirement is lowest when the
EEG becomes isoelectric, and does not decrease any further with increased anesthetic dose.
Intracranial pressure parallels the increases in cerebral blood flow. Because the
inhalants do not alter responsiveness of the cerebral circulation to changes in PaCO2
, hyperventilation to a PaCO2 of about 30 mmHg will prevent increases
pressure. exception is enflurane. Hyperventilation during enflurane anesthesia increases
the incidence of seizure activity, with concomitant increased oxygen consumption and
carbon dioxide production, cerebral blood flow and intracranial pressure. Enflurane
increases cerebrospinal fluid production and decreases its absorption increasing
intracranial pressure. Isoflurane decreases rate of production of CSF while increasing the
rate of its absorption.
Circulatory Effects
The inhalants induce dose-dependent but drug specific circulatory effects on blood
pressure, heart rate, cardiac output, stroke volume, right atrial pressure, systemic
vascular resistance, cardiac rhythm and coronary blood flow. In addition, these effects
may be different in the presence of controlled vs spontaneous ventilation, preexisting
cardiovascular disease, or other drugs that directly or indirectly effect cardiovascular
function. The mechanisms of circulatory effects are diverse but reflect the effects of
inhalants on myocardial contractility, peripheral vascular smooth muscle tone, and
autonomic nervous activity. Proposed mechanisms of inhalant-induced cardiovascular effects
are direct myocardial depression, inhibition of central nervous system sympathetic
outflow, blockade of peripheral autonomic ganglia, attenuation of the carotid sinus
reflex, decreased formation of cAMP, decreased release of adrenal medullary
catecholamines, and decreased influx of calcium ions through slow channels.
The volatile inhalants induce dose dependent decreases in arterial blood pressure with
enflurane and isoflurane producing greater changes than halothane. The decrease in
pressure with enflurane and halothane is attributable to decreased cardiac contractility
and cardiac output while isoflurane-, desflurane- and sevoflurane-induced decreases are
due to decreased vascular resistance. Halothane is the most myocardial depressant of the
volatile inhalants.
Changes in heart rate observed with inhalants are influenced by preexisting basal tone
of the autonomic nervous system. High sympathetic tone as occurs with anxiety may result
in a greater than expected slowing while high resting parasympathetic tone could result in
an unanticipated increase in heart rate following induction. In general, halothane and
sevoflurane have little effect on heart rate. Desflurane causes a dose-dependent increase
in heart rate at deep levels while isoflurane increases rate at all levels of anesthesia.
Cardiac output is well maintained with isoflurane, desflurane and sevoflurane because
decreases in stroke volume due to decreased contractility are offset by increased heart
rate and decreased systemic vascular resistance. Increases in right atrial pressure are a
reflection of decreased contractility; isoflurane increases right atrial pressure least
while halothane is associated with the greatest effect. Systemic vascular resistance is
largely unaffected by halothane, decreased modestly by ethrane and most by isoflurane,
desflurane and sevoflurane. The decrease in resistance is due in large part to an
increased blood flow to skeletal muscle. The volatile inhalants exert little to no effect
on pulmonary vascular resistance, but all decrease the pulmonary hypoxic vasoconstriction
response. Isoflurane, desflurane and sevoflurane induce greater coronary vasodilation than
isoflurane and ethrane. The ethers do not increase sensitivity to exogenously administered
catecholamines, while halothane predisposes to arrhythmias.
In summary, with regard to overall comparative cardiovascular depression enflurane >
methoxyflurane> or = halothane> sevoflurane> or = desflurane> or = isoflurane.
Ventilatory Effects
Volatile inhalants cause dose-dependent and drug specific changes in pattern of
breathing, response to hypercapnia, hypoxia and airway resistance. In general, all
inhalants cause minute volume of ventilation to decrease; tidal volume decreases and rate
increases. Enflurane is the most respiratory depressant and causes rate to decrease
severely. Inhalants directly depress the medullary respiratory center and the carotid
bodies leading to decreased responsiveness to C02 and hypoxia respectively.
Desflurane irritates the respiratory tract more than isoflurane, whereas halothane and
sevoflurane do not. Halothane is the least respiratory depressant, ethrane the most and
all other inhalants are equally and intermediately depressant to ventilation.
Nirtous oxide has been used as inhalant anesthetic for 150 years. It has many desirable
qualities including rapid onset and recovery, limited cardiopulmonary depression and
minimal toxicity. Its use in animals is limited by its low potency being only about half
as potent in animals as in people. As an example, nitrous oxide MAC in the dog is nearly
200% as compared to 100% in people. Nitrous oxide stimulates the sympathetic nervous
system. This increased sympathetic tone counteracts some of the cardiovascular depression
induced by nitrous oxide and other anesthetics concurrently administered. It has little or
no effect on hepatic or renal function and is eliminated by exhalation.
Barbiturates induce a dose-dependent state of sedation or hypnosis. Their
classification as long, intermediate, short and ultrashort is misleading in that drug
levels persist for several hours even with ultrashort acting drugs administered to induce
anesthesia. Furthermore, species differences in barbiturate pharmacokinetics are
responsible for the significant variation in duration of action among species. Presently,
barbiturates used in anesthesia are pentobarbital, thiopental, methohexital and
thiobutabarbital (Inactin). Barbiturates modulate gamma-aminobutyric acid (GABA)
transmission. GABA is the most common inhibitory transmitter in the mammalian nervous
system. Activation of postsynaptic GABA receptors increases chloride conductance through
the Cl ion channel resulting in hyperpolarization thereby inhibiting the postsynaptic
neuron. The GABA receptor is an oligomeric complex consisting of the GABA receptor, its
associated chloride ion channel, the barbiturate receptor, the benzodiazepine receptor,
and the picrotoxin binding site. Binding of barbiturates to their receptor decreases the
rate of dissociation of GABA from its receptor, thus prolonging the duration of
GABA-induced opening of the chloride channel. Benzodiazepines, on the other hand, bind
with their receptor and induce an allosteric modification of the GABA receptor increasing
the efficiency of the GABA receptor/chloride ion channel coupling. As a result
benzodiazepines increase the frequency of ion channel openings produced by GABA.
Barbiturates appear to be especially capable of depressing activity in the reticular
formation whose activity is necessary for maintenance of wakefulness. In addition,
barbiturates selectively depress transmission at sympathetic ganglia, which may contribute
to decreased blood pressure following their administration. High doses of barbiturates
reduce sensitivity of postsynaptic membranes of the neuromuscular junction to
acetylcholine thereby interfering with transmission.
Recovery from single doses of thiopental and methohexital is due to redistribution of
the drug from brain to non nervous tissues, primarily viscera and skeletal muscle. In the
case of methohexital, rapid hepatic metabolism contributes to recovery as well. While
redistribution of pentobarbital occurs, recovery is primarily due to metabolism. Ultimate
elimination of barbiturates from the body is by metabolism; less than 1% is recovered
unchanged in the urine. Repeated exposure to barbiturates results in tolerance due to
induction of hepatic enzymes. Conversely, drugs such as chloramphenicol that inhibit
hepatic microsomal enzyme activity cause sleep time to increase. In rats and mice, sleep
time is affected by age, sex, strain, nutritional status, bedding material, and
temperature. Administration of drugs that are highly protein bound, i.e., phenylbutazone,
sulphonamides, displace barbiturates from serum protein resulting in increased sleep time.
Administration of certain other agents during recovery can result in renarcotization. This
affect is of little clinical significance, but has been reported to occur following
glucose, fructose, lactate, pyruvate, glutamate, adrenergic agents, and chloramphenicol.
The hemodynamic effects of equivalent doses of thiopental and methohexital as
administered for intravenous induction are similar. In normal subjects, there is a
transient small decrease in arterial blood pressure that is compensated for by an increase
in heart rate. Myocardial depression is minimal and far less than would occur with
volatile inhalants. The compensatory tachycardia and unchanged myocardial contractility
appears to be due to increased peripheral sympathetic activity mediated by the carotid
sinus baroreceptor.
