CLINICAL PHARMACOLOGY OF LOCAL ANESTHETICS. CLINICAL PHARMACOLOGY OF GENERAL ANESTHETICS. CLINICAL PHARMACOLOGY OF NARCOTIC AND NONNARCOTIC ANALGESICS
Anesthesia means loss of sensation with or without loss of consciousness. Anesthetic drugs are given to prevent pain and promote relaxation during surgery, childbirth, some diagnostic tests, and some treatments. They interrupt the conduction of painful nerve impulses from a site of injury to the brain. The two basic types of anesthesia are general and regional. General anesthesia is usually induced with a fast-acting drug (eg, propofol or thiopental) given intravenously and is maintained with a gas mixture of an anesthetic agent and oxygen given by inhalation. The intravenous (IV) agent produces rapid loss of consciousness and provides a pleasant induction and recovery. Its rapid onset of action is attributed to rapid circulation to the brain and accumulation in the neuronal tissue of the cerebral cortex.
General Anesthetics
Barbiturates
methohexital thiopental
Nonbarbiturate General Anesthetics
droperidol etomidate ketamine midazolam propofol
Gases
cyclopropane ethylene nitrous oxide
Volatile Liquids
desflurane enflurane halothane isoflurane sevoflurane
Local Anesthetics
Esters
benzocaine chloroprocaine procaine tetracaine
Amides
bupivacaine dibucaine levobupivacaine lidocaine mepivacaine prilocaine ropivacaine
Other
pramoxine
The drugs are short acting because they are quickly redistributed from the brain to highly perfused organs (eg, heart, liver, kidneys) and muscles, and then to fatty tissues. Because they are slowly released from fatty tissues back into the bloodstream, anesthesia, drowsiness, and cardiopulmonary depression persist into the postoperative period. Duration of action can be prolonged and accumulation is more likely to occur with repeated doses or continuous IV infusion. An anesthetic barbiturate or propofol may be used alone for anesthesia during brief diagnostic tests or surgical procedures. Barbiturates are contraindicated in patients with acute intermittent porphyria, a rare hereditary disorder characterized by recurrent attacks of physical and mental disturbances.
Inhalation anesthetics vary in the degree of CNS depression produced and thereby vary in the rate of induction, anesthetic potency, degree of muscle relaxation, and analgesic potency. CNS depression is determined by the concentration of the drug in the CNS. Drug concentration, in turn, depends on the rate at which the drug is transported from the alveoli to the blood, transported past the blood–brain barrier to reach the CNS, redistributed by the blood to other body tissues, and eliminated by the lungs. Depth of anesthesia can be regulated readily by varying the concentration of the inhaled anesthetic gas. General inhalation anesthetics should be given only by specially trained people, such as anesthesiologists and nurse anesthetists, and only with appropriate equipment.
Regional or local anesthesia is usually safer than general anesthesia because it produces fewer systemic effects. For example, spinal anesthesia is often the anesthesia of choice for surgery involving the lower abdomen and lower extremities, especially in people who are elderly or have chronic lung disease.
A major advantage of spinal anesthesia is that it causes less CNS and respiratory depression. Guidelines for injections of local anesthetic agents include the following:
1. Local anesthetics should be injected only by people with special training in correct usage and only in locations where staff, equipment, and drugs are available for emergency use or cardiopulmonary resuscitation.
2. Choice of a local anesthetic depends mainly on the reason for use or the type of regional anesthesia desired. Lidocaine, one of the most widely used, is available in topical and injectable forms.
3. Except with IV lidocaine for cardiac dysrhythmias, local anesthetic solutions must not be injected into blood vessels because of the high risk of serious adverse reactions involving the cardiovascular system and CNS. To prevent accidental injection into a blood vessel, needle placement must be verified by aspirating before injecting the local anesthetic solution. If blood is aspirated into the syringe, another injection site must be selected.
4. Local anesthetics given during labor cross the placenta and may depress muscle strength, muscle tone, and rooting behavior in the newborn. Apgar scores are usually normal. If excessive amounts are used (eg, in paracervical block), local anesthetics may cause fetal bradycardia, increased movement, and expulsion of meconium before birth and marked depression after birth. Dosage used for spinal anesthesia during labor is too small to depress the fetus or the newborn.
5. For spinal or epidural anesthesia, use only local anesthetic solutions that have been specifically prepared for spinal anesthesia and are in single-dose containers. Multiple-dose containers are not used because of the risk of injecting contaminated solutions.
6. Epinephrine is often added to local anesthetic solutions to prolong anesthetic effects. Such solutions require special safety precautions, such as the following:
a. This combination of drugs should not be used for nerve blocks in areas supplied by end arteries (fingers, ears, nose, toes, penis) because it may produce ischemia and gangrene.
b. This combination should not be given IV or in excessive dosage because the local anesthetic and epinephrine can cause serious systemic toxicity, including cardiac dysrhythmias.
c. This combination should not be used with inhalation anesthetic agents that increase myocardial sensitivity to catecholamines. Severe ventricular dysrhythmias may result.
d. These drugs should not be used in clients with severe cardiovascular disease or hyperthyroidism.
e. If used in obstetrics, the concentration of epinephrine should be no greater than 1:200,000 because of the danger of producing vasoconstriction in uterine blood vessels. Such vasoconstriction may cause decreased placental circulation, decreased intensity of uterine contractions, and prolonged labor.
The smaller and more lipophilic the local anesthetic, the faster the rate of interaction with the sodium channel receptor. Potency is also positively correlated with lipid solubility as long as the agent retains sufficient water solubility to diffuse to the site of action on the neuronal membrane. Lidocaine, procaine, and mepivacaine are more water-soluble than tetracaine, bupivacaine, and ropivacaine. The latter agents are more potent and have longer durations of local anesthetic action. These long-acting local anesthetics also bind more extensively to proteins and can be displaced from these binding sites by other protein-bound drugs. In the case of optically active agents (eg, bupivacaine), the S(+)isomer can usually be shown to be moderately more potent than the R(-) isomer.
Toxicity
The two major forms of local anesthetic toxicity are: (1) systemic effects following absorption of the local anesthetic from their site of administration and (2) direct neurotoxicity from the local effects of these drugs when administered in close proximity to the spinal cord and other major nerve trunks. When blood levels of local anesthetics rise rapidly, adverse effects on several major organ systems may be observed.
A. CENTRAL NERVOUS SYSTEM
1. All local anesthetics At low concentrations, all local anesthetics have the ability to produce sleepiness, light-headedness, visual and auditory disturbances, and restlessness. An early symptom of local anesthetic toxicity is circumoral and tongue numbness and a metallic taste. At higher concentrations, nystagmus and muscular twitching occur, followed by overt tonic-clonic convulsions. Local anesthetics apparently cause depression of cortical inhibitory pathways, thereby allowing unopposed activity of excitatory neuronal pathways. This transitional stage of unbalanced excitation (ie, seizure activity) is then followed by generalized CNS depression.
Convulsions due to excessive blood levels can usually be prevented by administering the smallest effective dose of the local anesthetic required for adequate surgical analgesia and by avoiding inadvertent intravascular injection, or injection into highly perfused tissues. When large doses of a local anesthetic are required (eg, for major peripheral nerve block), premedication with a parenteral benzodiazepine (eg, diazepam or midazolam) provides significant prophylaxis against local anesthetic-induced CNS toxicity by raising the seizure threshold.
If seizures do occur, it is important to prevent hypoxemia and acidosis. Although administration of oxygen does not prevent seizure activity, hyperoxemia may be beneficial after onset of seizures. Hypercapnia and acidosis may lower the seizure threshold, and so hyperventilation is recommended during treatment of seizures. In addition, hyperventilation increases blood pH, which in turn lowers extracellular potassium. This action hyperpolarizes the transmembrane potential of axons, which favors the rested (or low-affinity) state of the sodium channels, resulting in decreased local anesthetic toxicity.
Seizures induced by local anesthetics can also be treated with intravenous anesthetic drugs (eg, thiopental 1-2 mg/kg, propofol 0.5-1 mg/kg, midazolam 0.03-0.06 mg/kg, or diazepam 0.1-0.2 mg/kg). The muscular manifestations of a seizure can be blocked using a short-acting neuromuscular relaxant drug (eg, succinylcholine, 0.5-1 mg/kg IV). It should be emphasized that succinylcholine does not obliterate CNS manifestations of seizure activity. Rapid tracheal intubation and mechanical ventilation can prevent pulmonary aspiration of gastric contents and facilitate hyperventilation.
2. Cocaine Since prehistoric times, the natives of Peru and Bolivia have chewed the leaves of the indigenous plant Erythroxylon coca, the source of cocaine, to obtain a feeling of well-being and reduce fatigue. Intense CNS effects can be achieved by sniffing cocaine powder and smoking cocaine base (“free basing”). Cocaine has become one of the most widely abused drugs. High doses of inhaled and injected cocaine have all of the toxicities described for other local anesthetics. In addition, cocaine can produce severe cardiovascular toxicity, including hypertension, arrhythmias, and myocardial failure.
B. NEUROTOXICITY When applied at excessively high concentrations, all local anesthetics can produce direct neural toxicity. Chloroprocaine and lidocaine appear to be more neurotoxic than other local anesthetics when used for spinal anesthesia, with high local concentrations producing so-called transient radicular irritation (or transient neuropathic symptoms). It has been suggested that this toxicity results from pooling of high concentrations of the local anesthetic in the cauda equina. Although the precise mechanism of this neurotoxic action has not been established, both interference with axonal transport and disruption of calcium homeostasis have been implicated. Spinal neurotoxicity does not result from excessive sodium channel blockade.
C. CARDIOVASCULAR SYSTEM The cardiovascular effects of local anesthetics result partly from direct effects on the cardiac and smooth muscle membranes and partly from indirect effects on the autonomic nervous system. Local anesthetics block cardiac sodium channels and thus depress abnormal cardiac pacemaker activity, excitability, and conduction. At extremely high concentrations, local anesthetics can also block calcium channels. With the notable exception of cocaine, local anesthetics also depress the strength of cardiac contraction and cause arteriolar dilation, leading to systemic hypotension. Cardiovascular collapse is rare, but has been reported after large doses of bupivacaine and ropivacaine.
Cocaine differs from the other local anesthetics with respect to its cardiovascular effects. Cocaine’s blockade of norepinephrine reuptake results in vasoconstriction and hypertension, as well as cardiac arrhythmias. The vasoconstriction produced by cocaine can lead to local ischemia and, in chronic abusers who use the nasal route, ulceration of the mucous membrane and damage to the nasal septum have been reported. The vasoconstrictor properties of cocaine can be used clinically to decrease bleeding from mucosal damage in the nasopharynx.
It has been suggested that bupivacaine may be more cardiotoxic than other long-acting local anesthetics. This reflects the fact that bupivacaine-induced blockade of sodium channels is potentiated by the long action potential duration of cardiac cells compared with nerve fibers. The most common electrocardiographic finding in patients with bupivacaine intoxication is a slow idioventricular rhythm with broad QRS complexes and eventually electromechanical dissociation.
Resuscitation from bupivacaine cardiovascular toxicity is extremely difficult even for experienced clinicians. The (S)-isomer, levobupivacaine, appears to have a lower propensity for cardiovascular toxicity than the racemic mixture or the (R)-isomer and has been approved for clinical use. Ropivacaine has clinical (pharmacodynamic) effects similar to those of bupivacaine, but is allegedly associated with a lower potential for cardiovascular toxicity. Ropivacaine is available only as the (S)-stereoisomer, which has inherently less affinity for the cardiac sodium channel. However, both cardiac toxicity and CNS toxicity have been reported when ropivacaine was used for peripheral nerve blocks.
