GENERAL ANESTHETICS
(Aether pro narcosi, Isophluranum, Nitrogenium oxydatum, Propanididum, Ketaminum,. Thiopentalum-natrium, Natrii oxibutas)
HYPNOTIC AGENTS. ANTIEPILEPTIC DRUGS. ANTIPARKINSONICAL PREPARATIONS
(Teturam (dysulphiram), Phenasepamum, dipheninum, Carbamasepinum, Clopamidum, Ethosuximidum, Natrii valproas, Lamotridzin, Nitasepamum, Bromisovalum, Chlorali hydras, Zolpidem, Zopiclon, Levodopa, Midantanum, Cyclodolum)
NARCOTIC AND NON-NARCOTIC ANALGESICS
(Morphini hydrochloridum, Omnoponum, Codeini phosphas, Promedolum, Phentanylum, Pentazocini hydrichlorium, Tramadolum, Buprenorphinum, Nalorphini hydrochloridum, Naloxoni hydrochloridum, Naltrexonum, acidum acetylsalicilicum, analginum, Acidum mephenamicum, Paracetamolum, Ibuprophenum, Diclofenac-natrium, Indometacinum, Piroxicamum, Amisonum, Meloxicsm (Movalis), Celecoxib)
General anesthetics
The attempted suppression of the pain of surgical procedures by the use of drugs dates from ancient times and include the oral administration of ethanol and opiates. The first scientific demonstration of drug-induced anesthesia during surgery was in 1864, when William Morton used diethyl ether in Boston Scotland
Intubation & extubation during general anaesthesia – Google Video
The state of “general anesthesia” usually includes analgesia, amnesia, loss of consciousness, inhibition of sensory and autonomic reflexes, and skeletal muscle relaxation. The extent to which any individual anesthetic drug can exert these effects is variable to be able to induce anesthesia smoothly and rapidly as well as to ensure rapid recovery from the effects of the anesthetic. An ideal anesthetic drug would also possess a wide margin of safety and be devoid of adverse effects. No single anesthetic agent is capable of achieving all of these desirable effects without some disadvantages when used alone. Thus, the modern practice of anesthesia involves the use of combinations of drugs, taking advantage of their individual desirable properties while attempting to minimize their potential for harmful actions. Balanced anesthesia includes the administration of medications preoperativelу for sedation and analgesia, the use of neuromuscular blocking drugs intraoperatively, and the use of both intravenous and inhaled anesthetic drugs.
Types of general anesthetics
Sites and mechanisms of action of drugs used for anesthesia.
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ANESTHETIC CLASSIFICATIONS
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General anesthetics are usually given by inhalation or by intravenous injection.
Inhalation Anesthetics: These are gases or volatile liquids (volatility is expressed as vapor pressure that vary greatly in the rate at which they induce anesthesia, potency, degree of circulatory or respiratory depression produced, muscle relaxant action, and analgesic effects. Inhalation anesthetics have advantages over intravenous agents in that the depth of anesthesia can be changed rapidly by altering the inhaled concentration and, because of their rapid elimination, they do not contribute to postoperative respiratory depression.
Intravenous Anesthetics: Cause rapid loss of consciousness and induction is pleasant. However, they produce little muscle relaxation and frequently do not obtund reflexes adequately. Repeated administration results in accumulation and prolongs the recovery time. Since these agents have little if any analgesic activity, they are seldom used alone except in brief minor procedures.
Ketamine (ketaject, ketalar), may be given intravenously or intramuscularly. It induces a dissociative state in which the patient may appear to be awake but is unconscious and does not respond to pain. Ketamine has been used in various diagnostic procedures; in brief, minor surgical procedures that do not require substantial skeletal muscle relaxation; and for changing dressings in burn patients. It also may be used as an induction agent, especially when cardiovascular or sympathetic depression is undesirable. When combined with nitrous oxide, diazepam, and a muscle relaxant, ketamine may be employed for major surgical procedures. Ketamine increases cerebral blood flow and postoperative hallucinations occur occasionally.
Inhalational Agents: Diethyl ether, halothane nitrous oxide, enflurane, methoxyflurane, cyclopropane, chloroform. Nitrous oxide, a gas at ambient temperature and pressure, continues to be an important component of many anesthesia regimens. Halothane, enflurane, and methoxyflurane are volatile liquids. Other inhalational agents include ether, cyclopropane, and chloroform, which have limited current use for reasons that include potential flammability (ether, cyclopropane) and organ toxicity (chloroform).
Intravenous Agents
Several drugs are used intravenuoisly to achieve anesthesia:
(1) Thiobarbiturates (thiopental, methohexital).
(2) Narcotic analgesics and neuroleptics.
(3) Arylcyclohexylamines (ketamine), which produce a state called dissociative anesthesia.
(4) Miscellaneous drugs (etomidate, steroid anesthetics, propanidid).
Signs and stages of anesthesia
Since the introduction of general anesthetics, attempts have been made to correlate their observable effects or signs with the depth of anesthesia. Descriptions of the signs and stages of anesthesia originate mainly from observations of the effects of diethyl enter, which has a slow onset of central action due to its high solubility in blood. These stages and signs may not occur so readily with the more rapidly acting modern inhaled anesthetics and are unusual with intravenous agents. Many of the signs refer to the effects anesthetic agents on respiration, reflex activity, and muscle tone. Traditionally, anesthetic effects are divided into 4 stages of increasing depth of CNS depression.