Direct negative inotropic effects occur in the absence of compensatory increases in
sympathetic activity. The initial decrease in arterial pressure is due to peripheral
vasodilation induced by depression of the medullary vasomotor center and decreased
sympathetic outflow. In the absence of carotid sinus baroreceptor activity or in
hypovolemic patients with less ability to compensate for vasodilation, vasodilation
results in pooling of blood in large capacitance vessels, decreased venous return and
decreased arterial blood pressure and cardiac output. Arrhythmias occur on induction but
are transient and well tolerated
Pentobarbital induces decreased contractility, arterial blood pressure, stroke volume,
pulse pressure and central venous pressure. Heart rate is increased.
Barbiturates induce a dose dependent depression of the medullary and pontine
respiratory centers resulting in decreased hypercapnic and hypoxic drive of ventilation.
Apnea may occur, especially in the presence of other depressant drugs, and when breathing
resumes it is at a reduced minute volume of ventilation.
Barbiturates decrease cerebral metabolic oxygen requirements by about 50% when the EEG
is isoelectric. This would indicate a reduction in neuronal, but not metabolic oxygen
needs. Barbiturate-induced decreases in cerebral metabolic oxygen requirements exceed the
decrease in cerebral blood flow. This may account for the protective effects against focal
cerebral ischemia.
Barbiturates have no direct effects on either liver or kidney function. They are
neither hepato- or nephrotoxic. Alterations in liver or kidney function associated with
their use is secondary to hemodynamic effects of the drugs and altered perfusion.
Placental transfer of barbiturates occurs rapidly. However, when used in proper induction
doses, excessive depression of the fetus does not occur.
Propofol is an isopropylphenyl compound that is available for intravenous use as a 1%
solution in soybean oil, glycerol and egg phosphatide. Propofol exerts its CNS effects via
modulation of the GABA-activated chloride channel. Its specific site of action appears to
be distinct from those of the barbiturates, steroids, benzodiazepines and GABA. It rapidly
induces unconsciousness. Recovery is more rapid and complete with minimal residual CNS
effects than that following induction with thiopental or methohexital.
Plasma clearance exceeds hepatic blood flow indicating that tissue uptake is also
important. Less than 0.3% of the drug is excreted unchanged in the urine. There is
however, no evidence of impaired elimination of propofol in either patients with cirrhosis
or renal impairment. Because of its rapid clearance, propofol can be administered as a
continuous infusion to maintain a level of basal narcosis as part of a balanced anesthetic
protocol.
Propofol is primarily used as an induction agent and to maintain short periods of
unconsciousness for short procedures such as bronchoscopy. It does not induce analgesia;
analgesics should accompany propofol when painful manipulations or procedures are
performed.
Cerebral blood flow, perfusion pressure and intracranial pressure decrease following
propofol administration. The cardiovascular effects of propofol resemble those of
thiopental but are of greater magnitude at comparable doses. Heart rate is less likely to
increase with propofol as compared to thiopental. Propofol is a potent respiratory
depressant. Apnea is common on induction unless the drug is given slowly. When used as the
sole anesthetic agent, apnea occurs at doses required to prevent movement in response to
painful manipulations.
Etomidate is an imidazole compound that appears to depress CNS function via GABA.
Duration of action is intermediate between thiopental and methohexital, and recovery from
a single dose is rapid with little residual depression. Like the barbiturates and
propofol, etomidate is does not induce analgesia. Etomidate induces unconsciousness within
one circulation time. Recovery is rapid as a result of extensive redistribution and rapid
metabolism. Etomidate is hydrolyzed by hepatic microsomal enzymes and plasma esterases.
Less than 3% is recovered unchanged in the urine. Overall clearance rate of etomidate is
3-5 times that of thiopental.
Etomidate is a potent direct cerebrovascular vasoconstrictor. Cerebral blood flow and
oxygen requirements decrease 35%- 45%, decreasing intracranial pressure. Etomidate may
activate seizure foci in a manner similar to that of methohexital.
Etomidate is relatively free of cardiovascular depressant effects. Heart rate, stroke
volume and cardiac output are minimally effected and blood pressure may decrease slightly
secondary to decreased vascular resistance. Unlike other anesthetics, etomidate does not
decrease renal blood flow. Hepatic function is not altered. Respiratory depression is less
than that induced by thiopental and of shorter duration.
Undesirable side effects of etomidate that may limit its use include pain on injection,
myoclonus and adrenocortical suppression lasting 4-6 hours following an induction dose.
Tribromoethanol produces generalized CNS depression including the cardiovascular and
respiratory centers. It is undergoes hepatic conjugation and the glucuronide is excreted
in the urine. Tribromoethanol is used intraperitoneally to induce short term anesthesia in
small rodents, primarily for the production of transgenic mice. Complications associated
with its use include intestinal ileus decreased fertility. It appears that the latter
complication may be due to decomposition products in the drug and the former due to the
concentration of the drug. At this time, it appears that the drug is safe and effective
for mice if properly prepared and stored.
Urethane is the ethyl ester of carbamic acid. It is a known carcinogen in animals and
is a potential carcinogen in people. Intravenous administration results in long-lasting
unconsciousness of 8-10 hours duration. Spinal reflexes, neural transmission and
cardiopulmonary function are minimally effected. Unlike chloralose, urethane appears to
induce analgesia sufficient for surgery in small rodents. Urethane has been administered
by most routes including topically to frogs.
Chloralose induces prolonged hypnosis, lasting up to 8-10 hours. It has minimal effects
on cardiopulmonary reflexes. Analgesia is generally considered to be poor. Its
effectiveness as an anesthetic varies among species, and is least effective in the dog. It
is not recommended for survival procedures because of rough induction, prolonged recovery
and seizure-like activity. The mechanism of action of chloralose has not been established.
In general, chloralose is used to induce chemical restraint without altering autonomic
reflex activity or myocardial function.
Chloral hydrate is a sedative hypnotic drug. It is an excellent sedative with a wide
margin of safety. It is, however, a poor anesthetic and when administered in anesthetic
doses the margin of safety is narrow. Analgesia and muscle relaxation are poor. Chloral
hydrate may be administered orally as well as intravenously. It is very irritating and
causes severe tissue necrosis and sloughing extravascularly. Chloral hydrate induces
dose-dependent sedation through its cerebral depressant effects with minimal medullary and
therefore cardiopulmonary depression. Severe depression may occur at anesthetic doses.
When administered intraperitoneally, pain, ileus and fibrosis may occur.
Saffan is a l:l combination of two progesteronal steroids. It is available for
veterinary use in the United Kingdom for use in cats and primates. This combination has
been used successfully in other species. In the dog, the vehicle, Cremophor, causes a
severe release of histamine with subsequent hypotension and death. Pretreatment with
antihistamines is protective and reportedly allows successful use of the drug in dogs.
Saffan can be administered intravenously or intramuscularly. Short-term anesthesia is
rapidly induced. Saffan is rapidly metabolized allowing for repeated doses without
accumulation. Saffan modulates GABAergic transmission, but not via the barbiturate or
benzodiazepine receptor. It is an anticonvulsive at anesthetic doses. Cardiovascular
effects are species specific and relate to the severity of the Cremophor-induced histamine
response. Intravenous administration can cause severe hypotension in cats but not in
people, sheep, rabbits or pigs. Renal and hepatic perfusion are maintained at near awake
values. Respiratory function is well maintained. Reproductive and hormonal effects are
minimal.
Dissociative anesthesia is a state wherein the patient is "dissociated" from
the environment, resembling a catatonic state. The eyes remain open, the patient is not
unconscious. Muscle relaxation is not a feature and varying degrees of hypertonus and
purposeful movement occur independent of surgical stimulation. There is
electroencephalographic evidence of dissociation between the neothalamocortical and limbic
systems, and differential depression and activation of various areas of the brain. Amnesia
is present and while somatic analgesia may be intense, visceral analgesia is less
reliable. Emergence excitement and delirium may occur. The dissociative anesthetics are
cyclohexamines. Presently, ketamine is the most commonly used dissociative. Tiletamine is
available in combination with zolazepam (a benzodiazepine) as Telazol. Phencyclidine is no
longer available.