D. HEMATOLOGIC EFFECTS The administration of large doses (> 10 mg/kg) of prilocaine during regional anesthesia may lead to accumulation of the metabolite o-toluidine, an oxidizing agent capable of converting hemoglobin to methemoglobin. When sufficient methemoglobin is present (3-5 mg/dL), the patient may appear cyanotic and the blood “chocolate-colored.” Although moderate levels of methemoglobinemia are well tolerated by healthy individuals, elevated methemoglobinemia may cause decompensation in patients with preexisting cardiac or pulmonary disease. The treatment of methemoglobinemia involves the intravenous administration of a reducing agent (eg, methylene blue or ascorbic acid), which rapidly converts methemoglobin to hemoglobin.
E. ALLERGIC REACTIONS The ester-type local anesthetics are metabolized to p-aminobenzoic acid derivatives. These metabolites are responsible for allergic reactions in a small percentage of the patient population. Amides are not metabolized to p-aminobenzoic acid, and allergic reactions to amide local anesthetics are extremely rare.
TYPES OF GENERAL ANESTHESIA
General anesthetics are usually administered by intravenous injection or by inhalation. For many years, inhalation anesthesia was used for all major procedures. Recently, intravenous anesthesia has become the more commonly used technique.
Several drugs are administered intravenously, alone or in combination with other anesthetic drugs, to achieve an anesthetic state or to sedate patients in intensive care units (ICUs) who must be mechanically ventilated. These drugs include the following: (1) barbiturates (eg, thiopental, methohexital); (2) benzodiazepines (eg, midazolam, diazepam); (3) propofol (4) ketamine; (5) opioid analgesics (morphine, fentanyl, sufentanil, alfentanil, remifentanil); and (6) miscellaneous sedative-hypnotics (eg, etomidate, dexmedetomidine).
. The most commonly used inhaled anesthetics are isoflurane, desflurane, and sevoflurane. These compounds are volatile liquids. Nitrous oxide, a gas at ambient temperature and pressure, continues to be an important adjuvant to the volatile agents.
Balanced Anesthesia
Although general anesthesia can be produced using only intravenous or only inhaled anesthetic drugs, modern anesthesia typically involves a combination of intravenous (eg, for induction of anesthesia) and inhaled (eg, for maintenance of anesthesia) drugs. Muscle relaxants are commonly used to facilitate tracheal intubation and optimize surgical conditions. Local anesthetics are often administered by tissue infiltration and peripheral nerve blocks to provide perioperative analgesia. In addition, potent opioid analgesics and cardiovascular drugs (eg, b blockers, a2 agonists, calcium channel blockers) are used to control autonomic responses to noxious (painful) surgical stimuli.
STAGES OF ANESTHESIA
The traditional description of the stages of anesthesia (the so-called Guedel’s signs) were derived from observations of the effects of diethyl ether, which has a slow onset of central action owing to its high solubility in blood. Using these signs, anesthetic drug effects can be divided into four stages of increasing depth of central nervous system depression: I. Stage of analgesia: The patient initially experiences analgesia without amnesia. Later in Stage I, both analgesia and amnesia are produced. II. Stage of excitement: During this stage, the patient often appears to be delirious and may vocalize but is definitely amnesic. Respiration is irregular both in volume and rate, and retching and vomiting may occur if the patient is stimulated. For these reasons, efforts are made to limit the duration and severity of this stage, which ends with the reestablishment of regular breathing. III. Stage of surgical anesthesia: This stage begins with the recurrence of regular respiration and extends to complete cessation of spontaneous respiration (apnea). Four planes of stage III have been described in terms of changes in ocular movements, eye reflexes, and pupil size, which under specified conditions may represent signs of increasing depth of anesthesia. IV. Stage of medullary depression: This deep stage of anesthesia includes severe depression of the vasomotor center in the medulla, as well as the respiratory center. Without circulatory and respiratory support, death rapidly ensues.
In current anesthesia practice, the distinctive signs of each of the four stages described above are usually obscured because of the more rapid onset of action of modern intravenous and inhaled anesthetics (compared with ether), and the fact that ventilation is often controlled mechanically. In addition, the practice of administering other pharmacologic agents preoperatively (eg, preanesthetic medication) or intraoperatively (eg, opioid analgesics, cardiovascular drugs) can also alter the clinical signs of anesthesia. The anticholinergic drugs, atropine and glycopyrrolate, are used to decrease secretions and to treat bradycardia; however, they also dilate the pupils. Muscle relaxants reduce muscle tone and prevent purposeful movements, whereas the opioid analgesics exert depressant effects on both the respiratory and heart rates. The most reliable indication that stage III (surgical anesthesia) has been achieved is loss of responsiveness to noxious stimuli (eg, trapezius muscle squeeze) and reestablishment of a regular respiratory pattern. The adequacy of the depth of anesthesia for a specific surgical stimulus is assessed by monitoring changes in respiratory and cardiovascular responses to the surgical stimulation, as well as electroencephalographic (EEG-based) cerebral indices.
Clinical Use of Inhaled Anesthetics
Volatile anesthetics are rarely used as the sole agents for both induction and maintenance of anesthesia. Most commonly, they are combined with intravenous agents as part of a balanced anesthesia technique. Of the inhaled anesthetics, nitrous oxide, desflurane, sevoflurane, and isoflurane are the most commonly used in the USA. Use of less soluble volatile anesthetics (especially desflurane and sevoflurane) has increased during the last decade as more surgical procedures are performed on an ambulatory (“short-stay”) basis. The low blood:gas coefficients of desflurane and sevoflurane afford a more rapid recovery and fewer postoperative adverse effects than halothane, enflurane, and isoflurane. Although halothane is still used in pediatric anesthesia, sevoflurane is rapidly replacing halothane in this setting. As indicated previously, nitrous oxide lacks sufficient potency to produce surgical anesthesia by itself and therefore is used with volatile or intravenous anesthetics to produce a state of balanced general anesthesia. Despite the obvious advantages of the less soluble inhaled anesthetics, there is reason to believe that better ones might be developed.
In the last two decades there has been increasing use of intravenous anesthetics in anesthesia, both as adjuncts to inhaled anesthetics and as part of techniques that do not include any inhaled anesthetics (eg, total intravenous anesthesia). Unlike inhaled anesthetics, intravenous agents do not require specialized vaporizer equipment for their delivery or facilities for the disposal of exhaled gases. Intravenous drugs such as thiopental, methohexital, etomidate, ketamine, and propofol have an onset of anesthetic action faster than the most rapid inhaled agents (eg, desflurane and sevoflurane). Therefore, intravenous agents are commonly used for induction of general anesthesia.
Recovery is sufficiently rapid with most intravenous drugs to permit their use for short ambulatory (outpatient) surgical procedures. In the case of propofol, recovery times are similar to those seen with sevoflurane and desflurane. The anesthetic potency of intravenous anesthetics is adequate to permit their use as the sole anesthetic in short surgical procedures when combined with nitrous oxide. Adjunctive use of potent opioids contributes cardiovascular stability, enhanced sedation, and profound perioperative analgesia. Benzodiazepines (eg, midazolam, diazepam) have a slower onset and slower recovery than the barbiturates or propofol and are rarely used for induction of anesthesia. However, preanesthetic administration of benzodiazepines (eg, midazolam) can be used to provide anxiolysis, sedation, and amnesia when used in conjunction with other anesthetic agents.
Propofol (2,6-diisopropylphenol) has become the most popular intravenous anesthetic. Its rate of onset of action is similar to that of the intravenous barbiturates but recovery is more rapid and patients are able to ambulate earlier after general anesthesia. Furthermore, patients subjectively “feel better” in the immediate postoperative period because of the reduction in postoperative nausea and vomiting. Propofol is used for both induction and maintenance of anesthesia as part of total intravenous or balanced anesthesia techniques and is the agent of choice for ambulatory surgery. The drug is also effective in producing prolonged sedation in patients in critical care settings. When administered by prolonged infusion for sedation or ventilatory management in the intensive care unit, cumulative effects can lead to delayed arousal. In addition, prolonged administration of conventional emulsion formulations can elevate serum lipid levels. Use of propofol for the sedation of critically ill young children has led to severe acidosis in the presence of respiratory infections and to possible neurologic sequelae upon withdrawal.
After intravenous administration of propofol, the distribution half-life is 2-8 minutes, and the redistribution half-life is approximately 30-60 minutes. The drug is rapidly metabolized in the liver at a rate ten times faster than thiopental. Propofol is excreted in the urine as glucuronide and sulfate conjugates, with less than 1% of the parent drug excreted unchanged. Total body clearance of the anesthetic is greater than hepatic blood flow, suggesting that its elimination includes extrahepatic mechanisms in addition to metabolism by liver enzymes. This property can be useful in patients with impaired ability to metabolize other sedative-anesthetic drugs.
Effects on respiratory function are similar to those of thiopental at usual anesthetic doses and include dose-related depression of central ventilatory drive and apnea. However, propofol causes a marked decrease in blood pressure during induction of anesthesia through decreased peripheral arterial resistance and venodilation. In addition, propofol has greater direct negative inotropic effects than other intravenous anesthetics. Pain at the site of injection is the most common adverse effect of bolus administration. Muscle movements, hypotonus, and (rarely) tremors have also been reported after prolonged use. Clinical infections due to bacterial contamination of the propofol emulsion have led to the addition of antimicrobial adjuvants (eg, ethylenediaminetetraacetic acid [EDTA] and metabisulfite). Newer formulations of propofol have been developed that contain less lipid for prolonged administration (eg, Ampofol). However, pain on injection is increased when the lipid content is reduced. Admixture or pretreatment with lidocaine (20-50 mg) is the most effective approach to minimizing the pain on injection of propofol.
KETAMINE
Ketamine is a racemic mixture of two optical isomers, S(+) and R(-) ketamine. The drug produces a dissociative anesthetic state characterized by catatonia, amnesia, and analgesia, with or without loss of consciousness (hypnosis). The drug is an arylcyclohexylamine chemically related to phencyclidine (PCP), a drug with a high abuse potential owing to its psychoactive properties. The mechanism of action of ketamine may involve blockade of the membrane effects of the excitatory neurotransmitter glutamic acid at the NMDA receptor subtype. Ketamine is a highly lipophilic drug and is rapidly distributed into well-perfused organs, including the brain, liver, and kidney. Subsequently ketamine is redistributed to less well perfused tissues with concurrent hepatic metabolism followed by both urinary and biliary excretion.
Ketamine is the only intravenous anesthetic that possesses both analgesic properties and the ability to produce dose-related cardiovascular stimulation. Heart rate, arterial blood pressure, and cardiac output can be significantly increased above baseline values. These variables reach a peak 2-4 minutes after an intravenous bolus injection, then slowly decline to normal values over the next 10-20 minutes. Ketamine produces its cardiovascular effects by stimulating the central sympathetic nervous system and, to a lesser extent, by inhibiting the reuptake of norepinephrine at sympathetic nerve terminals. Increases in plasma epinephrine and norepinephrine levels occur as early as 2 minutes after an intravenous bolus of ketamine and return to baseline levels in less than 15 minutes.