I. Stage of analgesia: The patient initially experiences analgesia without amnesia. However, later in stage I, both analgesia and amnesia ensue.
II. Stage of excitement: During this stage, the patient often appears to be delirious and excited but definitely is amnesic. Respiration is irregular both in volume and rate, and retching and vomiting may occur. Incontinence and struggling sometimes occur. 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: With the beginning of regular respiration, this stage extends to complete cessation of spontaneous respiration. 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 sings of increasing depth of anesthesia.
IV. Stage of medullary depression: When spontaneous respiration ceases, stage IV is present. This stage of anesthesia obviously includes severe depression of the respiratory center in the medulla and the vasomotor center as well. Without full circulatory and respiratory support, coma and death rapidly ensue.
General anesthesia is the induction of a balanced state of unconsciousness, accompanied by the absence of pain sensation and the paralysis of skeletal muscle over the entire body. It is induced through the administration of anesthetic drugs and is used during major surgery and other invasive surgical procedures.
General anesthesia is intended to bring about five distinct states during surgery:
- analgesia, or pain relief
- amnesia, or loss of memory of the procedure
- loss of consciousness
- motionlessness
- weakening of autonomic responses
Precautions
A complete medical history, including a history of allergies in family members, is an important precaution. Patients may have a potentially fatal allergic response to anesthesia known as malignant hyperthermia, even if there is no previous personal history of reaction.
General anesthetics should be administered only by board-certified medical professionals. Anesthesia providers consider many factors, including a patient’s age, weight, allergies to medications, medical history, and general health when deciding which anesthetic or combination of anesthetics to use. The American Society of Anesthesiologists has compiled guidelines for classifying patients according to risk levels as follows:
- I: healthy patient
- II: patient with mild systemic disease without functional limitations
- III: patient with severe systemic disease with definite functional limitations
- IV: patient with severe systemic disease that is life-threatening
- V: dying patient not expected to survive for 24 hours without an operation
Equipment for general anesthesia should be thoroughly checked before the operation; all items that might be needed, such as extra tubes or laryngoscope blades, should be available. Staff members should be knowledgeable about the problems that might arise with the specific anesthetic being used, and be able to recognize them and respond appropriately. General anesthetics cause a lowering of the blood pressure (hypotension), a response that requires close monitoring and special drugs to reverse it in emergency situations.
General anesthetics may be gases or volatile liquids that evaporate as they are inhaled through a mask along with oxygen. Other general anesthetics are given intravenously. The amount of anesthesia produced by inhaling a general anesthetic can be adjusted rapidly, if necessary, by adjusting the anesthetic-to-oxygen ratio that is inhaled by the patient. The degree of anesthesia produced by an intravenously injected anesthetic cannot be changed as rapidly and must be reversed by administration of another drug.
The precise mechanism of general anesthesia is not yet fully understood. There are, however, several hypotheses that have been advanced to explain why general anesthesia occurs. The first, the so-called Meyer-Overton theory, suggests that anesthesia occurs when a sufficient number of molecules of an inhalation anesthetic dissolve in the lipid cell membrane. The second theory maintains that protein receptors in the central nervous system are involved, in that inhalation anesthetics inhibit the enzyme activity of proteins. A third hypothesis, proposed by Linus Pauling in 1961, suggests that anesthetic molecules interact with water molecules to form clathrates (hydrated microcrystals), which in turn inhibit receptor function.
Stages of anesthesia
There are four stages of general anesthesia that help providers to better predict the course of events, from anesthesia induction to emergence.
- Stage I begins with the induction of anesthesia and ends with the patient’s loss of consciousness. The patient still feels pain in Stage I.
- Stage II, or REM stage, includes uninhibited and sometimes dangerous responses to stimuli, including vomiting and uncontrolled movement. This stage is typically shortened by administering a barbiturate, such as sodium pentothal, before the anesthetic agent.
- Stage III, or surgical anesthesia, is the stage in which the patient’s pupillary gaze is central and the pupils are constricted. This is the target depth of surgical anesthesia. During this stage, the skeletal muscles relax, the patient’s breathing becomes regular, and eye movements stop.
- Stage IV, or overdose, is marked by hypotension or circulatory failure. Death may result if the patient cannot be revived quickly.
Types of anesthetic agents
There are two major types of anesthetics used for general anesthesia, inhalation and intravenous anesthetics. Inhalation anesthetics, which are sometimes called volatile anesthetics, are compounds that enter the body through the lungs and are carried by the blood to body tissues. Inhalation anesthetics are less often used alone in recent clinical practice; they are usually used together with intravenous anesthetics. A combination of inhalation and intravenous anesthetics, often with opioids added for pain relief and neuromuscular blockers for muscle paralysis, is called balanced anesthesia.
INHALATION ANESTHETICS. The following are the most commonly used inhalation anesthetics:
- Halothane causes unconsciousness but provides little pain relief; often administered with analgesics . It may be toxic to the liver in adults. Halothane, however, has a pleasant smell and is therefore often the anesthetic of choice when mask induction is used with children.
- Enflurane is less potent, but produces a rapid onset of anesthesia and possibly a faster recovery. Enflurane is not used in patients with kidney failure.