The mechanism of action of ketamine has not been established. It appears that the
cyclohexamines exert their effects via antagonism of CNS muscarinic acetylcholine
receptors and by agonism of opioid receptors. Ketamine is thought to be a specific
antagonist of N-methyl-D-aspartate glutamate receptors (NMDA). NMDA is the principal
excitatory receptor system in the mammalian brain. Blockade of adrenergic and sertonergic
receptors attenuate ketamine-induced analgesia. Ketamine is available as a racemic mixture
of the two isomers of the drug. The positive isomer has been shown to produce more intense
analgesia, more rapid recovery and a lower incidence of emergence reactions than the
negative isomer. Both isomers appear to have a "cocaine-like" effect in that
they inhibit uptake of catecholamines into postganglionic sympathetic nerves.
Ketamine's pharmacokinetics resemble those of thiopental, being rapid in onset and of
short duration. Ketamine is 5-10 times more lipid soluble than thiopental, ensuring rapid
transfer to the CNS and recovery through rapid redistribution. Ultimate clearance from the
body is dependent upon hepatic metabolism. Norketamine, an intermediate metabolite, has
one-fifth to one-third the potency of ketamine and may contribute to prolonged effects.
There are significant differences among species in the relative amount of free ketamine
excreted in the urine. In people, dogs and horses, metabolism is extensive, while in cats,
most of the drug appears unchanged in the urine. Ketamine, like the barbiturates, can
induce hepatic enzymes with repeated exposure. This probably accounts, at least in part,
for the tolerance that occurs with repeated exposure to the drug.
The cardiovascular effects of ketamine resemble sympathetic nervous stimulation.
Systemic and pulmonary arterial blood pressure, heart rate, cardiac output, cardiac work
and myocardial oxygen consumption increase. These effects are obtunded by prior
administration of tranquilizers or sedatives. In intact patients with a functioning CNS,
ketamine increases myocardial contractility. However, in isolated pappilary muscle
preparations or in denervated hearts, myocardial depression occurs. Ketamine’s
cardiovascular effects are primarily due to direct stimulation of the CNS leading to
increased sympathetic outflow from the CNS. Plasma concentrations of norepinephrine and
epinephrine increase transiently following ketamine administration as a result of
inhibition of their uptake at postganglionic sympathetic nerve endings. The effect of
ketamine on arrhythmogenicity remains controversial. In hypovolemic patients, arterial
blood pressure is better maintained with ketamine because of vasoconstriction, however
tissue perfusion may suffer. In critical patients with depleted catecholamine stores and
exhaustion of sympathetic compensating mechanisms, ketamine can induce unexpected
decreases in arterial blood pressure and cardiac output.
Ketamine does not induce significant respiratory depression. An apneustic pattern of
breathing is commonly seen. Bronchial dilation secondary to increased sympathetic tone
occurs and protective upper airway reflexes are maintained. Airway and salivary secretions
are increased. Ketamine does not significantly effect hepatic or renal function.
Ketamine is a potent cerebral vasodilator. Cerebral blood flow, intracranial pressure
and cerebrospinal pressure increase significantly. The mechanism, while controversial,
appears to be secondary to increases in arterial carbon dioxide tension. Controlled
ventilation to maintain normocapnea effectively prevents ketamine-induced increases in
cerebral blood flow and intracranial pressure. Ketamine induces epileptiform bursts in the
thalamus and limbic system, but without spread to cortical areas. Ketamine does not induce
seizures in human epileptics and has been shown to increase the seizure threshold in rats
and mice. There have been reports of seizures occurring in dogs and cats. Hallucinations
and emergence delirium can occur. In cats, emergence reactions are characterized by
ataxia, increased motor activity, hyperreflexia, hypersensitivity to touch and
inappropriate avoidance behavior and violent recovery. While these responses usually cease
within several hours, they can be minimized by concurrent or pretreatment with
tranquilizers or sedatives. Other reported adverse reactions include hyperthermia and
blindness.
Tiletamine, a dissociative with potency and duration of action intermediate between
ketamine and phencyclidine is available in a 1:1 combination with zolazepam, a
benzodiazepine tranquilizer, as Telazol. This combination of drugs is an effort to provide
a longer acting dissociative for dogs and cats without the negative side effects of rough
recovery and muscle rigidity. The physiologic side effects are similar to those of
ketamine-benzodiazepine combinations. Heart rate and arterial blood pressure increase.
Respiration rate decreases transiently and minute ventilation is well maintained.
The prevention and control of pain is central to the practice of veterinary medicine.
In order to properly provide pain relief, it is essential to have an understanding of the
neurophysiologic pathways and processes (nociception) leading to the perception of pain,
the effects of analgesic drugs on the nociceptive process.
Nociception involves four physiologic processes that are subject to pharmacologic
modulation. Transduction is the translation of physical energy (noxious stimuli) into
electric activity at the peripheral nociceptor. Transmission is the propagation of nerve
impulses through the nervous system. Modulation occurs through the descending endogenous
analgesic systems, which modify nociceptive transmission. These endogenous systems
(opioid, serotonergic and noradrenergic) modulate nociception through inhibition of the
spinal dorsal horn (T) cells. Perception is the final process resulting from successful
transduction, transmission and modulation and integration of thalamocortical, reticular
and limbic function to produce the final conscious subjective and emotional experience of
pain.
Noxious stimuli activate nociceptors, resulting in the generation of impulses in
afferent A-delta and C nerve fibers. Both A-delta and C fiber nociceptors are essential
for perception of acute pain. A-delta receptors appear to be specialized for detection of
dangerous mechanical and thermal stimuli and for triggering rapid nociceptive responses.
C-fiber receptors respond to strong mechanical, thermal and chemical stimuli, are
sensitized by chemicals released in damaged or inflamed skin and mediate slow pain. C
fibers reinforce the immediate response of A fibers, signal the presence of damaged or
inflamed tissue and promote their protection and rest.
Nociceptors do not fatigue with repeated stimulation, but rather display enhanced
sensitivity and prolonged and enhanced response to stimulation (afterdischarge). Enhanced
sensitivity is induced by endogenous algogenic substances released into the extracellular
fluid by damaged, diseased or inflamed tissues. These substances include H+, K+,
serotonin, histamine, prostaglandins, bradykinin, substance P and many others. Although
the mechanisms are not well understood, injured primary afferents develop a sensitivity to
norepinephrine that can be released from sympathetic postganglionic neurons resulting in
chronic pain (sympathetic-dependent hyperalgesia).
Visceral innervation is different from skin in that it is primarily mediated by C
polymodal receptors. Visceral C-fiber axons are primarily associated with sympathetic
pathways, are relatively few in number compared to cutaneous afferents and have large
overlapping receptor fields. Mesenteric stretching, inflammation, ischemia and dilation or
spasm of hollow visci result in severe pain whereas burning, clamping or cutting do not
stimulate visceral pain.
Transmission
Impulses generated by nociceptors are carried to the central nervous system by A-delta
and C fibers whose cell body is in the dorsal root ganglion. The central processes of
these cells constitute the dorsal root and terminate on neurons in the dorsal horn of the
spinal cord. These dorsal horn neurons are called transmitter (T) cells because when
excited by afferent nociceptive impulses, they relay or transmit the activity to other
parts of the nervous system, primarily the reticular system and the thalamus.
The ascending spinal tracts are bundles of axons of T cells that terminate in the
brain. There are two types of T cell: nociceptive specific cells (NS) receive
excitatory input only from nociceptivc afforents; wide dynamic range neurons respond
maximally to intense noxious stimuli but also respond to hair movement and weak mechanical
stimuli (touch) . Wide dynamic range neurons receive convergent input from primary
afferents innervating skin, subcutaneous tissue, muscle and viscera. This convergence is
the neural basis for referred pain.