Risk Factors Associated with General Anesthetics
Use of general anesthetics involves a widespread CNS depression, which is not without risks. Several factors must be taken into consideration before the use of general anesthesia, which usually involves a series of drugs aimed at achieving the best effect with the fewest side effects. Because of the wide systemic effects of general anesthetics, patients should be evaluated for potential risks. When anesthetic drugs are selected, the following factors are kept in mind so that the potential risk to each particular patient is minimized:
CNS factors: Underlying neurological disease (e.g., epilepsy, stroke, myasthenia gravis) that presents a risk for abnormal reaction to the CNS-depressing and muscle-relaxing effects of these drugs.
Cardiovascular factors: Underlying vascular disease, coronary artery disease, or hypotension, which put patients at risk for severe reactions to anesthesia, such as hypotension and shock, dysrhythmias, and ischemia.
Respiratory factors: Obstructive pulmonary disease (e.g., asthma, chronic obstructive pulmonary disease, bronchitis), which can complicate the delivery of gas anesthetics as well as the intubation and mechanical ventilation that must be used in most cases of general anesthesia.
Renal and hepatic function: Conditions that interfere with the metabolism and excretion of anesthetics (e.g., acute renal failure, hepatitis) and could result in prolonged anesthesia and the need for continued support during recovery. Toxic reactions to the accumulation of abnormally high levels of anesthetic agents may even occur.
Clinical Pharmacology
Ketamine hydrochloride is a rapid-acting general anesthetic producing an anesthetic state characterized by profound analgesia, normal pharyngeal-laryngeal reflexes, normal or slightly enhanced skeletal muscle tone, cardiovascular and respiratory stimulation, and occasionally a transient and minimal respiratory depression.
A patent airway is maintained partly by virtue of unimpaired pharyngeal and laryngeal reflexes.
Following intravenous administration, the ketamine concentration has an initial slope (alpha phase) lasting about 45 minutes with a half-life of 10 to 15 minutes. This first phase corresponds clinically to the anesthetic effect of the drug. The anesthetic action is terminated by a combination of redistribution from the CNS to slower equilibrating peripheral tissues and by hepatic biotransformation to metabolite I. This metabolite is about 1/3 as active as ketamine in reducing halothane requirements (MAC) of the rat. The later half-life of ketamine (beta phase) is 2.5 hours.
The anesthetic state produced by ketamine hydrochloride has been termed “dissociative anesthesia” in that it appears to selectively interrupt association pathways of the brain before producing somatesthetic sensory blockade. It may selectively depress the thalamoneocortical system before significantly obtunding the more ancient cerebral centers and pathways (reticular-activating and limbic systems).
Elevation of blood pressure begins shortly after injection, reaches a maximum within a few minutes and usually returns to preanesthetic values within 15 minutes after injection. In the majority of cases, the systolic and diastolic blood pressure peaks from 10% to 50% above preanesthetic levels shortly after induction of anesthesia, but the elevation can be higher or longer in individual cases
Specific areas of application have included the following:
1. debridement, painful dressings, and skin grafting in burn patients, as well as other superficial surgical procedures.
2. neurodiagnostic procedures such as pneumonencephalograms, ventriculograms, myelograms, and lumbar punctures. See also Precaution concerning increased intracranial pressure.
3. diagnostic and operative procedures of the eye, ear, nose, and mouth, including dental extractions.
4. diagnostic and operative procedures of the pharynx, larynx, or bronchial tree. NOTE: Muscle relaxants, with proper attention to respiration, may be required
5. sigmoidoscopy and minor surgery of the anus and rectum, and circumcision.
6. extraperitoneal procedures used in gynecology such as dilatation and curettage.
7. orthopedic procedures such as closed reductions, manipulations, femoral pinning, amputations, and biopsies.
8. as an anesthetic in poor-risk patients with depression of vital functions.
9. in procedures where the intramuscular route of administration is preferred.
10. in cardiac catheterization procedures.
Indications
Ketamine hydrochloride injection is indicated as the sole anesthetic agent for diagnostic and surgical procedures that do not require skeletal muscle relaxation. Ketamine hydrochloride is best suited for short procedures but it can be used, with additional doses, for longer procedures. Ketamine hydrochloride injection is indicated for the induction of anesthesia prior to the administration of other general anesthetic agents. Ketamine hydrochloride injection is indicated to supplement low-potency agents, such as nitrous oxide.
Contraindications
Ketamine hydrochloride is contraindicated in those in whom a significant elevation of blood pressure would constitute a serious hazard and in those who have shown hypersensitivity to the drug.
Drug Interactions – Prolonged recovery time may occur if barbiturates and/or narcotics are used concurrently with ketamine hydrochloride.
Ketamine hydrochloride is clinically compatible with the commonly used general and local anesthetic agents when an adequate respiratory exchange is maintained.
Usage in Pregnancy – Since the safe use in pregnancy, including obstetrics (either vaginal or abdominal delivery), has not been established, such use is not recommended
Geriatric Use – Clinical studies of ketamine hydrochloride did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
Pediatric Use – Safety and effectiveness in pediatric patients below the age of 16 have not been established.
Adverse Reactions
Cardiovascular: Blood pressure and pulse rate are frequently elevated following administration of ketamine hydrochloride alone. However, hypotension and bradycardia have been observed. Arrhythmia has also occurred.
Respiration: Although respiration is frequently stimulated, severe depression of respiration or apnea may occur following rapid intravenous administration of high doses of ketamine hydrochloride. Laryngospasms and other forms of airway obstruction have occurred during ketamine hydrochloride anesthesia.
Eye: Diplopia and nystagmus have beeoted following ketamine hydrochloride administration. It also may cause a slight elevation in intraocular pressure measurement.
Genitourinary: Severe irritative and inflammatory urinary tract and bladder symptoms including cystitis have been reported in individuals with history of chronic ketamine use or abuse.
Psychological: Neurological: In some patients, enhanced skeletal muscle tone may be manifested by tonic and clonic movements sometimes resembling seizures Gastrointestinal: Anorexia, nausea and vomiting have been observed; however, this is not usually severe and allows the great majority of patients to take liquids by mouth shortly after regaining consciousness .
General: Anaphylaxis. Local pain and exanthema at the injection site have infrequently been reported. Transient erythema and/or morbilliform rash have also been reported.
Ketamine Injection Dosage and Administration
Note: Barbiturates and ketamine hydrochloride, being chemically incompatible because of precipitate formation, should not be injected from the same syringe.
If the ketamine hydrochloride dose is augmented with diazepam, the two drugs must be given separately. Do not mix ketamine hydrochloride and diazepam in syringe or infusion flask.
Preoperative Preparations:
1. While vomiting has been reported following ketamine hydrochloride administration, some airway protection may be afforded because of active laryngeal-pharyngeal reflexes. However, since aspiration may occur with ketamine hydrochloride and since protective reflexes may also be diminished by supplementary anesthetics and muscle relaxants, the possibility of aspiration must be considered. Ketamine hydrochloride is recommended for use in the patient whose stomach is not empty when, in the judgment of the practitioner, the benefits of the drug outweigh the possible risks.
2. Atropine, scopolamine, or another drying agent should be given at an appropriate interval prior to induction.
Dosage:
As with other general anesthetic agents, the individual response to ketamine hydrochloride is somewhat varied depending on the dose, route of administration, and age of patient, so that dosage recommendation cannot be absolutely fixed. The drug should be titrated against the patient’s requirements.
Intravenous Route:
The initial dose of ketamine hydrochloride administered intravenously may range from 1 mg/kg to 4.5 mg/kg (0.5 to 2 mg/lb). The average amount required to produce five to ten minutes of surgical anesthesia has been 2 mg/kg (1 mg/lb).
Alternatively, in adult patients an induction dose of 1 mg to 2 mg/kg intravenous ketamine at a rate of 0.5 mg/kg/min may be used for induction of anesthesia. In addition, diazepam in 2 mg to 5 mg doses, administered in a separate syringe over 60 seconds, may be used. In most cases, 15 mg of intravenous diazepam or less will suffice. The incidence of psychological manifestations during emergence, particularly dream-like observations and emergence delirium, may be reduced by this induction dosage program.
Rate of Administration: It is recommended that ketamine hydrochloride be administered slowly (over a period of 60 seconds). More rapid administration may result in respiratory depression and enhanced pressor response.
: – The initial dose of ketamine hydrochloride administered intramuscularly may range from 6.5 to 13 mg/kg (3 to 6 mg/lb). A dose of 10 mg/kg (5 mg/lb) will usually produce 12 to 25 minutes of surgical anesthesia.
Maintenance of Anesthesia:
The maintenance dose should be adjusted according to the patient’s anesthetic needs and whether an additional anesthetic agent is employed.
Increments of one-half to the full induction dose may be repeated as needed for maintenance of anesthesia. However, it should be noted that purposeless and tonic-clonic movements of extremities may occur during the course of anesthesia. These movements do not imply a light plane and are not indicative of the need for additional doses of the anesthetic.
It should be recognized that the larger the total dose of ketamine hydrochloride administered, the longer will be the time to complete recovery.
Adult patients induced with ketamine hydrochloride augmented with intravenous diazepam may be maintained on ketamine hydrochloride given by slow microdrip infusion technique at a dose of 0.1 to 0.5 mg/minute, augmented with diazepam 2 to 5 mg administered intravenously as needed. In many cases 20 mg or less of intravenous diazepam total for combined induction and maintenance will suffice. However, slightly more diazepam may be required depending on the nature and duration of the operation, physical status of the patient, and other factors. The incidence of psychological manifestations during emergence, particularly dream-like observations and emergence delirium, may be reduced by this maintenance dosage program.
Toxicity:
The acute toxicity of ketamine hydrochloride has been studied in several species. In mature mice and rats, the intraperitoneal LD50 values are approximately 100 times the average human intravenous dose and approximately 20 times the average human intramuscular dose. A slightly higher acute toxicity observed ieonatal rats was not sufficiently elevated to suggest an increased hazard when used in pediatric patients. Daily intravenous injections in rats of five times the average human intravenous dose and intramuscular injections in dogs at four times the average human intramuscular dose demonstrated excellent tolerance for as long as 6 weeks. Similarly, twice weekly anesthetic sessions of one, three, or six hours’ duration in monkeys over a four- to six-week period were well tolerated.
Interaction with Other Drugs Commonly Used for Preanesthetic Medication:
Large doses (three or more times the equivalent effective human dose) of morphine, meperidine, and atropine increased the depth and prolonged the duration of anesthesia produced by a standard anesthetizing dose of ketamine hydrochloride in Rhesus monkeys. The prolonged duration was not of sufficient magnitude to contraindicate the use of these drugs for preanesthetic medication in human clinical trials.
Blood Pressure: Blood pressure responses to ketamine hydrochloride vary with the laboratory species and experimental conditions. Blood pressure is increased in normotensive and renal hypertensive rats with and without adrenalectomy and under pentobarbital anesthesia.