- Isoflurane is not toxic to the liver but can induce irregular heart rhythms.
- Nitrous oxide (laughing gas) is used with other such drugs as thiopental to produce surgical anesthesia. It has the fastest induction and recovery time. It is regarded as the safest inhalation anesthetic because it does not slow respiration or blood flow to the brain. However, because nitrous oxide is a relatively weak anesthetic, it is not suited for use in major surgery. Although it may be used alone for dental anesthesia, it should not be used as a primary agent in more extensive procedures.
- Sevoflurane works quickly and can be administered through a mask since it does not irritate the airway. On the other hand, one of the breakdown products of sevoflurane can cause renal damage.
- Desflurane, a second-generation version of isoflurane, is irritating to the airway and therefore cannot be used for mask (inhalation) inductions, especially not in children. Desflurane causes an increase in heart rate, and so should be avoided for patients with heart problems. Its advantage is that it provides a rapid awakening with few adverse effects.
INTRAVENOUS ANESTHETICS. Commonly administered intravenous general anesthetics include ketamine, thiopental (a barbiturate), methohexital (Brevital), etomidate, and propofol (Diprivan). Ketamine produces a different set of reactions from other intravenous anesthetics. It resembles phencyclidine, which is a street drug that may cause hallucinations. Because patients who have been anesthetized with ketamine often have sensory illusions and vivid dreams during post-operative recovery, ketamine is not often given to adult patients. It is, however, useful in anesthetizing children, patients in shock, and trauma casualties in war zones where anesthesia equipment may be difficult to obtain.
General anesthesia in dental procedures
The use of general anesthesia in dental and oral surgery patients differs from its use in major surgery because the patient’s level of fear is usually a more important factor than the nature of the procedure. In 1985, an NIH Consensus Statement reported that high levels of preoperative anxiety, lengthy and complex procedures, and the need for a pain-free operative period may be indications for general anesthesia in healthy adults and very young children. The NIH statement specified that at least three professionals are required when general anesthesia is used during dental procedures: one is the operating dentist; the second is a professional responsible for observing and monitoring the patient; the third person assists the operating dentist.
Although the United States allows general anesthesia for dental procedures to be administered outside hospitals (provided that the facility has the appropriate equipment and emergency drugs), Scotland banned the use of general anesthesia outside hospitals in 2000, after a ten-year-old boy died during a procedure to have a tooth removed.
Depending on the patient’s level of anxiety and the procedure to be performed, the patient may be premedicated. Most medications given before general anesthesia are either anxiolytics, usually benzodiazepines; or analgesics. Patients in severe pain prior to surgery may be given morphine or fentanyl. Anticholinergics (drugs that block impulses from the parasympathetic nervous system) may be given to patients with a known history of bronchospasm or heavy airway secretions.
The anesthetist and medical personnel provide supplemental oxygen and monitor patients for vital signs and monitor their airways. Vital signs include an EKG (unless the patient is hooked up to a monitor), blood pressure, pulse rate, oxygen saturation, respiratory rate, and temperature. The staff also monitors the patient’s level of consciousness as well as signs of excess bleeding from the incision
Although the risk of serious complications from general anesthesia are low, they can include heart attack, stroke, brain damage, and death. The risk of complications depends in part on the patient’s age, sex, weight, allergies, general health, and history of smoking, alcohol or drug use.
The overall risk of mortality from general anesthesia is difficult to evaluate, because so many different factors are involved, ranging from the patient’s overall health and the circumstances preceding surgery to the type of procedure and the skill of the physicians involved. The risk appears to be somewhere between 1:1,000 and 1:100,000, with infants younger than age one and patients older than 70 being at greater risk.
One possible complication is the patient’s “waking up” during the operation. It is estimated that about 30,000 patients per year in the United States “come to” during surgery. This development is in part the result of the widespread use of short-acting general anesthetics combined with blanket use of neuromuscular blockade. The patients are paralyzed with regard to motion, but otherwise “awake and aware.” At present, special devices that measure brain wave activity are used to monitor the patient’s state of consciousness. The bispectral index monitor was approved by the FDA in 1996 and the patient state analyzer in 1999.
Post-operative nausea and vomiting is a common problem during recovery from general anesthesia. In addition, patients may feel drowsy, weak, or tired for several days after the operation, a combination of symptoms sometimes called the hangover effect. Fuzzy thinking, blurred vision, and coordination problems are also possible. For these reasons, anyone who has had general anesthesia should not drive, operate machinery, or perform other activities that could endanger themselves or others for at least 24 hours, or longer if necessary.
Anesthetic toxicity
Inhalation anesthetics are sometimes toxic to the liver, the kidney, or to blood cells. Halothane may cause hepatic necrosis or hepatitis. Sevoflurane may react with the carbon dioxide absorbents in anesthesia machines to form compound A, a haloalkene that is toxic to the kidneys. The danger to red blood cells comes from carbon monoxide formed by the breakdown products of inhalation anesthetics in the circuits of anesthesia machines.