Nociceptive information is conveyed to the brain by multiple spinal tracts which can be
divided into lateral and medial groups. The lateral ascending pathways (spinothalamic
tracts) terminate in the ventrobasal thalamus which in turn relays to the somatosensory
cortex. Lesions in the lateral ascending pathways interfere with the
individual's ability to recognize the type of stimulus and to accurately localize the area
being stimulated without affecting the aversive or emotional aspects of the pain
experience. The lateral tracts are not as effective as the medial tracts in mediating
reflexes or in altering generalized brain function, i.e., general arousal or alertness.
The medial pathways (spinoreticular) terminate in the reticular
formation, the periaqueductal grey, hypothalamus and thalamus. People with lesions in
these medial ascending tracts state that they can perceive and localize pain and describe
the type of stimulus causing the pain, but that the pain is tolerable. In animals, medial
tract lesions decrease aversive responses to noxious stimuli from those observed in normal
subjects. The terminations of the medial pathways in the reticular formation and thalamus
establish connections with the hypothalamus and limbic system. The hypothalamic-limbic
system mediates emotional states and reactions.
There are species differences in these systems; however, the similarities outweigh the
differences. The size of the medial tracts is relatively constant relative to brain size
but the lateral pathways are most highly developed in primates. The
differences in numbers of ascending fibers in the lateral tracts of humans compared to
that of animals suggest that animals may not be able to receive as much
sensory-discriminative information as a person, i.e., less refined ability to localize and
to determine the type of stimulus. In contrast, non-primates have as large or larger
medial ascending nociceptive tracts than do people suggesting that they may have greater
access to the motivational-affective aspects of the stimulus, i.e., autonomic responses,
unpleasant qualities of the stimulus, life-threatening consequences of the tissue damage.
In people whose lateral tracts were sectioned to alleviate intractable pain, the pain
often reappeared a year later and was reported as being even more disagreeable than before
tractotomy. The return of pain was attributed to recruitment of propriospinal and dorsal
column-postsynaptic tracts to perform the functions of the spinothalamic and
spinoreticular tracts.
Nociception involves portions of the medulla oblongata, mesencephalon, diencephalon
(thalamus, hypothalamus) and the cerebral cortex. The medulla and mesencephalon
participate in nociceptive function through their contributions to the reticular system.
The thalamus serves as the relay for ascending sensory information entering the cerebral
cortex. The cerebral cortex plays a major role in pain perception. The somatosensory
cortex functions to provide the sensory-discriminitve dimension of pain. The frontal
cortex appears to play a significant role in mediating between cognitive activities and
motivational-affective features of pain because it receives input from virtually all
sensory and associated cortical areas via intracortical fiber systems and projects to the
reticular and limbic systems. The frontal cortex appears to be necessary to the
maintenance of the negative affective and aversive motivational aspects of pain.
Neocortical processes subserve cognition and psychological factors, including prior
experience, conditioning, anxiety, attention, background and evaluation of the
pain-producing situation.
Reticular function is critical to integration of the pain experience and behavior.
Ascending reticular neurons mediate the affective / motivational aspects of pain via their
input into the medial thalamus, hypothalamus and their projections into the limbic system.
The limbic system or paleocortex consists of phylogenetically old parts of the
telencephalon and parts of the diencephalon and mesencephalon. These structures include:
the amygdala, hippocampus, septal nuclei, the preoptic region, hypothalamus, parts of the
thalamus and the epithalamus. The limbic system is concerned with mood and incentives to
action, i.e., motivational interactions and emotions. The limbic system endows information
derived from internal and external events with its particular significance to the
individual and thus determines purposeful behavior. The hypothalamus and limbic structures
have an important role in motivated, emotional and affective behaviors which are integral
parts of the pain experience. Lesions of the limbic system in both humans and animals
markedly obtund the aversive quality of noxious stimuli without interfering with the
discriminative aspects of somesthesias. The ability of opioids to reduce pain-induced
suffering while preserving discriminative function is attributed to their effects on
reticular neurons. Opioids depress activity in the amygdala and have been characterized as
inducing a "pharmacologic amygdalectomy".
The pain experience has three dimensions, each subserved by distinct neural systems: 1.
The sensory-discriminitive dimension provides information on the onset, location,
intensity, type and duration of the pain-inducing stimulus. This aspect is subserved
primarily by the lateral ascending nociceptive tracts, thalamus and somatosensory cortex.
2. The motivational-affective dimension disturbs the feeling of well-being of the
individual resulting in the unpleasant affect of pain and suffering and triggers the
organism to action. It is subserved by the medial ascending nociceptive tracts, reticular
formation and limbic system. This dimension is closely linked to the autonomic nervous
system and the associated. cardiovascular, respiratory and gastrointestinal responses. 3.
The cognitive-evaluative dimension encompasses the effects of prior experience,
social and cultural values, anxiety, attention and conditioning. These activities are
largely due to neocortical (frontal) activity and is dependent on reticular activity. The
frontal cortex appears to play a significant role in mediating between cognitive
activities and motivational-affective features of pain.
Massive nociceptive input has profound effects on dorsal horn neurons and interneurons
and anterior motor neurons. C fibers from muscles, joints and periosteum can produce
long-latency long-duration facilitation and very prolonged increased excitability of
dorsal horn cells ("wind-up"). Receptive fields are expanded and nociceptive
cells become sensitive to nonnoxious stimuli such as light touch. Cells with receptive
fields distant from that of the stimulated nerve are also affected. This facilitation,
while triggered by peripheral C fibers, is maintained by intrinsic spinal cord processes.
This facilitated activity appears to be the basis for widespread prolonged tenderness,
hyperalgesia, and bouts of intense skeletal muscle spasm associated with excruciating pain
that may persist for days or weeks following injury. These responses can be obtunded or
largely prevented by the preoperative administration of analgesic agents (pre-emptive
analgesia).
A significant portion of central nervous system activity is concerned with selection,
modulation and control of ascending sensory information by fibers descending from
telencephalic structures. The descending inhibitory system has been described as being
activated centrally by enkephlins and opioids and sending serotonergic and noradrenergic
fibers to terminate in the spinal and medullary dorsal horn. In addition, noradrenergic
neurons arising from the locus coeruleus and other brain stem nuclei contribute to the
endogenous system.
Analgesia in the strictest sense is an absence of pain. Clinically, analgesia refers to
the reduction in the intensity of the pain perceived. The goal is not to completely
abolish or eliminate pain, but to make the pain as tolerable as possible without undue
depression of the patient. In the clinical setting, analgesia may be induced by obtunding
or interrupting the nociceptive process at one or more points between the peripheral
nociceptor and the cerebral cortex.
Transduction can be obtunded by the administration of nonsteroidal antiinflammatory
drugs (NSAIDs). NSAIDs relieve pain by blocking production of algogenic substances by
injured and inflamed tissues which cause hypersensitization of nociceptors. Transduction
can be largely abolished by infiltration of local anesthetics at the site of injury or
incision. Transmission can be prevented by local anesthetic blockade of peripheral nerves,
nerve plexuses or by epidural or subarachnoid injection. Modulation can be augmented by
epidural or subarachnoid injection of opioids and/or alpha-2 adrenergic agonists. Other
drugs that experimentally have been shown to augment modulation following spinal
administration include benzodiazepines, ketamine and neostigmine. Perception can be
prevented by unconsciousness induced by general anesthetics. Perception is obtunded by
systemic administration of opioids or alpha-2 adrenergic agonists, either alone or in
combination. The ability of opicids and alpha-2 adrenergic agonists to reduce pain-induced
suffering while preserving discriminative function is attributed to their effects on
reticular and limbic neurons. Tranquilizers, e.g., acepromazine, while having no analgesic
properties of their own, can enhance analgesia by interfering with reticular-dependent
neocortical cognitive-evaluative function. Tranquilizers can induce hysteria when given to
a painful patient unless accompanied by an analgesic drug.
Balanced analgesia results from the administration of analgesic drugs in combination
and at multiple sites to induce analgesia by altering more than one portion of the
nociceptive process. Thus, transduction could be reduced by nonsteroidal
antiinflamatories; transmission decreased by epidural local anesthetics; modulation
increased by spinal opioids and/or a-2 agonists; and perception obtunded by systemic
opioids and alpha-2 adrenergics. Balanced analgesic techniques appear to offer several
advantages in the management of postoperative pain: when used preemptively, they prevent
nociceptive-induced neuroplastic changes within the spinal cord (wind-up); prevent
development of tachyphylaxis; suppress the neuroendocrine response to pain more
effectively than when single drug regimens are used; and shorten convalescence through
improved tissue healing and mobility.