Intravenous ketamine hydrochloride produces a fall in arterial blood pressure in the Rhesus monkey and a rise in arterial blood pressure in the dog. In this respect the dog mimics the cardiovascular effect observed in man. The pressor response to ketamine hydrochloride injected into intact, unanesthetized dogs is accompanied by a tachycardia, rise in cardiac output and a fall in total peripheral resistance. It causes a fall in perfusion pressure following a large dose injected into an artificially perfused vascular bed (dog hindquarters), and it has little or no potentiating effect upon vasoconstriction responses of epinephrine or norepinephrine. The pressor response to ketamine hydrochloride is reduced or blocked by chlorpromazine (central depressant and peripheral α-adrenergic blockade), by β-adrenergic blockade, and by ganglionic blockade. The tachycardia and increase in myocardial contractile force seen in intact animals does not appear in isolated hearts (Langendorff) at a concentration of 0.1 mg of ketamine hydrochloride or in Starling dog heart-lung preparations at a ketamine hydrochloride concentration of 50 mg/kg of HLP. These observations support the hypothesis that the hypertension produced by ketamine hydrochloride is due to selective activation of central cardiac stimulating mechanisms leading to an increase in cardiac output. The dog myocardium is not sensitized to epinephrine and ketamine hydrochloride appears to have a weak antiarrhythmic activity.
Metabolic Disposition:
Ketamine hydrochloride is rapidly absorbed following parenteral administration. Animal experiments indicated that ketamine hydrochloride was rapidly distributed into body tissues, with relatively high concentrations appearing in body fat, liver, lung, and brain; lower concentrations were found in the heart, skeletal muscle, and blood plasma. Placental transfer of the drug was found to occur in pregnant dogs and monkeys. No significant degree of binding to serum albumin was found with ketamine hydrochloride.
Balance studies in rats, dogs, and monkeys resulted in the recovery of 85% to 95% of the dose in the urine, mainly in the form of degradation products. Small amounts of drug were also excreted in the bile and feces. Balance studies with tritium-labeled ketamine hydrochloride in human subjects (1 mg/lb given intravenously) resulted in the mean recovery of 91% of the dose in the urine and 3% in the feces. Peak plasma levels averaged about 0.75 μg/mL, and CSF levels were about 0.2 μg/mL, 1 hour after dosing.
Ketamine hydrochloride undergoes N-demethylation and hydroxylation of the cyclohexanone ring, with the formation of water-soluble conjugates which are excreted in the urine. Further oxidation also occurs with the formation of a cyclohexanone derivative. The unconjugated N-demethylated metabolite was found to be less than one-sixth as potent as ketamine hydrochloride. The unconjugated demethyl cyclohexanone derivative was found to be less than one-tenth as potent as ketamine hydrochloride. Repeated doses of ketamine hydrochloride administered to animals did not produce any detectable increase in microsomal enzyme activity.
Droperidol
Clinical Pharmacology
Droperidol produces marked tranquilization and sedation. It allays apprehension and provides a state of mental detachment and indifference while maintaining a state of reflex alertness.
Droperidol produces an antiemetic effect as evidenced by the antagonism of apomorphine in dogs. It lowers the incidence of nausea and vomiting during surgical procedures and provides antiemetic protection in the postoperative period.
Droperidol potentiates other CNS depressants. It produces mild alpha-adrenergic blockade, peripheral vascular dilatation and reduction of the pressor effect of epinephrine. It can produce hypotension and decreased peripheral vascular resistance and may decrease pulmonary arterial pressure (particularly if it is abnormally high). It may reduce the incidence of epinephrine-induced arrhythmias but it does not prevent other cardiac arrhythmias.
The onset of action of single intramuscular and intravenous doses is from three to ten minutes following administration, although the peak effect may not be apparent for up to thirty minutes. The duration of the tranquilizing and sedative effects generally is two to four hours, although alteration of alertness may persist for as long as twelve hours.
Indications
Droperidol injection is indicated to reduce the incidence of nausea and vomiting associated with surgical and diagnostic procedures.
Contraindications
Droperidol is contraindicated in patients with known or suspected QT prolongation (i.e., QTc interval greater than 440 msec for males or 450 msec for females). This would include patients with congenital long QT syndrome.
Droperidol is contraindicated in patients with known hypersensitivity to the drug.
Droperidol is not recommended for any use other than for the treatment of perioperative nausea and vomiting in patients for whom other treatments are ineffective or inappropriate (see WARNINGS).
Warnings
Droperidol should be administered with extreme caution in the presence of risk factors for development of prolonged QT syndrome, such as: 1) clinically significant bradycardia (less than 50 bpm), 2) any clinically significant cardiac disease, 3) treatment with Class I and Class III antiarrhythmics, 4) treatment with monoamine oxidase inhibitors (MAOI’s), 5) concomitant treatment with other drug products known to prolong the QT interval, and 6) electrolyte imbalance, in particular hypokalemia and hypomagnesemia, or concomitant treatment with drugs (e.g., diuretics) that may cause electrolyte imbalance.
Effects on Cardiac Conduction:
A dose-dependent prolongation of the QT interval was observed within 10 minutes of Droperidol administration in a study of 40 patients without known cardiac disease who underwent extracranial head and neck surgery. Significant QT prolongation was observed at all three dose levels evaluated, with 0.1, 0.175, and 0.25 mg/kg associated with prolongation of median QTc by 37, 44, and 59 msec, respectively.
Cases of QT prolongation and serious arrhythmias (e.g., torsade de pointes, ventricular arrhythmias, cardiac arrest, and death) have been observed during post-marketing treatment with Droperidol. Some cases have occurred in patients with no known risk factors and at doses at or below recommended doses. There has been at least one case of nonfatal torsade de pointes confirmed by rechallenge.
Based on these reports, all patients should undergo a 12-lead ECG prior to administration of Droperidol to determine if a prolonged QT interval (i.e., QTc greater than 440 msec for males or 450 msec for females) is present. If there is a prolonged QT interval, Droperidol should NOT be administered. For patients in whom the potential benefit of Droperidol treatment is felt to outweigh the risks of potentially serious arrhythmias, ECG monitoring should be performed prior to treatment and continued for 2-3 hours after completing treatment to monitor for arrhythmias.
FLUIDS AND OTHER COUNTERMEASURES TO MANAGE HYPOTENSION SHOULD BE READILY AVAILABLE.
As with other CNS depressant drugs, patients who have received Droperidol should have appropriate surveillance.
It is recommended that opioids, when required, initially be used in reduced doses.
As with other neuroleptic agents, very rare reports of neuroleptic malignant syndrome (altered consciousness, muscle rigidity and autonomic instability) have occurred in patients who have received Droperidol.
Since it may be difficult to distinguish neuroleptic malignant syndrome from malignant hyperpyrexia in the perioperative period, prompt treatment with dantrolene should be considered if increases in temperature, heart rate or carbon dioxide production occur.
Precautions
General: The initial dose of Droperidol should be appropriately reduced in elderly, debilitated and other poor-risk patients. The effect of the initial dose should be considered in determining incremental doses.
Certain forms of conduction anesthesia, such as spinal anesthesia and some peridural anesthetics, can alter respiration by blocking intercostal nerves and can cause peripheral vasodilatation and hypotension because of sympathetic blockade. Through other mechanisms, Droperidol can also alter circulation. Therefore, when Droperidol is used to supplement these forms of anesthesia, the anesthetist should be familiar with the physiological alterations involved, and be prepared to manage them in the patients elected for these forms of anesthesia.
If hypotension occurs, the possibility of hypovolemia should be considered and managed with appropriate parenteral fluid therapy. Repositioning the patient to improve venous return to the heart should be considered when operative conditions permit. It should be noted that in spinal and peridural anesthesia, tilting the patient into a head-down position may result in a higher level of anesthesia than is desirable, as well as impair venous return to the heart. Care should be exercised in the moving and positioning of patients because of a possibility of orthostatic hypotension. If volume expansion with fluids plus these other countermeasures do not correct the hypotension, then the administration of pressor agents other than epinephrine should be considered. Epinephrine may paradoxically decrease the blood pressure in patients treated with Droperidol due to the alpha-adrenergic blocking action of Droperidol.
Since Droperidol may decrease pulmonary arterial pressure, this fact should be considered by those who conduct diagnostic or surgical procedures where interpretation of pulmonary arterial pressure measurements might determine final management of the patient.
Vital signs and ECG should be monitored routinely.
When the EEG is used for postoperative monitoring, it may be found that the EEG pattern returns to normal slowly.
Impaired Hepatic or Renal Function: Droperidol should be administered with caution to patients with liver and kidney dysfunction because of the importance of these organs in the metabolism and excretion of drugs.
Pheochromocytoma: In patients with diagnosed/ suspected pheochromocytoma, severe hypertension and tachycardia have been observed after the administration of Droperidol.
Drug Interactions:
Potentially Arrhythmogenic Agents: Any drug known to have the potential to prolong the QT interval should not be used together with Droperidol. Possible pharmacodynamic interactions can occur between Droperidol and potentially arrhythmogenic agents such as class I or III antiarrhythmics, antihistamines that prolong the QT interval, antimalarials, calcium channel blockers, neuroleptics that prolong the QT interval, and antidepressants.
Caution should be used when patients are taking concomitant drugs known to induce hypokalemia or hypomagnesemia as they may precipitate QT prolongation and interact with Droperidol. These would include diuretics, laxatives and supraphysiological use of steroid hormones with mineralocorticoid potential.
CNS Depressant Drugs: Other CNS depressant drugs (e.g., barbiturates, tranquilizers, opioids and general anesthetics) have additive or potentiating effects with Droperidol. Following the administration of Droperidol, the dose of other CNS depressant drugs should be reduced.
Carcinogenesis, Mutagenesis, Impairment of Fertility: No carcinogenicity studies have been carried out with Droperidol. The micronucleus test in female rats revealed no mutagenic effects in single oral doses as high as 160 mg/kg. An oral study in rats (Segment I) revealed no impairment of fertility in either males or females at 0.63, 2.5 and 10 mg/kg doses (approximately 2, 9 and 36 times maximum recommended human I.V./I.M. dosage).
Pregnancy — Category C: Droperidol administered intravenously has been shown to cause a slight increase in mortality of the newborn rat at 4.4 times the upper human dose. At 44 times the upper human dose, mortality rate was comparable to that for control animals. Following intramuscular administration, increased mortality of the offspring at 1.8 times the upper human dose is attributed to CNS depression in the dams who neglected to remove placentae from their offspring. Droperidol has not been shown to be teratogenic in animals. There are no adequate and well-controlled studies in pregnant women. Droperidol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nursing Mothers: It is not known whether Droperidol is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Droperidol is administered to a nursing mother.
Pediatric Use: The safety of Droperidol in children younger than two years of age has not been established.
Adverse Reactions
QT interval prolongation, torsade de pointes, cardiac arrest, and ventricular tachycardia have been reported in patients treated with Droperidol. Some of these cases were associated with death. Some cases occurred in patients with no known risk factors, and some were associated with Droperidol doses at or below recommended doses.
Physicians should be alert to palpitations, syncope, or other symptoms suggestive of episodes of irregular cardiac rhythm in patients taking Droperidol and promptly evaluate such cases.
The most common somatic adverse reactions reported to occur with Droperidol are mild to moderate hypotension and tachycardia, but these effects usually subside without treatment. If hypotension occurs and is severe or persists, the possibility of hypovolemia should be considered and managed with appropriate parenteral fluid therapy.
The most common behavioral adverse effects of Droperidol include dysphoria, postoperative drowsiness, restlessness, hyperactivity and anxiety, which can either be the result of an inadequate dosage (lack of adequate treatment effect) or of an adverse drug reaction (part of the symptom complex of akathisia).