In modern anesthesia practice, the distinctive sings of each of the 4 stages described above are often obscured. Reasons for this include the relatively rapid onset of action of many inhaled anesthetics compared to that of diethyl ether and the fact that pulmonary ventilation is often controlled with the aid of a mechanical ventilator. In addition, the presence of other pharmacologic agents given pre- or intraoperatively can also influence the signs of anesthesia. Atropine, used to decrease secretions, also dilates pupils; drugs such as tubocurarine and succinylcholine affect muscle tone; and the narcotic analgesics exert depressant effects on respiration. The most reliable indications that stage III (surgical anesthesia) has been achieved are loss of the eyelash reflex and establishment of a respiratory pattern that is regular in rate and depth. The adequacy of ensuing depth of anesthesia for the particular surgical situation is assessed mainly by changes in respiratory and cardiovascular responses to stimulation.
Mechanisms of action
A commoeurophysiologic action of general anesthetics is to increase the threshold of cells to firing, resulting in decreased activity. Almost all anesthetics also reduce the rate of rise of the action potential by interfering with sodium influx. One interpretation of this effects is that the physical presence of anesthetic molecules blocks or distorts neuronal membrane channels involved in sodium conductance. Current theories of the possible mechanisms by which anesthetics interfere with the sodium channel include consideration of their molecular interactions with the lipid matrix of the membrane and with hydrophobic regions of specific membrane proteins. This interpretation is encouraged by several facts: (1) There are few, if any, characteristics of chemical structure common to all general anesthetic molecules. This suggests that “receptor sites” for these drugs, if they exist, are quite nonselective. (2) The potency of general anesthetics is well correlated with their lipid solubility (Meyer-Overton principle). (3) The interaction of anesthetics with artificial lipid membranes causes changes in the physicochemical characteristics of these membranes suggestive of a reduction of structural order in the lipid matrix. These changes in the lipid matrix could alter the function of proteins in the membrane – eg, reducing sodium conductance. Conversely, in experimental animals, general anesthesia can be reversed quite rapidly by high pressure (eg, 50-100 atm), which increases the ordering of lipids in the membrane bilayer. This has led to suggestions that as the anesthetic molecule dissolves in the neuronal membrane, it causes a small expansion that distorts the sodium channel. High pressure restores the membrane to its former state to permit the normal influx of sodium that occurs during generation of the action potential.
The neuropharmacologic basis for the effects that characterize the stages of anesthesia appears to be a differential sensitivity to the anesthetics of specific neurons or neuronal pathways. Cells of the substantia gelatinosa in the dorsal horn of the spinal cord are very sensitive to relatively low anesthetic concentration in the central nervous system. A decrease in the activity of the dorsal horn interrupts sensory transmission in the spinothalamic tract, including that concerning nociceptive stimuli. These effects contribute to stage I, or analgesia. The disinhibitory effects of general anesthetics (stage II), which occur at higher brain concentrations, result from complex neuronal actions including blockade of many small inhibitiry neurons such as Golgi type II cells, together with a paradoxic facilitation of excitatory neurotransmitters. A progressive depression of ascending pathways in the reticular activating system occurs during stage III, or surgical anesthesia, together with suppression of spinal reflex activity that contributes to muscle relaxation. Neurons in the respiratory and vasomotor centers of the medulla are relatively unsensitive to the effects of the general anesthetics, but at high concentrations their activity is depressed, leading to cardiorespiratory collapse (stage IV).
Pharmacokinetics of inhaled anesthetics
Depth of anesthesia is determined by the concentrations of anesthetics in the central nervous system. The rate at which an effective brain concentration is reached (the rate of induction of anesthesia) depends on multiple pharmacokinetic factors that influence the uptake and distribution of the anesthetic. These factors determine the different rates of transfer of the inhaled anesthetic from the lung to the blood and from the blood to the brain and other tissues. These factors also influence the rate of recovery anesthesia when inhalation of the anesthetic is terminated.
The concentration of an individual gas in a mixture of gases is proportionate to its partial pressure or tension. These terms are often used interchangeably in discussing the various transfer processes of anesthetic gases in the body. Achievement of a brain concentration of an anesthetic adequate to cause anesthesia requires transfer of that anesthetic from the alveolar air to blood and then to brain. The rate at which a given concentration of anesthetic in the brain is reached depends on the solubility properties of the anesthetic, its concentration in the inspired air, pulmonary ventilation rate, pulmonary blood flow, and the concentration gradient of the anesthetic between arterial and mixed venous blood.
Solubility: One of the most important factors influencing the transfer of an anesthetic from the lugs to the arterial blood is its solubility. The blood: gas partition coefficient is a useful index of solubility and defines the relative affinity of an anesthetic for the blood compared to air. This partition coefficient may be as low as 0.5 for anesthetics such as nitrous oxide or cyclopropane, which are quite insoluble in blood. Alternatively, the value may be higher than 10 for agents such as diethyl ether or methoxyflurane, which are very soluble in blood. When an anesthetic with low blood solubility diffuses from the lung into the arterial blood, relatively few molecules are required to raise its partial pressure, and the arterial tension rises quickly. Conversely, for anesthetics with moderate to high solubility, more molecules dissolve before partial pressure is changed, and arterial tension of the gas will increase slowly. The blood: gas partition coefficients for nitrous oxide, halothane, and methoxyflurane are o.47, 2.3. and 12, respectively. Nitrous oxide, with low solubility in blood, reaches high arterial tensions rapidly, which in turn results in more rapid equilibrium with the brain and faster induction of anesthesia. In contrast, even after 40 minutes, methoxyflurane has reached only 20 % of the equilibrium concentration.