Preemptive analgesia refers to the application of balanced analgesic techniques prior
to exposing the patient to noxious stimuli (surgical trespass). By so doing, the spinal
cord is not exposed to the barrage of afferent nociceptive impulses that induce the
neuroplastic changes leading to hypersensitivity. This concept has gained acceptance as
the most effective means of controlling pain and detrimental stress responses.
Because the anatomic structures and neurophysiologic mechanisms leading to the
perception of pain (nociception) are remarkably similar in human beings and animals, it is
reasonable to assume that if a stimulus were painful to people, were damaging or
potentially damaging to tissues, and induces escape and emotional responses in an animal,
it must be considered to be painful to that animal. That animals exhibit signs of
distress, learned avoidance behavior, and vocalize in response to noxious (painful)
stimuli is further evidence of their capacity to suffer pain. Pain may not always be
overtly expressed and may be evidenced only by subtle changes in behavior or posture. A
degree of anthropomorphism is appropriate and desirable, especially in situations which
are known to cause pain in people.
Just as antibiotics are administered prophylactically to prevent infection, it is
appropriate to administer analgesics to prevent pain where it is likely to occur. The
commonly stated reasons for withholding analgesics, e.g., to avoid opioid-induced
respiratory depression or because pain relief would result in increased activity leading
to self-injury are seldom valid and should be carefully examined before a decision is made
to withhold analgesic drugs. Accurate selection and dosing of analgesic drugs provides
relief of pain without severe respiratory depression. Where pulmonary function is
compromised, monitoring for signs of respiratory depression will provide all the
information that is required to prevent hypoventilation or apnea. Appropriate splinting,
bandaging, or confinement will prevent self-injury. Animals should not have to endure pain
because of real or imagined sequelae to its relief.
Opioids act as agonists of stereospecific pre- and postsynaptic receptors in the CNS
(primarily the brain stem and spinal cord) and in other tissues. Opioid receptors are
normally activated by endogenous endorphins. By binding to endorphin receptors, opioids
activate the endogenous pain modulating system. Strong binding of the drug to the receptor
requires a high degree of ionization, and only the levorotary form is active. The affinity
of most opioids for the receptor correlates well with their analgesic potency.
Furthermore, increasing opioid receptor occupancy parallels opioid effects. Binding of the
opioid to the receptor inhibits adenylate cyclase activity and hyperpolarization of the
neuron results in suppression of spontaneous discharge and evoked responses. Opioids may
also interfere with transmembrane transport of calcium ion and act presynaptically to
interfere with release of neurotransmitters including acetylcholine, dopamine,
norepinephrine, and substance P. Depression of cholinergic transmission in the CNS as a
result of opioid-induced inhibition of acetylcholine release may be an important mechanism
for the analgesic and side effects of opioids. Opioids do not effect responsiveness of
afferent nerve endings to noxious stimuli nor impair transmission of impulses along
peripheral nerves.
There are several types of opioid receptors each mediating a spectrum of pharmacologic
effects in response to activation by an opioid agonist. It appears that there are
subpopulations of receptors within each major classification. Mu receptors are
morphine-preferring and principally responsible for superspinal analgesia. Analgesia is
associated with the mu-l receptor subpopulation, whereas mu-2 receptors appear to mediate
hypoventilation, bradycardia, physical dependence, euphoria and ileus. Beta endorphin is
the endogenous mu receptor agonist; other mu agonists include morphine, meperidine,
fentanyl,sufentanil and alphentanil. Naloxone is a mu receptor antagonist, binding to the
receptor without activating it. Delta receptors appear to modulate the activity of mu
receptors and bind leuenkephalin. Kappa opioid receptors mediate analgesia (primarily
spinal) with little depression of ventilation, sedation and miosis. Opioid
agonist-antagonist drugs, i.e., butorphanol, nalbuphine buprenorphine, pentazocine, act at
kappa receptors. Lastly activation of sigma receptors results in excitation, dysphoria,
hypertonia, tachycardia, tachypnea and mydriasis. It is postulated that some of ketamine's
effects are sigma receptor mediated.
Opioid receptors are located in areas of the brain and spinal cord involved with pain
perception, integration of nociceptive activity and responses to noxious (painful)
stimuli, particularly the periaqueductal grey matter of the brain stem, amygdala, corpus
striatum, hypothalamus and substantia gelatinosa. Opioids or endorphins upon binding with
the receptors inhibit to release of excitatory neurotransmitters from terminals of neurons
carrying nociceptive stimuli.
Morphine is the prototype opioid to which all others are compared. Although actions and
effects of most drugs differ little among mammalian species, there are marked differences
in response to selected analgesics (e.g., opioids) that are independent of
pharmacokinetics among species. The concentration of opioid receptors in the amygdala and
frontal cortex of species that are depressed by opioids, e.g., dogs, primates, is nearly
twice as great as in those species that become excited in response to opioids, e.g.,
horses, cats. By decreasing the dose, excitement can be avoided in those species prone to
bizarre reactions. Excitement may result indirectly from increased release of
norepinephrine and dopamine. This may explain the mechanism whereby dopaminergic and
noradrenergic blocking drugs such as phenothiazine and butyrophenone tranquilizers
suppress clinical evidence of opioid-induced excitement. Xylazine and detomidine, a -2 adrenergic agonists, are effective in preventing opioid-induced
excitement. Because analgesia and excitement are mediated by different receptors, i.e., mu
- analgesia and sigma - excitement, they can occur concurrently and are not mutually
exclusive.
Opioid analgesics induce CNS depression characterized by miosis, hypothermia,
bradycardia, and respiratory depression in primates, dogs, rats, and rabbits. Stimulation
occurs in horses, cats, ruminants, and swine characterized by mydriasis, panting,
tachycardia, hyperkinesis, and sweating in horses. Systemic effects of opioids include
release of ADH, prolactin, and somatotropin; inhibition of the release of luteinizing
hormone; increased vagal tone; release of histamine and attendant hypotension; decreased
motility and increased tone of the gastrointestinal tract; spasm of the biliary and
pancreatic ducts; spasm of ureteral-smooth muscle and increased bladder tone; and
decreased uterine tone.
Opioids raise the pain threshold or decrease the perception of pain by acting at
receptors in the dorsal horn of the spinal cord and mesolimbic system, i.e.,
brainstem-nucleus raphe magnus and locus coeruleus, midbrain periaquaductal gray matter,
and several thalamic and hypothalamic nuclei. In the dorsal horn, opioids induce
postsynaptic inhibition of nociceptive projection neurons (T cells). In addition, there is
some evidence that opioids may act presynaptically to inhibit release of substance P from
primary afferents. Centrally, at the level of the mesencephalon and medulla, opioids
activate the descending endogenous antinociceptive system that modulates nociception in
the dorsal horn via release of serotonin and perhaps norepinephrine. Opioids act at the
limbic system to alter the emotional component of the pain response thus making it more
bearable. Successful use of opioids requires appropriate selection of the drug and dose
for the given species to avoid undesirable side effects. They must be used with caution in
animals having impaired pulmonary function because they depress the respiratory and cough
centers, decrease secretions, and may induce bronchospasm secondary to histamine release.
In species that can freely vomit, nausea and vomiting may occur. Repeated doses can result
in constipation and ileus and urinary retention. Mice and rats rapidly develop tolerance
and physical dependence to opioid agonists. Morphine decreases the number and phagocytic
function of macrophages and polymorphonuclear leukocytes in mice and may alter their
immune function. Opioids are the analgesic drugs of choice for treatment of severe, acute
pain.
Morphine is well absorbed following parenteral administration, but not following oral
administration. Its pharmacologic effects do not correlate well with peak plasma
concentrations. Presumably this is due to morphine's low lipid solubility resulting in a
slow penetration of the blood-brain barrier. Morphine is conjugated and most of the drug
is excreted as the conjugate in the urine.