Care should be taken to search for extrapyramidal signs and symptoms (dystonia, akathisia, oculogyric crisis) to differentiate these different clinical conditions. When extrapyramidal symptoms are the cause, they can usually be controlled with anticholinergic agents.
Postoperative hallucinatory episodes (sometimes associated with transient periods of mental depression) have also been reported.
Other less common reported adverse reactions include anaphylaxis, dizziness, chills and/or shivering, laryngospasm and bronchospasm.
Elevated blood pressure, with or without pre-existing hypertension, has been reported following administration of Droperidol combined with fentanyl citrate or other parenteral analgesics. This might be due to unexplained alterations in sympathetic activity following large doses; however, it is also frequently attributed to anesthetic or surgical stimulation during light anesthesia.
Dosage and Administration
Dosage should be individualized. Some of the factors to be considered in determining dose are age, body weight, physical status, underlying pathological condition, use of other drugs, the type of anesthesia to be used, and the surgical procedure involved.
Vital signs and ECG should be monitored routinely.
Adult Dosage: The maximum recommended initial dose of Droperidol is 2.5 mg I.M. or slow I.V. Additional 1.25 mg doses of Droperidol may be administered to achieve the desired effect. However, additional doses should be administered with caution, and only if the potential benefit outweighs the potential risk.
Pediatric Dosage: For children two to 12 years of age, the maximum recommended initial dose is 0.1 mg/kg, taking into account the patient’s age and other clinical factors. However, additional doses should be administered with caution, and only if the potential benefit outweighs the potential risk.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. If such abnormalities are observed, the drug should not be administered.
Thiopental Sodium
Indications
Induction of anesthesia; supplementation of other anesthetic agents; IV anesthesia for short surgical procedures with minimal painful stimuli; induction of hypnotic state; control of convulsions and increased intracranial pressure (IV administration); induction of preanesthetic sedation or basal narcosis (PR administration).
Contraindications
Hypersensitivity to barbiturates; variegate or acute intermittent porphyria; absence of suitable veins for IV administration; status asthmaticus.
Rectal administration
Patients undergoing rectal surgery; lesions of bowel.
Dosage and Administration
Test Dose: Adults – IV 25 to 75 mg; observe for 60 sec.
Anesthesia Adults – IV 50 to 75 mg slowly every 20 to 40 sec until anesthesia is established then 25 to 50 mg as needed or continuous infusion of 0.2% or 0.4%. Children – IV 5 to 6 mg/kg then 1 mg/kg as needed. Infants – IV 5 to 8 mg/kg then 1 mg/kg as needed. Newborns – IV 3 to 4 mg/kg then 1 mg/kg as needed.
Convulsive States
Adults – IV 75 to 125 mg; may need 125 to 250 mg over 10 min.
Children – IV 2 to 3 mg/kg/dose; repeat as needed.
Increased Intracranial Pressure
Adults – IV 1.5 to 3.5 mg/kg.
Children – IV 1.5 to 5 mg/kg/dose; repeat as needed.
Psychiatric Disorders
Adults – IV 100 mg/min slowly with patient counting backwards or as infusion of 50 mL/min of 0.2% solution.
Preanesthetic Sedation
Adults – PR 1 g/34 kg (30 mg/kg).
Basal Narcosis
Adults – PR 1 g/22.5 kg (44 mg/kg) (max, 3 to
Children over 3 mo – PR 25 mg/kg/dose; if not sedated within 15 to 20 min, may repeat with single dose of 15 mg/kg/dose (max,
Children under 3 mo – PR 15 mg/kg/dose; if not sedated within 15 to 20 min, may repeat with single dose of less than 7.5 mg/kg/dose.
Drug Interactions
Narcotics – May cause additive barbiturate effects and increase risk of apnea.
Phenothiazines – May increase frequency and severity of neuromuscular excitation and hypotension.
Probenecid – May extend barbiturate effects or effects may be achieved at lower doses.
Sulfisoxazole – May enhance barbiturate effects.
Adverse Reactions
Cardiovascular – Myocardial depression; arrhythmias.
CNS – Delirium, headache; amnesia; seizures.
Dermatologic – Rash.
GI – Abdominal pain; rectal irritation; diarrhea; cramping; rectal bleeding (rectal suspension).
Respiratory – Apnea; laryngospasm; bronchospasm; hiccoughs; sneezing; coughing.
Miscellaneous – Thrombophlebitis; pain at injection site; salivation; shivering.
Precautions – Pregnancy – readily crosses placental barrier.
Lactation – Excreted in breast milk.
Elderly – At increased risk of prolonged or potentiated hypnotic effects. Dosage reduction is required when administered rectally.
Renal Function – Use drug with caution in patients with renal disease. Dosage reduction is required (75% of normal dose if CrCl is less than 10 mL/min).
Hepatic Function – Use drug with caution in patients with hepatic disease.
Special Risk Patients – Use drug with caution in patients with severe CV, respiratory, renal, hepatic, or endocrine disease, hypotension or shock, conditions in which hypnotic effects may be prolonged or potentiated, potential rectal surgery (rectal suspension), or presence of inflammatory, ulcerative, bleeding, or neoplastic lesions of lower bowel (rectal suspension).
Overdosage: Symptoms – Respiratory depression, hypotension, shock, apnea, occasional laryngospasm, coughing, respiratory difficulties.
Tetracaine HCl Injection
for Prolonged Spinal Anesthesia
Tetracaine hydrochloride is 2-(Dimethylamino)ethyl p-(butylamino)benzoate monohydrochloride. It is a white crystalline, odorless powder that is readily soluble in water, physiologic saline solution, and dextrose solution.
Tetracaine hydrochloride is a local anesthetic of the ester-linkage type, related to procaine.
CLINICAL PHARMACOLOGY
Parenteral administration of tetracaine hydrochloride stabilizes the neuronal membrane and prevents initiation and transmission of nerve impulses thereby effecting local anesthesia.
The onset of action is rapid, and the duration is prolonged (up to two or three hours or longer of surgical anesthesia).
Tetracaine hydrochloride is detoxified by plasma esterases to aminobenzoic acid and diethylaminoethanol.
INDICATIONS – Tetracaine hydrochloride is indicated for the production of spinal anesthesia for procedures requiring two to three hours.
CONTRAINDICATIONS
Spinal anesthesia with tetracaine hydrochloride is contraindicated in patients with known hypersensitivity to tetracaine hydrochloride or to drugs of a similar chemical configuration (ester-type local anesthetics), or aminobenzoic acid or its derivatives; and in patients for whom spinal anesthesia as a technique is contraindicated.
The decision as to whether or not spinal anesthesia should be used for an individual patient should be made by the physician after weighing the advantages with the risks and possible complications. Contraindications to spinal anesthesia as a technique can be found in standard reference texts, and usually include generalized septicemia, infection at the site of injection, certain diseases of the cerebrospinal system, uncontrolled hypotension, etc.
RESUSCITATIVE EQUIPMENT AND DRUGS SHOULD BE IMMEDIATELY AVAILABLE WHENEVER ANY LOCAL ANESTHETIC DRUG IS USED.
Large doses of local anesthetics should not be used in patients with heartblock.
Reactions resulting in fatality have occurred on rare occasions with the use of local anesthetics, even in the absence of a history of hypersensitivity.
Drug Interactions: Tetracaine hydrochloride should not be used if the patient is being treated with a sulfonamide because aminobenzoic acid inhibits the action of sulfonamides.
Carcinogenesis, Mutagenesis, Impairment of Fertility: There have beeo long-term animal studies to evaluate carcinogenic potential and reproduction studies in animals. There is no evidence from human data that tetracaine hydrochloride may be carcinogenic or that it impairs fertility.
Pregnancy Category C: There have beeo animal reproduction studies conducted with tetracaine hydrochloride. It is not known whether tetracaine hydrochloride can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Tetracaine hydrochloride should be given to a pregnant woman only if clearly needed and the potential benefits outweigh the risk.
Nursing Mothers: It is not known whether tetracaine hydrochloride is excreted in human milk; however, it is rapidly metabolized following absorption into the plasma. Because many drugs are excreted in human milk, caution should be exercised when tetracaine hydrochloride is administered to a nursing woman.
Pediatric Use: Safety and effectiveness of tetracaine hydrochloride in pediatric patients have not been established.
ADVERSE REACTIONS
Systemic adverse reactions to tetracaine hydrochloride are characteristic of those associated with other local anesthetics and can involve the central nervous system and the cardiovascular system. Systemic reactions usually result from high plasma levels due to excessive dosage, rapid adsorption, or inadvertent intravascular injection.
A small number of reactions to tetracaine hydrochloride may result from hypersensitivity, idiosyncrasy or diminished tolerance to normal dosage.
Central nervous system effects are characterized by excitation or depression. The first manifestation may be nervousness, dizziness, blurred vision, or tremors, followed by drowsiness, convulsions, unconsciousness and possibly respiratory and cardiac arrest. Since excitement may be transient or absent, the first manifestation may be drowsiness, sometimes merging into unconsciousness and respiratory and cardiac arrest. Other central nervous system effects may be nausea, vomiting, chills, constriction of the pupils, or tinnitus.
Cardiovascular system reactions include depression of the myocardium, blood pressure changes (usually hypotension), and cardiac arrest.
Allergic reactions, which may be due to hypersensitivity, idiosyncrasy, or diminished tolerance, are characterized by cutaneous lesions (eg. urticaria), edema, and other manifestations of allergy. Detection of sensitivity by skin testing is of limited value. Severe allergic reactions including anaphylaxis have rarely occurred and are not usually dose-related.
Reactions Associated with Spinal Anesthesia Techniques: Central Nervous System: post-spinal headache, meningismus, arachnoiditis, palsies, or spinal nerve paralysis. Cardiovascular: hypotension due to vasomotor paralysis and pooling of the blood in the venous bed. Respiratory: respiratory impairment or paralysis due to the level of anesthesia extending to the upper thoracic and cervical segments. Gastrointestinal: nausea and vomiting.
Treatment of Reactions: Toxic effects of local anesthetics require symptomatic treatment; there is no specific cure. The most important measure is oxygenation of the patient by maintaining an airway and supporting ventilation. Supportive treatment of the cardiovascular system includes intravenous fluids and, when appropriate, vasopressors (preferably those that stimulate the myocardium). Convulsions are usually controlled with adequate oxygenation alone but intravenous administration in small increments of a barbiturate (preferably an ultrashort-acting barbiturate such as thiopental and thiamylal), or diazepam can be utilized. Intravenous barbiturates or anticonvulsant agents should only be administered by those familiar with their use and only if ventilation and oxygenation have first been assured. In spinal anesthesia, sympathetic blockade also occurs as a pharmacological action, resulting in peripheral vasodilation and often hypotension. The extent of the hypotension will usually depend on the number of dermatomes blocked. The blood pressure should therefore be monitored in the early phases of anesthesia. If hypotension occurs, it is readily controlled by vasoconstrictors administered either by the intramuscular or the intravenous route, the dosage of which would depend on the severity of the hypotension and the response to treatment.
Dosage and Administration
As with all anesthetics, the dosage varies and depends upon the area to be anesthetized, the number of neuronal segments to be blocked, individual tolerance, and the technique of anesthesia. The lowest dosage needed to provide effective anesthesia should be administered. For specific techniques and procedures, refer to standard textbooks.
The extent and degree of spinal anesthesia depend upon dosage, specific gravity of the anesthetic solution, volume of solution used, force of the injection, level of puncture, position of the patient during and immediately after injection, etc.