Anesthetic Concentration in the Inspired Air: The concentration of an inhaled anesthetic in the inspired gas mixture has direct effects on both the maximum tension that can be achieved in the alveoli and the rate of increase in its tension in arterial blood. Increases in the inspired anesthetic concentration will increase the rate of induction of anesthesia by increasing the rate of transfer into the blood. Iincreases in the inspired anesthetic concentration will increase the rate of induction of anesthesia by increasing the rate of transfer into the blood. Advantage is taken of this effect in anesthetic practice with inhaled anesthetics of moderate blood solubility such as enflurane or halothane, which have a relatively slow onset. For example, a 3-4 % concentration of halothane may be inspired initially to increase rate of induction, and this reduced to 1-2 % for maintenance when adequate anesthesia is achieved.
Pulmonary Ventilation: The rate of rise of anesthetic gas tension in arterial blood is directly dependent on both the rate and depth of ventilation, ie, minute ventilation. The magnitude of the effect varies according to the blood: gas partition coefficient. An increase in pulmonary ventilation is accompanied by only a sling increase in arterial tension of an anesthetic with low blood solubility or low coefficient but can significantly increase tension of agents with moderate or high blood solubility. For example, a 4-fold increase in ventilation rate may double the arterial tension of halothane during the first 10 minutes of anesthesia, with little effect on the arterial tension of nitrous oxide. Hyperventilation by mechanical control of respiration or by CO2 stimulation increases the speed of induction of anesthesia with inhaled anesthetics that would normally have a slow onset. Depression of respiration by other pharmacologic agents, including narcotic analgesics, may slow the onset of anesthesia of some inhaled anesthetics if ventilation is not controlled.
Pulmonary Blood Flow: Changes in the rates of blood flow to and from the lungs influence transfer processes of the anesthetic gases. An increase in pulmonary blood flow (increased cardiac output0 slows the rate of rise in arterial tension, particularly for those anesthetics with moderate to high blood solubility. This is because increased pulmonary blood flow exposes a larger volume of blood to the anesthetic; thus, blood “capacity” increases and tension rises slowly. A decrease in pulmonary blood flow has the opposite effect and increases the rate of rise of arterial tension of inhaled anesthetics. In a patient with circulatory shock, the combined effects of decreased cardiac output (decreased pulmonary flow) and increased ventilation may accelerate the induction of anesthesia with some anesthetics. This is least likely to occur with nitrous oxide because of its low solubility.
Arterial-Venous Concentration Gradient: The anesthetic concentration gradient between arterial and mixed venous blood is dependent mainly on uptake of the anesthetic by the tissues; depending on the rate and extent of tissue uptake, venous blood returning to the lungs may contain significantly less anesthetic than that present in arterial blood. The greater this difference in tensions, the more time it takes to achieve equilibrium. Anesthetic entry into tissues is influenced by factors similar to those that determine transfer from lung to blood, including tissue: blood partition coefficient, rates of blood flow to the tissues, and concentration gradients.
During the induction phase of anesthesia, the tissues that exert greatest influence on the arterial-venous anesthetic concentration gradient are those which are highly perfused. These include the brain, heart, liver, kidneys, and splanchnic bed, which together receive over 75 % of the resting cardiac output. In the case of anesthetics with relatively high solubility in these tissues, venous blood concentration will initially be very low, and equilibrium with arterial blood is achieved slowly.
During maintenance of anesthesia with inhaled anesthetics, there may continue to be transfer of these drugs between various at rates dependent on solubility and blood flow. Muscle and skin, which together constitute 50 % of body mass, accumulate anesthetics more slowly than the richly vascularized tissues, since they receive only one-fifth of the blood flow of the latter group. Although most anesthetic gases have high solubility in adipose tissues, low blood perfusion rates to these tissues delay accumulation, and equilibrium is unlikely to occur with anesthetics such as halothane and enflurane during the time anesthetics are usually required for surgery.
Elimination
The time to recovery from inhalational anesthesia depends on the rate elimination of anesthetics from the brain after the inspired concentration of anesthetic has been decreased. Many of the processes of anesthetic transfer during recovery are similar to those that occur during induction of anesthesia. Factors controlling rate recovery include the pulmonary blood flow and the magnitude of ventilation as well as solubility of the anesthetic in the tissues and the blood and in the gas phase in the lung. Two features of recovery, however, are quite different from what happens during induction of anesthesia. First, while transfer of an anesthetic from the lungs to blood can be enhanced by increasing its concentration in inspired air, the reverse transfer process cannot be enhanced, since the concentration in the lungs cannot be reduced below zero. Second, at the beginning of recovery, the anesthetic gas tension in different tissues may be quite variable, depending on the specific agent and the duration of anesthesia. With indication of anesthesia, the initial anesthetic tension in all tissues is zero.
Inhaled anesthetics that are relatively insoluble in blood and the brain are eliminated at faster rates than more soluble anesthetics. For example, the “washout” of nitrous oxide occurs at a fast rate, which leads to a rapid recovery from its anesthetic effects. Halothane is approximately twice as soluble in brain tissue and 5 times more soluble in blood thaitrous oxide; its elimination therefore takes place more slowly, and recovery from halothane anesthesia is less rapid. The duration of exposure to the anesthetic can have a marked effect on the time of recovery, especially in the case of more soluble anesthetics such as methoxyflurane. Accumulation of agents in tissues, including muscle, skin, and fat, increases with continuous inhalation; and blood tension may decline slowly during recovery as the anesthetic gradually leaves such tissues. Thus, if exposure to the anesthetic is short, recovery may be rapid. After prolonged anesthesia, recovery may be delayed even with anesthetics of modest solubility such as halothane.