Morphine's side effects are characteristic of all opioids, although incidence and
severity may vary. Morphine is not a direct myocardial depressant and doesn't induce
hypotension in supine normovolemic patients. Morphine reduces sympathetic nervous tone
which can lead to decreased venous tone, pooling of blood in capacitance vessels, and
decreased cardiac output and arterial pressure secondary to decreased return. Morphine may
indirectly reduce blood pressure via histamine release. Heart rate is decreased as a
result of increased vagal tone due to stimulation of the medullary vagal nucleus.
Opioids induce respiratory depression via direct depression of the medullary
respiratory center resulting in a shift of the C02 response curve to the right
(decreased sensitivity to C02). Periodic or altered patterns of breathing are
the result of mu opioid activity at the pontine and medullary centers that regulate rhythm
of breathing. Pain counteracts the respiratory effects of opioids.
Opioids decrease cerebral blood flow and intracranial pressure if normocapnea is
maintained. The effect of morphine on the EEG resembles changes associated with normal
sleep.
While opioids induce analgesia by interfering with nociceptive neural transmission
centrally, the nonopioid, nonsteroidal, anti-inflammatory analgesics (NSAID) act
peripherally to decrease production of algogenic substances, primarily prostanoids, that
facilitate generation and conduction of impulses which give rise to pain. When tissues are
damaged, mediators are synthesized or released which activate nociceptors and primary
afferent neurons leading to the sensation of pain. The nonopioid analgesics induce
analgesia by suppressing inflammation and the production and elaboration of kinins and
prostaglandins. These drugs are effective primarily against pain of low to moderate
intensity associated with inflammation. They are generally regarded as being useful for
treating chronic pain of somatic or integumental origin but of little use for visceral
pain. An exception is flunixin which appears to effectively blunt visceral pain in horses.
Recently, the efficacy of NSAID's has been investigated for acute postoperative pain. In
dogs, the preemptive (preoperative) administration of carprofen has been shown to induce
superior postoperative analgesia with less sedation than meperidine following orthopedic
surgery. Similarly, carprofen has been shown to induce profound analgesia as effective as
that induced by papaveretum with quicker anesthetic recovery and less post recovery
sedation. In horses, administration of carprofen, flunixen and phenylbutazone at the
termination of surgery were equally effective at inducing postoperative analgesia with
flunixen providing the longest duration of action and phenylbutazone the shortest
duration. In rats undergoing midline laparotomy, buprenorphine or carprofen administration
result in greater food and water consumption and less weight loss than occurs in rats
receiving saline.
Pharmacokinetics of these drugs vary widely amongst species. Following oral
administration, wide species variations in plasma concentration results in part from size
of the GI tract and gastric emptying time affecting rate of absorption, and also in part
to rate of metabolism and elimination. Toxicity of the nonopioid nonsteroidal
anti-inflammatory analgesics also varies widely among species and drugs and deserves some
consideration. Most common toxic side effects include gastric and intestinal ulceration,
with secondary anemia and hypoproteinemia. Impaired platelet function and delayed
parturition have been reported. Nephropathy occurs in patients with hypovolemia,
congestive heart failure, or other cardiovascular impairment due to inhibition of renal
prostaglandin function in the face of increased norepinephrine and angiotensin II. Chronic
or repeated use has been associated with chronic interstitial nephritis and renal
papillary necrosis. Phenylbutazone and dipyrone have been associated with blood
dyscrasias.
The nonopioid analgesic, antipyretic and antunflammatory drugs while varying greatly in
chemical structure are similar in their therapeutic actions, side effects and mechanism of
action. Aspirin is the prototypic drug of this category of drugs. Aspirin and similar
drugs induce analgesia by inhibition of cyclooxygenase leading to decreased synthesis and
release of prostaglandins. These drugs appear to be effective analgesics only in
situations where prostaglandins are produced locally around sensitized nerve endings. The
antipyretic effect of aspirin is due to blockade of pyrogen-released prostaglandin in the
hypothalamus.
Aspirin is rapidly absorbed following oral administration from the small intestine. It
is highly protein bound and can displace other protein bound drugs, i.e., thiopental.
Following absorption, aspirin is rapidly hydrolyzed in the liver to salicylic acid and
excreted in the urine. Side effects of aspirin include; gastric irritation and ulceration;
prolongation of bleeding time; CNS stimulation; hepatic and renal dysfunction; metabolic
alterations. Prostaglandin production in the gastric mucosa inhibits gastric acid
secretion and helps to prevent gastric mucosa ulceration. Aspirin increases bleeding time
by inhibiting thromboxane , a potent platelet aggragant. Excessive doses stimulate the CNS
and directly stimulate the medullary respiratory center. An early sign of aspirin toxicity
in people is tinnitus induced by increased labyrinthine pressure or by an effect on
cochlear hair cells. Aspirin can increase plasma concentrations of transaminase enzymes
indicating hepatic damage. Chronic administration results in decreased ability to
concentrate urine; renal papillary necrosis and chronic interstitial nephritis result from
a loss of prostaglandin-dependent control of renal circulation.
Acetaminophen is an alternative to aspirin because it does not cause gastric irritation
and does not affect platelet function. Acetaminophen is weakly antunflammatory reflecting
its modest ability to inhibit prostaglandin synthesis peripherally. Its efficacy as an
analgesic and antipyretic is due to its strong central inhibition of prostaglandin
synthesis. Acetaminophen is rapidly and completely absorbed, metabolized in the liver and
not bound to plasma proteins. High doses of acetaminophen result in production of
N-acetyl-p-benzoquinone, which is believed to be responsible for hepatotoxicity. Side
effects of acetaminophen include hepatotoxicity, renal failure and hypoglycemia.
Phenylbutazone has antunflammatory effects similar to aspirin but its analgesic
properties appear to be less potent. The pharmacokinetics of phenylbutazone, like those of
most NSAID's, vary widely amongst species resulting in wide variations in dose, dose
interval and toxicity. Side effects of phenylbutazone are frequent and include anemia,
granulocytosis, nausea and vomiting. Phenylbutazone can cause significant sodium retention
due to a direct effect on renal tubular function.
Indomethacin and sulindac are indole derivatives with analgesic, antipyretic and
antunflammatory effects. They are very potent inhibitors of cyclooxygenase and as a result
their use is limited by the severe side effects elicited. Side effects include inhibition
of platelet aggregation, gastrointestinal irritation, renal and hepatic dysfunction.
Ibuprophen, naproxen, carprofen and ketoprofen are propionic acid derivatives with
strong analgesic, antipyretic and antiinflammatory effects due to their inhibition of
prostaglandin synthesis. Ketoprofen in addition to inhibiting cyclooxygenase, also
inhibits lipoxygenase which is believed to account for its greater analgesic properties
than other propionic acid derivatives. While gastrointestinal irritation is less than with
salicylates, platelet function and renal effects are similar to those of salicylates. All
these drugs are highly protein bound with the exception of ibuprofen. Chronic ibuprofen
administration has been associated with suppression of hematopoiesis. Ibuprofen and
naproxen appear to be poorly tolerated by the dog as compared with other species.
Carprofen and etodolac appear to be well tolerated in the dog. Preliminary reports
indicate that carprofen administered preemptively prior to surgery may effectively
decrease pain scores postoperatively.
Ketorolac is a nonsteroidal drug with potent analgesic but only moderate
antunflammatory activity. Ketorolac can be administered as an injectable postoperative
analgesic free of cardiovascular and respiratory depressant effects. It inhibits platelet
function and can cause renal insufficiency if fluid balance is not maintained or if renal
function is dependent on renal prostaglandin production, i.e., congestive heart failure,
hypovolemia or hepatic cirrhosis.
Flunixin is a nicotinic acid derivative with potent antunflammatory and analgesic
effects. It is approved for use in the horse and has been used effectively in dogs,
calves, mice, rats and monkeys. The side effects, gastrointestinal ulceration, and renal
and hepatic toxicity have limited, but not precluded, its use in these species.