When spinal fluid is added to 1% tetracaine hydrochloride injection, some turbidity results, the degree depending on the pH of the spinal fluid, the temperature of the solution during mixing, as well as the amount of drug and diluent employed. Liberation of base (which is completed within the spinal canal) is held to be essential for satisfactory results with any spinal anesthetic.
Narcotic agents are potent analgesics which are effective for the relief of severe pain. Analgesics are selective central nervous system depressants used to relieve pain. The term analgesic means “without pain”. Even in therapeutic doses, narcotic analgesics can cause respiratory depression, nausea, and drowsiness. Long term administration produces tolerance, psychic, and physical dependence called addiction.
Narcotic agents may be classified into four categories:
1) Morphine and codeine – natural alkaloids of opium.
2) Synthetic derivatives of morphine such as heroin.
3) Synthetic agents which resemble the morphine structure.
4) Narcotic antagonists which are used as antidotes for overdoses of narcotic analgesics.
The main pharmacological action of analgesics is on the cerebrum and medulla of the central nervous system. Another effect is on the smooth muscle and glandular secretions of the respiratory and gastro-intestinal tract. The precise mechanism of action is unknown although the narcotics appear to interact with specific receptor sites to interfere with pain impulses.
Receptor Site:
A schematic for an analgesic receptor site may look as shown in the graphic on the left with morphine. Three areas are needed: a flat areas to accommodate a flat nonpolar aromatic ring, a cavity to accept another series of rings perpendicular, and an anionic site for polar interaction of the amine group.
Natural Peptide Analgesics – Enkephalins:
Recently investigators have discovered two compounds in the brain called enkephalins which resemble morphine in structure. Each one is a peptide composed of 5 amino acids and differ only in the last amino acid. The peptide sequences are: tyr-gly-gly-phe-leu and tyr-gly-gly-phe-met. Molecular models show that the structures of the enkephalins has some similarities with morphine. The main feature in common appears to be the aromatic ring with the -OH group attached (tyr). Methadone and other similar analgesics have 2 aromatic rings which would be similar to the enkephalins (tyr and phe).
Analgesics may relieve pain by preventing the release of acetylcholine. Enkephalin molecules are released from a nerve cell and bind to analgesic receptor sites on the nerve cell sending the impulse. The binding of enkephalin or morphine-like drugs changes the shape of the nerve sending the impulse in such a fashion as to prevent the cell from releasing acetylcholine. As a result, the pain impulse cannot be transmitted and the brain does not preceive pain.
CLINICAL USE OF OPIOID ANALGESICS
A. ANALGESIA
Severe, constant pain is usually relieved with opioid analgesics with high intrinsic activity; whereas sharp, intermittent pain does not appear to be as effectively controlled.
The pain associated with cancer and other terminal illnesses must be treated aggressively and often requires a multidisciplinary approach for effective management. Such conditions may require continuous use of potent opioid analgesics and are associated with some degree of tolerance and dependence. However, this should not be used as a barrier to providing patients with the best possible care and quality of life. Research in the hospice movement has demonstrated that fixed-interval administration of opioid medication (ie, a regular dose at a scheduled time) is more effective in achieving pain relief than dosing on demand. New dosage forms of opioids that allow slower release of the drug are now available, eg, sustained-release forms of morphine (MSContin) and oxycodone (OxyContin). Their purported advantage is a longer and more stable level of analgesia.
If disturbances of gastrointestinal function prevent the use of oral sustained-release morphine, the fentanyl transdermal system (fentanyl patch) can be used over long periods. Furthermore, buccal transmucosal fentanyl can be used for episodes of breakthrough pain (see G. Alternative Routes of Administration). Administration of strong opioids by nasal insufflation has been shown to be efficacious, and nasal preparations are now available in some countries. Approval of such formulations in the USA is growing. In addition, stimulant drugs such as the amphetamines have been shown to enhance the analgesic actions of the opioids and thus may be very useful adjuncts in the patient with chronic pain.
Opioid analgesics are often used during obstetric labor. Because opioids cross the placental barrier and reach the fetus, care must be taken to minimize neonatal depression. If it occurs, immediate injection of the antagonist naloxone will reverse the depression. The phenylpiperidine drugs (eg, meperidine) appear to produce less depression, particularly respiratory depression, iewborn infants than does morphine; this may justify their use in obstetric practice.
The acute, severe pain of renal and biliary colic often requires a strong agonist opioid for adequate relief. However, the drug-induced increase in smooth muscle tone may cause a paradoxical increase in pain secondary to increased spasm. An increase in the dose of opioid is usually successful in providing adequate analgesia.
B. ACUTE PULMONARY EDEMA
The relief produced by intravenous morphine in dyspnea from pulmonary edema associated with left ventricular failure is remarkable. Proposed mechanisms include reduced anxiety (perception of shortness of breath), and reduced cardiac preload (reduced venous tone) and afterload (decreased peripheral resistance). Morphine can be particularly useful when treating painful myocardial ischemia with pulmonary edema.
Suppression of cough can be obtained at doses lower than those needed for analgesia. However, in recent years the use of opioid analgesics to allay cough has diminished largely because a number of effective synthetic compounds have been developed that are neither analgesic nor addictive. These agents are discussed below.
D. DIARRHEA
Diarrhea from almost any cause can be controlled with the opioid analgesics, but if diarrhea is associated with infection such use must not substitute for appropriate chemotherapy. Crude opium preparations (eg, paregoric) were used in the past to control diarrhea, but now synthetic surrogates with more selective gastrointestinal effects and few or no CNS effects, eg, diphenoxylate, are used. Several preparations are available specifically for this purpose
E. SHIVERING
Although all opioid agonists have some propensity to reduce shivering, meperidine is reported to have the most pronounced anti-shivering properties. It is interesting that meperidine apparently blocks shivering through its action on subtypes of the 2 adrenoceptor.
F. APPLICATIONS IN ANESTHESIA
The opioids are frequently used as premedicant drugs before anesthesia and surgery because of their sedative, anxiolytic, and analgesic properties. They are also used intraoperatively both as adjuncts to other anesthetic agents and, in high doses (eg, 0.02-0.075 mg/kg of fentanyl), as a primary component of the anesthetic regimen. Opioids are most commonly used in cardiovascular surgery and other types of high-risk surgery in which a primary goal is to minimize cardiovascular depression. In such situations, mechanical respiratory assistance must be provided.
Because of their direct action on the superficial neurons of the spinal cord dorsal horn, opioids can also be used as regional analgesics by administration into the epidural or subarachnoid spaces of the spinal column. A number of studies have demonstrated that long-lasting analgesia with minimal adverse effects can be achieved by epidural administration of 3-5 mg of morphine, followed by slow infusion through a catheter placed in the epidural space. It was initially assumed that the epidural application of opioids might selectively produce analgesia without impairment of motor, autonomic, or sensory functions other than pain. However, respiratory depression can occur after the drug is injected into the epidural space and may require reversal with naloxone. Effects such as pruritus and nausea and vomiting are common after epidural and subarachnoid administration of opioids and may also be reversed with naloxone if necessary. Currently, the epidural route is favored because adverse effects are less common. Morphine is the most frequently used agent, but the use of low doses of local anesthetics in combination with fentanyl infused through a thoracic epidural catheter has also become an accepted method of pain control in patients recovering from major upper abdominal surgery. In rare cases, chronic pain management specialists may elect to surgically implant a programmable infusion pump connected to a spinal catheter for continuous infusion of opioids or other analgesic compounds.
G. ALTERNATIVE ROUTES OF ADMINISTRATION
Rectal suppositories of morphine and hydromorphone have long been used when oral and parenteral routes are undesirable. The transdermal patch provides stable blood levels of drug and better pain control while avoiding the need for repeated parenteral injections. Fentanyl has been the most successful opioid in transdermal application and finds great use in patients experiencing chronic pain. The intranasal route avoids repeated parenteral drug injections and the first-pass metabolism of orally administered drugs. Butorphanol is the only opioid currently available in the USA in a nasal formulation, but more are expected. Another alternative to parenteral administration is the buccal transmucosal route, which uses a fentanyl citrate lozenge or a “lollipop” mounted on a stick.
Another type of pain control called patient-controlled analgesia (PCA) is now in widespread use for the management of breakthrough pain. With PCA, the patient controls a parenteral (usually intravenous) infusion device by depressing a button to deliver a preprogrammed dose of the desired opioid analgesic. Claims of better pain control using less opioid are supported by well-designed clinical trials, making this approach very useful in postoperative pain control. However, health care personnel must be very familiar with the use of PCAs to avoid overdosage secondary to misuse or improper programming. There is a proven risk of respiratory depression with hypoxia that requires careful monitoring of vital signs and sedation level.
Toxicity Undesired Effects
Direct toxic effects of the opioid analgesics that are extensions of their acute pharmacologic actions include respiratory depression, nausea, vomiting, and constipation. In addition, tolerance and dependence, diagnosis and treatment of overdosage, as well as contraindications must be considered.
A. TOLERANCE AND DEPENDENCE
Drug dependence of the opioid type is marked by a relatively specific withdrawal or abstinence syndrome. Just as there are pharmacologic differences between the various opioids, there are also differences in psychologic dependence and the severity of withdrawal effects. For example, withdrawal from dependence on a strong agonist is associated with more severe withdrawal signs and symptoms than withdrawal from a mild or moderate agonist. Administration of an opioid antagonist to an opioid-dependent person is followed by brief but severe withdrawal symptoms (see antagonist-precipitated withdrawal, below). The potential for physical and psychologic dependence of the partial agonist-antagonist opioids appears to be less than that of the agonist drugs.
1. Tolerance Although development of tolerance begins with the first dose of an opioid, tolerance generally does not become clinically manifest until after 2-3 weeks of frequent exposure to ordinary therapeutic doses. Tolerance develops most readily when large doses are given at short intervals and is minimized by giving small amounts of drug with longer intervals between doses.
Depending on the compound and the effect measured, the degree of tolerance may be as great as 35-fold. Marked tolerance may develop to the analgesic, sedating, and respiratory depressant effects. It is possible to produce respiratory arrest in a nontolerant person with a dose of 60 mg of morphine, whereas in addicts maximally tolerant to opioids as much as 2000 mg of morphine taken over a 2- or 3-hour period may not produce significant respiratory depression. Tolerance also develops to the antidiuretic, emetic, and hypotensive effects but not to the miotic, convulsant, and constipating actions.
Tolerance to the sedating and respiratory effects of the opioids dissipates within a few days after the drugs are discontinued. Tolerance to the emetic effects may persist for several months after withdrawal of the drug. The rates at which tolerance appears and disappears, as well as the degree of tolerance, may also differ considerably among the different opioid analgesics and among individuals using the same drug. For instance, tolerance to methadone develops more slowly and to a lesser degree than to morphine.
Tolerance also develops to analgesics with mixed receptor effects but to a lesser extent than to the agonists. Such effects as hallucinations, sedation, hypothermia, and respiratory depression are reduced after repeated administration of the mixed receptor drugs. However, tolerance to the latter agents does not generally include cross-tolerance to the agonist opioids. It is also important to note that tolerance does not develop to the antagonist actions of the mixed agents or to those of the pure antagonists.