Clearance of inhaled anesthetics by the lung into the expired air is the major route of their elimination from the body. However, metabolism by enzymes of the liver and other tissues may also contribute to the elimination of anesthetics. For example, the washout of halothane during recovery is more rapid than that of enflurane, which would not be predicted from their respective solubility. However, 15-20 % of inspired halothane is methabolized during an average anesthetic procedure, while only 2-3 % of enflurane is metabolized over the same period. Oxidative methabolism of halothane results in the formation of trifluoroacetic acid and release of bromide and chloride ions. Under conditions of low oxygen tension, halothane is methabolized to the chlorotrifluoroethyl free radical, which is capable of reacting with hepatic membrane components. The slow rate methabolism of enflurane results in the formation of difluoromethoxydifluoroacetic acid and fluoride ion, which do not reach toxic levels. Methoxyflurane is methabolized by the liver at a faster rate than any other inhaled anesthetic and releases fluoride ions at levels that can be nephrotoxic. Nitrous oxide is methabolized to a very small extent.
Inhaled anesthetics
As indicated previously, nitrous oxide lacks sufficient potency to produce surgical anesthesia by itself and therefore is usually used in combination with another inhaled or intravenous anesthetic to produce the total anesthetic state. Methoxyflurane is occasionally used, especially in obstetrical anesthesia, but not for prolonged procedures because of its nephrotoxicity. Chloroform is not used because of its hepatotoxicity. Although cyclopropane and diethyl ether were the most commonly used anesthetics before 1960, they are rarely used now because of their flammable and explosive characteristics.
General Pharmacologic Effects
Effects on Cardiovascular System: Halothane, enflurane, and isoflurane all decrease mean arterial pressure in direct proportion to their alveolar concentration. With halothane and enhflurane, the reduced arterial pressure appears to be caused by a reduction in cardiac output, since there is little change in systemic vascular resistance. In contrast, isoflurane has a depressant effect on arterial pressure as a result of a marked decrease in systemic vascular resistance; it has little effect on cardiac output.
Older anesthetics such as cyclopropane, diethyl ether, and fluroxene generally do not reduce arterial blood pressure or significantly change cardiac output. In fact, diethyl ether and cyclopropane often increase arterial blood pressure as a result of their ability to liberate catecholamines.
Inhaled anesthetics change heart rate either by altering the rate of node depolarization directly or by shifting the balance of autonomic nervous system . Arrhythmias may develop during administration of any inhalation anesthetic. Supraventricular arrhythmias are common and are usually benign except when cardiac output and arterial pressure are reduced. Ventricular arrhythmias occur only rarely unless hypoxia or hypercapnia is present. Halothane sensitized the heart to the actions of catecholamines. Therefore, use of epinephrine, norepinephrine, or large doses of isoproterenol during halothane anesthesia may increase the risk of ventricular arrhythmias. Administration of halothane may be hazardous to patiernts with high levels of endogenous catecholamines (eg, pheochromocytoma, severe anxiety). Bradycardia is often seen with halohane and may be a result of direct depression of atrial rate. In contrast, methoxyflurane, enflurane, and isoflurane increase heart rate. All of these changes in heart rate have been determined iormal subjects undergoing surgery. The patient’s excited state preoperatively or the stimulation of surgery intraoperatively will often alter the heart rate response to inhaled anesthetics.
All inhaled anesthetics tend to increase right atrial pressure in a dose-related fashion that reflects depression of myocardial function. In general, enflurane and halothane are very depressant to the myocardium, but cyclopropane, and diethyl ether, are not. Inhaled anesthetics reduce myocardial oxygen consumption, primarily by decreasing those variables that control oxygen demand, such as arterial blood pressure and contractile force. Although certainly less depressant than the other inhaled anesthetics, nitrous oxide has also been found to depress the myocardium in a dose-dependent manner. However, nitrous oxide alone or in combination with potent inhaled anesthetics produces sympathetic stimulation that may obscure any cardiac depressant effects of the inhaled anesthetic. The combination of nitrous oxide plus halothane or enflurane, for example, appears to produce less depression at a given level of anesthesia than either more potent anesthetic given alone.
Effects on Respiratory System: With the exception of nitrous oxide and diethyl ether, all inhaled anesthetics cause a decrease in tidal volume and an increase in respiratory rate. However, the increase in rate is insufficient to compensate for the decrease in volume, resulting in a decrease in minute ventilation. All inhaled anesthetics are respiratory depressants, as gauged by the reduced response to various levels of carbon dioxide. The degree of ventilatory depression varies with anesthetic agents, with isoflurane and enflurane being the most depressant and diethyl ether the least depressant. All inhaled anesthetics except diethyl ether increase the resting level of PaCO2 (the partial pressure of carbon dioxide in arterial blood). Because diethyl ether is a respiratory irritant, ventilation may remain sufficiently high to maintaiormal PaCO2 . however, if the patient is challenged with increasing inspired concentrations of carbon dioxide, the respiratory depressant effect of diethyl ether will become apparent. The ventilatory depressant effects of anesthetics are overcome by assisting or controlling ventilation via a mechanical ventilator during surgery. Inhaled anesthetics also depress mucociliary function in the airway. Thus, prolonged anesthesia may lead to pooling of mucus and then result in atelectasis and respiratory infections. On the other hand, inhaled anesthetics tend to be bronchodilators, with halothane probably one of the most potent. This effect has been utilized in the treatment of asthma.