Local anesthetics prevent depolarization of nervous tissues by blocking the Na channel
in the cell membrane. Thus they prevent activation of peripheral nociceptors and block
transmission of impulses along nerve fibers. Their mechanism of action has not been fully
elucidated. It appears that the unionized molecule must diffuse into the nerve tissue
where it then ionizes and binds to the cytoplasmic side of the Na channel rendering it
inactive. In myelinated nerve fibers the drug gains access to the nerve at the node of
Ranvier. It has been shown that 3 consecutive nodes are the minimum number needed to be
blocked to prevent transmission.
Depending on the structure of the molecule’s intermediate chain, local
anesthetics are classified as either amides of aniline or esters of benzoic acid.
Ester-linked local anesthetics are readily hydrolyzed in the blood by plasma
cholinesterases whereas amides undergo hepatic metabolism. Lipid solubility of the drug
determines the intrinsic local anesthetic potency. Protein binding determines the duration
of action and pKa determines the rate of onset of action. Greater lipid solubility, a high
degree of protein binding and a pKa near physiologic pH will result in rapid onset, long
duration and greater potency. The ester local anesthetics are procaine, chiorprocaine and
tetracaine. The amides are lidocaine, mepivacaine, bupivacaine, etidocaine, prilocaine,
and ropivacaine. Procaine and chlorprocaine are of low potency and have a short duration
of action. Mepivacaine, prilocaine and lidocaine are of intermediate potency and duration.
Tetracaine, bupivacaine, etidocaime and ropivacaine are of high potency and duration.
Toxic reactions to local anesthetics include local tissue reactions including
inflammation and necrosis. Systemic reactions are a result of inadvertant intravascular
injection or overdosage and systemic absorption. Cardiovascular reactions include
bradycardia and or conduction disturbances, myocardial depression and peripheral
vasodilation. CNS toxicity is dose dependent and ranges from depression (sedation)
progressing to excitation, muscle twitching and convulsions. Large doses produce
generalized CNS depression and an isoelectric EEG. CNS signs of toxicity usually occur
before cardiovascular changes occur. Allergic reactions may also occur and are most
commonly associated with the esters.
Alpha-2 adrenergic agonists (e.g., xylazine, detomidine, medetomidine and romifidine)
are generally regarded as sedative-hypnotics and are most commonly administered to induce
sedation. They are, however, potent analgesics; xylazine has been shown to be a more
potent analgesic agent in the horse for the relief of both visceral and somatic pain, than
opioids and NSAID. These drugs exert their effects through stimulation of a-2 adrenoceptors in the brain resulting in decreased norepinephrine
release. Sedation results from decreased activity of ascending neural projections to the
cerebral cortex and limbic system. Analgesia appears to be the result of both cerebral and
spinal effects, possibly in part mediated by serotonin and the descending endogenous
analgesia system. Alpha-2 adrenergic and opioid receptors are intimately related and
appear to interact in ways that are not fully understood. Administration of a-2 agonists (i.e., clonidine) have been shown to relieve symptoms of
withdrawal in opioid-dependent humans. Clinically, the combination of an opioid and an a-2 agonist induces profound analgesia in dogs, cats and horses.
Side effects of alpha-2 adrenergic drugs are both dose and time dependent and vary
somewhat among species. They have no direct myocardial effects. Following their
administration, arterial blood pressure increases transiently due to direct peripheral
alpha-2 mediated vasoconstriction. Heart rate decreases due to the carotid baroreceptor
reflex and due to increased vagal tone. These initial transient responses of hypertension
and bradycardia are followed by the centrally-mediated alpha-2 effect of generalized
decreased sympathetic tone and resultant decreased arterial blood pressure.
Gastrointestinal side effects include salivation, vomition, relaxation and decreased
intestinal motility. Gastric secretion is reduced. Uterine tone is increased. Mydriasis
occurs and intraocular pressure is decreased. Alpha-2 adrenergic agonists because of their
inhibitory effect on sympathetic outflow directly inhibit stress responses. Additionally
they inhibit endocrine mediated stress responses including adrenal medullary and cortical
activity resulting in decreased ACTH, cortisol and catecholamine plasma concentrations.
Antidiuretic hormone, insulin and renin release are inhibited as well.
Although xylazine is the most commonly used sedative-analgesic in veterinary medicine,
its comparative pharmacokinetics have not been studied extensively. When administered
intravenously, xylazine has a rapid onset of action and short duration. There is a wide
variation in species sensitivity and response to xylazine. Detomidine is more potent and
longer acting than xylazine. Medetomidine is the most potent and selective a-2 agonist to date, being capable of reducing the minimal alveolar
concentration of halothane in dogs by more than 85%. Thus, these agents are nearly
complete anesthetics. Their role as analgesic agents remains to be established. In
addition to having profound sedative and analgesic activity, a-2
agonists induce cardiovascular and metabolic responses also related to their peripheral
adrenergic effects. Following their administration, arterial blood pressure increases then
decreases; cardiac output is decreased. Insulin release is inhibited resulting in
hyperglycemia. Urinary output is increased as a result of decreased ADH release.
Berthelsen and Pittinger demonstrated a-1 and a-2 receptors. Stimulation of a receptors located on the nerve
terminal itself (presynaptic receptors) result in decreased exocytotic release of
norepinephrine by the nerve. The order of potencies for a adrenergic agonists and
antagonists for presynaptic receptors is different from that for classic postsynaptic
receptors. For this reason, receptors with pharmacologic properties of the postsynaptic
receptor have been termed a-1, whereas those with properties of
the presynaptic receptor have been designated a-2. There is
evidence that a-2 receptors are also located postsynaptically
in some vascular beds and in the brain. Thus, the classification is functional rather than
anatomic.
Adrenergic receptors are divided into a and ß types based
on their pharmacological properties, i.e., their relative responsiveness to norepinephrine
vs isoproterenol. The a's have been further subtyped into a-lA, a-lB, a-1C;
a-2A, a-2B, a-2C,
and a-2D (12). Alpha-1 receptors have been thought to be
located postsynaptically and a-2's presynaptically, but this is
now recognized as an oversimplification, a-2's having been
demonstrated to occur at both locations. The a-1 receptor is
found in peripheral vascular smooth muscle of the coronary arteries, skin, intestinal
mucosa and splanchnic beds. They are postsynaptic activators of vascular and intestinal
smooth muscle as well as endocrine glands. Their stimulation results in either increased
or decreased tone depending on the effector organ. In resistance and capacitance vessels
constriction results, while relaxation occurs in the intestine. The myocardium per se has
been thought to have no a receptors but a-1 receptor-mediated
effects have been reported. The physiological and clinical significance of myocardial a-1 receptors is unknown at this time.
Alpha-2 receptors occur both pre and postsynaptically in peripheral tissues. Alpha-2
receptors occur on prejunctional sympathetic nerve terminals and function to decrease the
amount of norepinephrine released thus serving as a negative feedback mechanism. In
addition, prejunctional a-2 receptors have been identified on
cholinergic, serotonergic and GABA-ergic neurons where they are thought to be important in
neuromodulation. Stimulation of central a-2 receptors is
associated with sedation, analgesia, decreased sympatho-adrenal outflow, anxiolysis, and
decreased thermal-induced shivering.
In the arterial vasculature, a-1 receptors are thought to
occur postsynaptically on the neuroeffector junction near the amine uptake pump while a-2's are located at a location distant from this site. Thus it would
seem that the a-1 receptor mediates sympathetically driven
neuronally-induced vasoconstriction while a-2 receptors mediate
vasoconstriction induced by circulating catecholamines. This arrangement appears to be
reversed in the venous capacitance vessels. There appears to be some differences in the
way the receptors utilize calcium in mediating vasoconstriction; a-1
receptors utilize intracellular calcium while a-2's utilize
extracellular calcium.