Cross-tolerance is an extremely important characteristic of the opioids, ie, patients tolerant to morphine show a reduction in analgesic response to other agonist opioids. This is particularly true of those agents with primarily u-receptor agonist activity. Morphine and its congeners exhibit cross-tolerance not only with respect to their analgesic actions but also to their euphoriant, sedative, and respiratory effects. However, the cross-tolerance existing among the u-receptor agonists can often be partial or incomplete. This clinical observation has led to the concept of “opioid rotation,” which has been used in the treatment of cancer pain for many years. A patient who is experiencing decreasing effectiveness of one opioid analgesic regimen is “rotated” to a different opioid analgesic (eg, morphine to hydromorphone; hydromorphone to methadone) and typically experiences significantly improved analgesia at a reduced overall equivalent dosage. Another approach is to “recouple” opioid receptor function through the use of adjunctive nonopioid agents. NMDA-receptor antagonists (eg, ketamine) have shown promise in preventing or reversing opioid-induced tolerance in animals and humans. Use of these agents, especially ketamine, is increasing because well-controlled studies have shown clinical effectiveness in reducing postoperative pain and opioid requirements in opioid-tolerant patients.
The novel use of -receptor antagonists with u-receptor agonists is also emerging as a strategy to avoid the development of tolerance. This idea has developed around the observation that mice lacking the opioid receptor fail to develop tolerance to morphine.
2. Physical dependence The development of physical dependence is an invariable accompaniment of tolerance to repeated administration of an opioid of the u type. Failure to continue administering the drug results in a characteristic withdrawal or abstinence syndrome that reflects an exaggerated rebound from the acute pharmacologic effects of the opioid.
The signs and symptoms of withdrawal include rhinorrhea, lacrimation, yawning, chills, gooseflesh (piloerection), hyperventilation, hyperthermia, mydriasis, muscular aches, vomiting, diarrhea, anxiety, and hostility. The number and intensity of the signs and symptoms are largely dependent on the degree of physical dependence that has developed. Administration of an opioid at this time suppresses abstinence signs and symptoms almost immediately.
The time of onset, intensity, and duration of abstinence syndrome depend on the drug previously used and may be related to its biologic half-life. With morphine or heroin, withdrawal signs usually start within 6-10 hours after the last dose. Peak effects are seen at 36-48 hours, after which most of the signs and symptoms gradually subside. By 5 days, most of the effects have disappeared, but some may persist for months. In the case of meperidine, the withdrawal syndrome largely subsides within 24 hours, whereas with methadone several days are required to reach the peak of the abstinence syndrome, and it may last as long as 2 weeks. The slower subsidence of methadone effects is associated with a less intense immediate syndrome, and this is the basis for its use in the detoxification of heroin addicts. After the abstinence syndrome subsides, tolerance also disappears, as evidenced by a restoration in sensitivity to the opioid agonist. However, despite the loss of physical dependence on the opioid, craving for it may persist for many months.
A transient, explosive abstinence syndromeantagonist-precipitated withdrawalcan be induced in a subject physically dependent on opioids by administering naloxone or another antagonist. Within 3 minutes after injection of the antagonist, signs and symptoms similar to those seen after abrupt discontinuance appear, peaking in 10-20 minutes and largely subsiding after 1 hour. Even in the case of methadone, withdrawal of which results in a relatively mild abstinence syndrome, the antagonist-precipitated abstinence syndrome may be very severe.
In the case of agents with mixed effects, withdrawal signs and symptoms can be induced after repeated administration followed by abrupt discontinuance of pentazocine, cyclazocine, or nalorphine, but the syndrome appears to be somewhat different from that produced by morphine and other agonists. Anxiety, loss of appetite and body weight, tachycardia, chills, increase in body temperature, and abdominal cramps have beeoted.
3. Psychologic dependence The euphoria, indifference to stimuli, and sedation usually caused by the opioid analgesics, especially when injected intravenously, tend to promote their compulsive use. In addition, the addict experiences abdominal effects that have been likened to an intense sexual orgasm. These factors constitute the primary reasons for opioid abuse liability and are strongly reinforced by the development of physical dependence.
Obviously, the risk of causing dependence is an important consideration in the therapeutic use of these drugs. Despite that risk, under no circumstances should adequate pain relief ever be withheld simply because an opioid exhibits potential for abuse or because legislative controls complicate the process of prescribing narcotics. Furthermore, certain principles can be observed by the clinician to minimize problems presented by tolerance and dependence when using opioid analgesics:
Establish therapeutic goals before starting opioid therapy. This tends to limit the potential for physical dependence. The patient and his or her family should be included in this process.
Once a therapeutic dose is established, attempt to limit dosage to this level. This goal is facilitated by use of a written treatment contract which specifically prohibits early refills and having multiple prescribing physicians.
Instead of opioid analgesicsespecially in chronic managementconsider using other types of analgesics or compounds exhibiting less pronounced withdrawal symptoms on discontinuance.
Frequently evaluate continuing analgesic therapy and the patient’s need for opioids.
B. DIAGNOSIS AND TREATMENT OF OPIOID OVERDOSAGE
Intravenous injection of naloxone dramatically reverses coma due to opioid overdose but not that due to other CNS depressants. Use of the antagonist should not, of course, delay the institution of other therapeutic measures, especially respiratory support.
C. CONTRAINDICATIONS AND CAUTIONS IN THERAPY
1. Use of pure agonists with weak partial agonists When a weak partial agonist such as pentazocine is given to a patient also receiving a full agonist (eg, morphine), there is a risk of diminishing analgesia or even inducing a state of withdrawal; combining full agonist with partial agonist opioids should be avoided.
2. Use in patients with head injuries Carbon dioxide retention caused by respiratory depression results in cerebral vasodilation. In patients with elevated intracranial pressure, this may lead to lethal alterations in brain function.
3. Use during pregnancy In pregnant women who are chronically using opioids, the fetus may become physically dependent in utero and manifest withdrawal symptoms in the early postpartum period. A daily dose as small as 6 mg of heroin (or equivalent) taken by the mother can result in a mild withdrawal syndrome in the infant, and twice that much may result in severe signs and symptoms, including irritability, shrill crying, diarrhea, or even seizures. Recognition of the problem is aided by a careful history and physical examination. When withdrawal symptoms are judged to be relatively mild, treatment is aimed at control of these symptoms with such drugs as diazepam; with more severe withdrawal, camphorated tincture of opium (paregoric; 0.4 mg of morphine/mL) in an oral dose of 0.12-0.24 mL/kg is used. Oral doses of methadone (0.1-0.5 mg/kg) have also been used.
4. Use in patients with impaired pulmonary function In patients with borderline respiratory reserve, the depressant properties of the opioid analgesics may lead to acute respiratory failure.
5. Use in patients with impaired hepatic or renal function Because morphine and its congeners are metabolized primarily in the liver, their use in patients in prehepatic coma may be questioned. Half-life is prolonged in patients with impaired renal function, and morphine and its active glucuronide metabolite may accumulate; dosage can often be reduced in such patients.
6. Use in patients with endocrine disease Patients with adrenal insufficiency (Addison’s disease) and those with hypothyroidism (myxedema) may have prolonged and exaggerated responses to opioids.
Drug Interactions
Because seriously ill or hospitalized patients may require a large number of drugs, there is always a possibility of drug interactions when the opioid analgesics are administered.
The following section describes the most important and widely used opioid analgesics, along with features peculiar to specific agents. Data about doses approximately equivalent to 10 mg of intramuscular morphine, oral versus parenteral efficacy, duration of analgesia, and intrinsic activity (maximum efficacy) are presented in
1. Phenanthrenes
Morphine, hydromorphone, and oxymorphone are strong agonists useful in treating severe pain. These prototypic agents have been described in detail above.
Heroin (diamorphine, diacetylmorphine) is potent and fast-acting, but its use is prohibited in the USA and Canada. In recent years, there has been considerable agitation to revive its use. However, double-blind studies have not supported the claim that heroin is more effective than morphine in relieving severe chronic pain, at least when given by the intramuscular route.
2. Phenylheptylamines
Methadone has undergone a dramatic revival as a potent and clinically useful analgesic. It can be administered by the oral, intravenous, subcutaneous, spinal, and rectal routes. It is well absorbed from the gastrointestinal tract and its bioavailability far exceeds that of oral morphine.
Methadone is not only a potent u-receptor agonist but its racemic mixture of D- and L-methadone isomers can also block both NMDA receptors and monoaminergic reuptake transporters. These nonopioid receptor properties may help explain its ability to relieve difficult-to-treat pain (neuropathic, cancer pain), especially when a previous trial of morphine has failed. In this regard, when analgesic tolerance or intolerable side effects have developed with the use of increasing doses of morphine or hydromorphone, “opioid rotation” to methadone has provided superior analgesia at 10-20% of the morphine-equivalent daily dose. In contrast to its use in suppressing symptoms of opioid withdrawal, use of methadone as an analgesic typically requires administration at intervals of no more than 8 hours. However, given methadone’s highly variable pharmacokinetics and long half-life (25-52 hours), initial administration should be closely monitored to avoid potentially harmful adverse effects, especially respiratory depression.
Methadone is widely known for its use in the treatment of opioid abuse. Tolerance and physical dependence develop more slowly with methadone than with morphine. The withdrawal signs and symptoms occurring after abrupt discontinuance of methadone are milder, although more prolonged, than those of morphine. These properties make methadone a useful drug for detoxification and for maintenance of the chronic relapsing heroin addict.
For detoxification of a heroin-dependent addict, low doses of methadone (5-10 mg orally) are given two or three times daily for 2 or 3 days. Upon discontinuing methadone, the addict experiences a mild but endurable withdrawal syndrome.
For maintenance therapy of the opioid recidivist, tolerance to 50-100 mg/d of oral methadone may be deliberately produced; in this state, the addict experiences cross-tolerance to heroin, which prevents most of the addiction-reinforcing effects of heroin. One rationale of maintenance programs is that blocking the reinforcement obtained from abuse of illicit opioids removes the drive to obtain them, thereby reducing criminal activity and making the addict more amenable to psychiatric and rehabilitative therapy. The pharmacologic basis for the use of methadone in maintenance programs is sound and the sociologic basis is rational, but some methadone programs fail because nonpharmacologic management is inadequate.
The concurrent administration of methadone to heroin addicts known to be recidivists has been questioned because of the increased risk of overdose death secondary to respiratory arrest. Buprenorphine, a partial u-receptor agonist with long-acting properties, has been found to be effective in opioid detoxification and maintenance programs and is presumably associated with a lower risk of such overdose fatalities.
3. Phenylpiperidines
Fentanyl is one of the most widely used agents in this family of synthetic opioids. The fentanyl subgroup now includes sufentanil, alfentanil, and remifentanil in addition to the parent compound, fentanyl.
These opioids differ mainly in their potency and biodisposition. Sufentanil is five to seven times more potent than fentanyl. Alfentanil is considerably less potent than fentanyl, but acts more rapidly and has a markedly shorter duration of action. Remifentanil is metabolized very rapidly by blood and nonspecific tissue esterases, making its pharmacokinetic and pharmacodynamic half-lives extremely short. Such properties are useful when these compounds are used in anesthesia practice. Although fentanyl is now the predominant analgesic in the phenylpiperidine class, meperidine continues to be widely used. This older opioid has significant antimuscarinic effects, which may be a contraindication if tachycardia would be a problem. Meperidine is also reported to have a negative inotropic action on the heart. In addition, it has the potential for producing seizures secondary to accumulation of its metabolite, normeperidine, in patients receiving high doses or with concurrent renal failure.