Effects on Brain: Inhaled anesthetics decrease the metabolic rate of the brain. Nevertheless, most of them increase cerebral blood flow because they decrease cerebral vascular resistance. The increase in cerebral blood flow is often clinically undesirable. For example, in patients who have an elevated intracranial pressure because of brain tumor or head injury, the administration of an inhaled anesthetic may increase cerebral blood flow, which in turn will increase cerebral blood volume and further increase intracranial pressure. This appears to be significant only in patients with intracranial lesions. Hypocapnia induced by hyperventilation essentially eliminates the increase in intracranial pressure. Patients with intracranial lesions should not receive halothane until hyperventilation has been instituted.
Of the inhaled anesthetics, nitrous oxide increases cerebral blood flow the least, although when 60 % nitrous oxide is added to halothane anesthesia, cerebral blood flow usually increases more than with halothane alone. Halothane, enflurane, and isoflurane in low doses have similar effects on cerebral blood flow. At higher doses, enflurane and isoflurane increase cerebral blood flow less than does halothane. If the patient is hyperventilated before the anesthetic is given, increase in intracranial pressure from inhaled anesthetics can be minimized. Thiopental constricts cerebral vessels and also may be used to attenuate the increase in intracranial pressure during the use of volatile anesthetics.
Effects on Kidney: to varying degrees, all inhaled anesthetics decrease glomerular filtration rate and effective renal plasma flow and increase filtration fraction. alL the anesthetics tend to increase renal vascular resistance. Since renal blood flow decreases during general anesthesia in spite of well-maintained or even increased perfusion pressures, autoregulation of renal flow is probably impaired.
Effects on Liver: All anhaled anesthetics cause a decrease in hepatic blood flow, ranging from 15 to 45 % of the preanesthetic flow. Despite transient changes in liver function tests intraoperatively, rarely does permanent change of liver function occur from the use of these agents. The possible hepatotoxicity of halothane is discussed below.
Effects on Uterine Smooth Muscle: Nitrous oxide appears to have little effects on uterine musculature. However, isoflurane, halothane, and enflurane are potent uterine muscle relaxants. This pharmacologic effect can be used to advantage when profound uterine relaxation is required for intrauterine fetal manipulation during delivery. In contrast, during dilatation and curettage for therapeutic abortion, these anesthetics may cause increased bleeding.
Inhalation Anesthetics
Nitrous oxide
Actions and uses. Nitrous oxide is a sweet smelling, nonexplosive gas with low anesthetic potency. In must always be administered with at least 30 % oxygen during induction and maintenance. Induction with 70 % nitrous oxide is facilitated by premedication with a narcotic analgesic or barbiturate.
For surgical anesthesia, nitrous oxide must be supplemented with other agents (eg, thiopental, benzodiazepines, narcotic analgesics, more potent inhalation agents). It reduces the requirement for other inhalation anesthetics, and thus is included as one of the inhalation agents in almost all patients undergoing general anesthesia. A neuromuscular blocking agent often is given concomitantly if muscle relaxation is necessary.
Nitrous oxide has good analgesic properties and thus is the sole analgesic in brief procedures, in dentistry, and in the second stage of labor. However, it should not be used to produce analgesia or light narcosis for longer than 48 hours (eg, in patients receiving artificial ventilation) because of its tendency to produce leukopenia.
Adverse reaction and precautions. Serious adverse effects on the cardiovascular or ventilatory systems, liver, kidneys, or metabolic function usually do not occur when the inhalation mixture contains an adequate concentration of oxygen and ventilation is maintained. Severe hypotension may occur when hypovolemia, shock, or significant heart disease exists.
Reversible bone marrow depression has been observed following continuous administration of nitrous oxide for more than three days (eg, in tetanus). Epidemiologic and experimental evidence indicates that long exposure to trace concentrations of nitrous oxide may produce abortion. Similar but less complete evidence suggests that prolonged exposure to nitrous oxide may cause neurologic injury and congenital anomalies.
Usual Dosage. Inhalation: for sedation, 25 %; for analgesia, 25 % to 50 % nitrous oxide with oxygen. Laryngeal incompetence may develop with use of the 50 % concentration. Nitrous oxide cannot be used as the sole agent for induction because of its low potency without large doses of a narcotic for premedication. For induction, 70 % nitrous oxide with 30 % oxygen for two to three minutes. For maintenance, 30 % to 70 % nitrous oxide with oxygen, depending upon the condition of the patient and the type and amount of supplemental agents used.