There are no known direct effects of a-2 stimulation on
myocardial tissue. However, a-2 activation indirectly effects
cardiac function through centrally-mediated decreases in sympathetic tone (CNS
postsynaptic receptors), decreased release of norepinephrine from sympathetic nerve
terminals (prejunctional receptors) and by altering coronary blood flow (vascular
receptors). In the gastrointestinal tract, a-2's act pre- and
postjunctionally to regulate motility and secretions. Vagally-mediated increases in
motility and secretions are inhibited, at the intramural parasympathetic ganglia and
prejunctionally at postganglionic cholinergic neurons. Alpha-2 stimulation decreases
gastric secretion and increases net fluid absorption. The uterus is richly supplied with a-2 receptors and their number increases under the influence of
estrogen but no functional role has been identified. In the endothelium, a-2A receptors have been shown to mediate release of nitric oxide,
the endothelium-derived relaxing factor. Other substances that result in nitric oxide
release include acetyicholine, bradykinin and substance-P. Alpha-2 stimulation has been
shown to offset adrenergic vasoconstriction in coronary vessels of dogs.
Renal effects of a-2 stimulation include diuresis induced by
inhibition of release of ADH, blockade of ADH's action at the renal tubule, increased GFR,
and inhibition of renin release. Endocrine effects include decreased insulin,
norepinephrine, ACTH, and cortisol release and enhanced GH release. Lastly, a-2 receptors on platelets stimulate aggregation.
Interaction of acetyicholine or norepinephrine (the first messenger) with their
receptors alters flux of sodium or potassium ions across ion channels or most often
activates or inhibits effector enzymes such as adenylate cyclase. The a-2
receptor is comprised of a single polypeptide chain which weaves back and forth through
the cell membrane seven times. The transmembranous portion is very similar to that of
other adrenoceptors suggesting that these are the recognition/binding site for
norepinephrine. The cytoplasmic side forms the contact point for the guanine nucleotide
binding protein (G protein). G proteins couple the receptor to a discrete effector
mechanism which may be a transmembrane ion channel or an intracellular second messenger
cascade. There are at least 4 different pertussis toxin-sensitive G proteins which can
couple to the a-2 receptor. A common feature of all a-2 adrenergic receptors is their ability, when activated, to inhibit
adenylate cyclase. The resulting decrease in the accumulation of cAMP (the second
messenger) attenuates the stimulation of cAMP-dependent protein kinase and hence the
phosphorylation of target regulatory proteins. Other possible effector mechanisms of a-2 adrenoceptors include eflux of potassium or suppression of
calcium influx.
Tranquilizers are psychopharmacologic drugs whose primary therapeutic action is to
relieve anxiety (anxiolysis). They have other effects in addition to anxiolysis. While
they do not produce sleep, analgesia or anesthesia, at increased doses they may induce
decreased responsiveness to environmental stimuli and some degree of muscle relaxation. At
any dose, however, their depressant effects can be overcome with sufficient stimuli. In
general, these drugs are seldom used alone but in combination with other anesthetics and
adjuncts as part of a balanced anesthetic.
Phenothiazines demonstrate a dose-dependent spectrum of activity ranging from
anxiolysis to sedation and drowziness. They have virtually no analgesic effects but appear
to potentiate the analgesic effects of opioids. Centrally, phenothiazines mediate their
effects via dopamine blockade particularly in the reticular formation. Peripherally they
block dopamine and adrenergic receptors resulting in vasodilation and hypotension.
Acepromazine decreases heart rate, arterial blood pressure, body temperature, respiratory
rate but not minute volume. Other side effects include hyperglycemia, antipyretic,
anticholinergic, antiemetic, antihistarninic and antispasmodic effects. In high doses,
they have been shown to raise the arrhythmogenic dose of epinephrine in
halothane-anesthetized dogs. Gastrointestinal secretions are reduced. The seizure
threshold is also decreased.
The butyrophenones, like the phenothiazines, are major tranquilizers, i.e., they are
antipsychotic drugs in people. Butyrophenones are similar to the phenothiazines in their
mechanism of action, having antidopaminergic effects in the basal ganglia and forebrain.
Unlike acepromazine, butyrophenones when used alone may induce dysphoria and excitement in
some species, i.e., horses, or individuals, i.e., dogs. Because the response in any given
patient is somewhat unpredictable and because they have no analgesic properties, they are
most commonly used in combination with opioids to induce a state of neuroleptanalgesia.
Cardiovascular effects are dose dependent and similar to phenothiazines and include
hypotension, bradycardia, decreased cardiac output and contractility. Hypotension is
mediated at least in part by peripheral alpha blockade. When used in combination with
opioids, there is less myocardial depression than occurs with either phenothiazine- or
benzodiazepine-opioid combinations. Droperidol has the most commonly used butyrophenone,
usually in combination with fentanyl (Innovar-Vet). Azaperone is a butyrophenone whose
main use has been a tranquilizer for swine to reduce aggression. In the UK, fluanizone is
combined with fentanyl (Hypnorm).
Benzodiazepines, unlike the phenothiazines and butyrophenones lack antipsychotic
effects in people and as a result are classified as minor tranquilizers. They have potent
anxiolytic, anticonvulsant and muscle relaxant effects. They do not induce the degree of
tranquilization-sedation of the other tranquilizers. In veterinary medicine, they are most
commonly used as anticonvulsants and as co-induction agents in combination with injectable
anesthetics. Benzodiazepines are undergo hepatic metabolism and the metabolites are active
contributing to the relatively long duration of action of these drugs. Ultimately the
metabolites are excreted in the urine. Unlike barbiturates, benzodiazepines do not appear
to induce hepatic enzyme production. The half-life of these drugs varies among species
being shortest in rodents. The dog appears to clear benzodiazepines more rapidly than the
cat. Elimination half life increases up to 5 fold with liver disease. In addition,
sensitivity and increased duration of action increases with age not related to hepatic
function.
Benzodiazepine receptors are located on the alpha subunit of the GABA receptor on
postsynaptic nerve endings in the CNS. The resulting effect is to enhance the
chloride-channel gating effect of GABA. Increased chloride channel conductance leads to
hyperpolarization of the cell and decreased (inhibition) of transmission. Benzodiazepine
receptors occur nearly exclusively on postsynaptic membranes in the CNS resulting in
minimal non-CNS (cardiopulmonary) effects. The highest density of benzodiazepine receptors
occurs in the cerebral cortex followed in decreasing order by the hypothalamus,
cerebellum, midbrain, hippocampus, medulla, and spinal cord. The EEG effects are similar
to those of the barbiturates, decreased alpha and increased low beta activity. Unlike the
barbiturates, tolerance to the EEG effects of benzodiazepines does occur. Unlike the
phenothiazines and butyrophenones, benzodiazepines have a specific antagonist, or reversal
drug, flumazenil.
Benzodiazepines have minimal depressant effects on cardiopulmonary, renal or hepatic
function. While respiratory effects are minimal, they can enhance respiratory depression
of other drugs, e.g., opioids. Benzodiazepines induce minimal decreases in arterial blood
pressure, cardiac output and vascular resistance similar to those observed during natural
sleep. Skeletal muscle relaxant effects are due to decreased transmission at the
internuncial neuron in the spinal cord and not at the myoneural junction.
The most commonly used benzodiazepine in veterinary medicine are diazepam, midazolam
and zolazepam (available only in combination with tiletamine, i.e., Telazol). Midazolam is
more potent than diazepam and is water soluble. It has a shorter half-life than diazepam
but is otherwise similar to diazepam in its effects. Zolazepam is a water soluble
benzodiazepine that is available in combination with tiletamine (Telazol). Zolazepam's
pharmacokinetics are similar to diazepam and midazolam. It produces less tranquilization
than diazepam or midazolam and at high doses can induce dysphoria and excitement.
- Anesthesia and Analgesia in Laboratory Animals. DF Kohn, 5K Wixson, WJ White and GJ
Benson (eds). American College of Laboratory Animal Medicine Series, Academic Press, New
York, 1997.
- Lumb and Jones Veterinary Anesthesia, 3rd edition. JC Thurmon, WJ Tranquilli, GJ Benson
(eds). Williams and Wilkins,Baltimore, 1996.
- Pharmacology and Physiology in Anesthetic Practice, 2nd edition. RK Stoelting. JB
Lippincott, Philidelphia, 1991.
 
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