4. Morphinans
Levorphanol is a synthetic opioid analgesic closely resembling morphine in its action.
Codeine, oxycodone, dihydrocodeine, and hydrocodone are all somewhat less efficacious than morphine (they are partial agonists) or have adverse effects that limit the maximum tolerated dose when one attempts to achieve analgesia comparable to that of morphine.
These compounds are rarely used alone but are combined in formulations containing aspirin or acetaminophen and other drugs.
2. Phenylheptylamines
Propoxyphene is chemically related to methadone but has low analgesic activity. Various studies have reported its potency at levels ranging from no better than placebo to half as potent as codeine; that is, 120 mg propoxyphene = 60 mg codeine. Its true potency probably lies somewhere between these extremes, and its analgesic effect is additive to that of an optimal dose of aspirin. However, its low efficacy makes it unsuitable, even in combination with aspirin, for severe pain. Although propoxyphene has a low abuse liability, the increasing incidence of deaths associated with its misuse has caused it to be scheduled as a controlled substance with low potential for abuse.
3. Phenylpiperidines
Diphenoxylate and its metabolite, difenoxin, are not used for analgesia but for the treatment of diarrhea. They are scheduled for minimal control (difenoxin is schedule IV, diphenoxylate schedule V) because the likelihood of their abuse is remote. The poor solubility of the compounds limits their use for parenteral injection. As antidiarrheal drugs, they are used in combination with atropine. The atropine is added in a concentration too low to have a significant antidiarrheal effect but is presumed to further reduce the likelihood of abuse.
Loperamide is a phenylpiperidine derivative used to control diarrhea. Its potential for abuse is considered very low because of its limited access to the brain. It is therefore available without a prescription.
The usual dose with all of these antidiarrheal agents is two tablets to start and then one tablet after each diarrheal stool.
OPIOIDS WITH MIXED RECEPTOR ACTIONS
Care should be takeot to administer any partial agonist or drug with mixed opioid receptor actions to patients receiving pure agonist drugs because of the unpredictability of both drugs’ effects: reduction of analgesia or precipitation of an explosive abstinence syndrome may result.
1. Phenanthrenes
Nalbuphine is a strong k receptor agonist and a u receptor antagonist; it is given parenterally. At higher doses there seems to be a definite ceiling¾not noted with morphine¾to the respiratory depressant effect. Unfortunately, when respiratory depression does occur, it may be relatively resistant to naloxone reversal.
Buprenorphine is a potent and long-acting phenanthrene derivative that is a partial u receptor agonist. When administered orally, the sublingual route is preferred to avoid significant first-pass effect. Its long duration of action is due to its slow dissociation from u receptors. This property renders its effects resistant to naloxone reversal. Its clinical applications are much like those of nalbuphine. In addition, studies continue to suggest that buprenorphine is as effective as methadone in the detoxification and maintenance of heroin abusers. Buprenorphine was approved by the US Food and Drug Administration (FDA) in 2002 for the management of opioid dependence. In contrast to methadone, high-dose administration of buprenorphine results in a u opioid antagonist action, limiting its properties of analgesia and respiratory depression. Moreover, buprenorphine is also available combined with a pure u opioid antagonist to help prevent its diversion for illicit intravenous abuse.
2. Morphinans
Butorphanol produces analgesia equivalent to nalbuphine and buprenorphine but appears to produce more sedation at equianalgesic doses. Butorphanol is considered to be predominantly a k agonist. However, it may also act as a partial agonist or antagonist at the u-receptor.
3. Benzomorphans
Pentazocine is a k agonist with weak u antagonist or partial agonist properties. It is the oldest mixed agent available. It may be used orally or parenterally. However, because of its irritant properties, the injection of pentazocine subcutaneously is not recommended.
MISCELLANEOUS
Tramadol is a centrally acting analgesic whose mechanism of action is predominantly based on blockade of serotonin reuptake. Tramadol has also been found to inhibit norepinephrine transporter function. Because it is only partially antagonized by naloxone, it is believed to be only a weak u-receptor agonist. The recommended dosage is 50-100 mg orally four times daily. Toxicity includes association with seizures; the drug is relatively contraindicated in patients with a history of epilepsy and for use with other drugs that lower the seizure threshold. Other side effects include nausea and dizziness, but these symptoms typically abate after several days of therapy. It is surprising that no clinically significant effects on respiration or the cardiovascular system have thus far been reported. Given the fact that the analgesic action of tramadol is largely independent of u receptor action, tramadol may serve as an adjunct with pure opioid agonists in the treatment of chronic neuropathic pain.
ANTITUSSIVES
The opioid analgesics are among the most effective drugs available for the suppression of cough. This effect is often achieved at doses below those necessary to produce analgesia. The receptors involved in the antitussive effect appear to differ from those associated with the other actions of opioids. For example, the antitussive effect is also produced by stereoisomers of opioid molecules that are devoid of analgesic effects and addiction liability
The physiologic mechanism of cough is complex, and little is known about the specific mechanism of action of the opioid antitussive drugs. It is likely that both central and peripheral effects play a role.
The opioid derivatives most commonly used as antitussives are dextromethorphan, codeine, levopropoxyphene, and noscapine (levopropoxyphene and noscapine are not available in the USA). Although these agents (other than codeine) are largely free of the adverse effects associated with the opioids, they should be used with caution in patients taking monoamine oxide inhibitors. Antitussive preparations usually also contain expectorants to thin and liquefy respiratory secretions.
Dextromethorphan is the dextrorotatory stereoisomer of a methylated derivative of levorphanol. It is purported to be free of addictive properties and produces less constipation than codeine. The usual antitussive dose is 15-30 mg three or four times daily. It is available in many over-the-counter products. Dextromethorphan has also been found to enhance the analgesic action of morphine and presumably other u-receptor agonists.
Codeine, as noted, has a useful antitussive action at doses lower than those required for analgesia. Thus, 15 mg are usually sufficient to relieve cough.
Levopropoxyphene is the stereoisomer of the weak opioid agonist dextropropoxyphene. It is devoid of opioid effects, although sedation has been described as a side effect. The usual antitussive dose is 50-100 mg every 4 hours.
Narcotic Antagonists:
Narcotic Antagonists prevent or abolish excessive respiratory depression caused by the administration of morphine or related compounds. They act by competing for the same analgesic receptor sites. They are structurally related to morphine with the exception of the group attached to nitrogen.
Nalorphine precipitates withdrawal symptoms and produces behavioral disturbances in addition to the antogonism action. Naloxane is a pure antagonist with no morphine like effects. It blocks the euphoric effect of heroin when given before heroin.
Naltrexone became clinically available in 1985 as a new narcotic antagonist. Its actions resemble those of naloxone, but naltrexone is well is well absorbed orally and is long acting, necessitating only a dose of 50 to 100 mg. Therefore, it is useful iarcotic treatment programs where it is desired to maintain an individual on chronic therapy with a narcotic antagonist. In individuals taking naltrexone, subsequent injection of an opiate will produce little or no effect. Naltrexone appears to be particularly effective for the treatment of narcotic dependence in addicts who have more to gain by being drug-free rather than drug dependant.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are some of the most widely used drugs in the
Acetaminophen also is a widely used agent. It has antipyretic and analgesic properties but does not have the anti-inflammatory effects of the salicylates or the NSAIDs. Because many anti-inflammatory drugs are available over the counter (OTC), there is a potential for abuse and overdosing. In addition, patients may take these drugs and block the signs and symptoms of a present illness, thus potentially causing the misdiagnosis of a problem. Patients also may combine these drugs and unknowingly induce toxicity. All of these drugs have adverse effects that can be dangerous if toxic levels of drug circulate in the body.
Sensitivity to Anti-inflammatory Drugs
African Americans have a documented decreased sensitivity to the pain-relieving effects of many of the anti-inflammatory drugs. They do, however, have an increased risk of developing gastrointestinal adverse effects to these drugs, including acetaminophen. This should be taken into consideration when using these drugs as analgesics. Increased dosages may be needed to achieve a pain-blocking effect, but the increased dosage will put these patients at an even greater risk for development of the adverse GI effects associated with these drugs. These patients should be monitored closely, and efforts should be made to decrease pain using nondrug measures such as positioning, environmental control, physical therapy, warm soaks, and so on. If African American patients are prescribed anti-inflammatory drugs, they should be educated about the signs and symptoms of gastrointestinal bleeding and what to report. They also should be monitored regularly for any adverse reactions to these drugs.
Salicylates
Salicylates are some of the oldest anti-inflammatory drugs used. They were extracted from willow bark, poplar trees, and other plants by ancient peoples to treat fever, pain, and what we now call inflammation. The synthetic salicylates include the following drugs (see also Table)
Propionic Acids
Fenoprofen (Nalfon) is used to treat pain and manage arthritis.
Flurbiprofen (Ansaid) is used for the long-term management of arthritis and as a topical preparation for managing pain after eye surgery.
Ibuprofen (Motrin, Advil, and others) is used as an OTC pain medication and for long-term management of arthritis pain and dysmenorrhea; it is the most widely used of the NSAIDs.
Ketoprofen (Orudis) is available for short-term management of pain and as a topical agent to relieve ocular itching caused by seasonal rhinitis.
Naproxen (Naprosyn) is available for OTC pain relief and to treat arthritis and dysmenorrhea.
Oxaprozin (Daypro) is very successfully used to manage arthritis.
Acetic Acids
Diclofenac (Voltaren, Cataflam) is used to treat acute and long-term pain associated with inflammatory conditions.
Etodolac (Lodine) is widely used for arthritis pain.
Indomethacin (Indocin) is available in oral, topical, and rectal preparations for the relief of moderate to severe pain associated with inflammatory conditions and in intravenous form to promote closure of the patent ductus arteriosus in premature infants.
Ketorolac (Toradol) is used for short-term management of pain and topically to relieve ocular itching.
Nabumetone (Relafen) is used to treat acute and chronic arthritis pain.
Sulindac (Clinoril) is used for long- and short-term treatment of the signs and symptoms of various inflammatory conditions.
Tolmetin (Tolectin) is used to treat acute attacks of rheumatoid arthritis and juvenile arthritis.
Fenamates
Mefenamic acid (Ponstel) is used only for short-term treatment of pain.
Piroxicam (Feldene) is used to treat acute and chronic arthritis.
Diflunisal (Dolobid) is used for moderate pain and for the treatment of arthritis.
Oxicam Derivative
Meloxicam (Mobic) is used for the relief of the signs and symptoms of juvenile arthritis, osteoarthritis, and rheumatoid arthritis.
Cyclooxygenase-2 Inhibitor
Celecoxib (Celebrex) is used for the acute and long-term treatment of arthritis, particularly in patients who cannot tolerate the GI effects of other NSAIDs; for acute pain in adults; for ankylosing spondylitis; and for primary dysmenorrhea. Celecoxib is also being studied for its potential ability to block angiogenesis in various cancers.
References:
1. White JL, Durieux ME: Clinical pharmacology of local anesthetics. Anesthesiol Clin North Am 2005;23:73
2. White PF: The changing role of non-opioid analgesic techniques in the management of postoperative pain. Anesth Analg 2005;101:S5
3. Trapani G et al: Propofol in anesthesia. Mechanism of action, structure-activity relationships, and drug delivery. Curr Med Chem 2000;7:249.