Halothane
Actions, uses, and drug interactions. Halothane is a non flammable, halogenated hydrocarbon anesthetic that provides relatively rapid induction with little or no excitement. Analgesia may not be adequate and, since high concentrations cause circulatory depression, nitrous oxide is generally given concomitantly to reduce the concentratioeeded. Because halothane may not produce sufficient muscle relaxation, neuromuscular blocking agents may be required. However, this anesthetic markedly augments the neuromuscular blocking effects of nondepolarizing muscle relaxants, and the dose of the latter must be reduced.
Halothane is not irritating to the respiratory tract. It depresses pharyngeal and laryngeal reflexes, dilates the bronchioles, and reduces salivation and bronchial secretions. It depresses the depth of respiration, produces tachypnoa, and increases the alveolar-arterial oxygen difference; ventilation may be controlled to avoid respiratory acidosis.
Halothane diminishes sympathetic activity, augments vagal tone, depresses the contractility of the heart, and induces venodilation. Cardiac output, arterial pressure, and pulse rate are reduced, usually in proportion to the depth of anesthesia. Severe hypotension and circulatory failure may occur with overdosage. Arrhythmias, including nodal rhythm, may be observed during induction or deep anesthesia; ventricular arrhythmias are increased over awake levels but are uncommon unless ventilation is inadequate.
Transient, slight abnormalities in the results of liver function tests have been observed after a single administration. The changes are similar to those noted following administration of other anesthetics but occur more frequently. Although many cases of liver damage, ranging from mild hepatitis to massive hepatic necrosis, have been reported after such use, the incidence of unexplained cases of massive hepatic necrosis is about
Dose-dependent, reversible effects on the kidney (eg, decreased renal blood flow, glomerular filtration rate, and urine volume) have been observed during anesthesia, particularly in dehydrated patients or those with intraoperative hypotension.
Recovery from anesthesia is usually rapid and uneventful; shivering is observed commonly but restlessness, delirium, nausea, and vomiting are infrequent.
Usual Dosage
Inhalation: For induction, a 1 % to 4 % concentration vaporized by a flow of oxygen or a nitrous oxide-oxygen mixture. For maintenance, a 0.5 % to 2 % concentration.
Intravenous anesthetics
Barbiturates
Thiopental sodium
Actions and uses. This barbiturate is useful to induce general anesthesia, since loss of consciousness occurs within 30 to 60 seconds after intravenous administration. Thiopental usually is not employed for maintenance (even with nitrous oxide) for procedures lasting longer than 15 to 20 minutes, because the cumulative dosage results in delayed awakening. it has poor analgesic properties. The use of nitrous oxide 67 % decreases requirements for thiopental by two-thirds. Depending upon the type of surgery, narcotic analgesics and neuromuscular blocking agents also may be required. Usual doses have no significant effects at the myoneural junction. There is no effect on uterine muscle tone.
Although this anesthetic may be administered rectally for basal sedation or anesthesia, absorption from the rectum is unpredictable.
Pharmacokinetics. The duration of unconsciousness after a single dose of thiopental is determined by the rate of redistribution from the central nervous system into muscle. Factors that diminish blood flow into muscle, eg, hypovolemia, delay awakening. Thiopental is almost completely metabolized (more than 99 %) in the liver.
Adverse reactions and precautions. In most instances, the arterial pressure is only slightly affected by thiopental. However, a reduction in cardiac output caused by myocardial depression and in arterial pressure caused by peripheral vasodilation may occur immediately after rapid intravenous injection of enough thiopental to produce deep anesthesia.
Thiopental is a potent respiratory depressant, and apnea may occur immediately after intravenous injection, particularly in the presence of hypovolemia, cranial trauma, or narcotic premedication. Respiratory depression may be prolonged in patients with myasthenia gravis.
Rapid redistribution of thiopental out of the brain can result in light anesthesia characterized in part by reflex hyperactivity of the airway to mechanical stimulation (eg. intubation, instrumentation, secretions, blood). Therefore, an adequate depth of anesthesia should be assured in patients sensitive to bronchospasm; in those with upper airway obstruction; when coughing, hiccuping, or straining is undesirable; and to avoid laryngospasm, which might otherwise occur at any time from direct or indirect stimulation (eg, rectal dilation). Introduction of an artificial airway or painful stimulus also may cause hypertension in patients who are lightly anesthetized.
Thiopental is absolutely contraindicated in patients with acute intermittent porphyria or other hepatic porphyrias.
Anaphylaxis has been reported following injection of thiopental, but this response is very rare.
Care should be taken to avoid extravasation or intra-arterial injection, for neuritis and skin sloughs may occur with the former (especially with concentrations exceeding 25 mg/ml) and arteritis, followed by vasospasm, edema, thrombosis, and gangrene, with the latter. Damage is reduced when dilute solutions are asdministered; concentrations should not exceed 2.5 %. If intra-arterial injection does occur, it is usually accompanied by immediate intense pain prior to loss of consciousness. The injection must be discontinued immediately and local injection (preferably through the needle used for the thiopental) of a vasodilator (eg, nitroprusside0 or a local anesthetic without epinephrine given. If the needle has been removed from the artery prior to identification of the adverse response, the injection of the vasodilator should be made into the subclavian artery, since the affected artery will be in spasm. Local injection of heparin may reduce thrombosis, and sympathetic block or general anesthesia with halothane may relieve pain and vascular spasm and assist in opening collateral circulation.
Consciousness returns rapidly unless large doses have been given. Postoperative nausea and vomiting are uncommon, but shivering occurs often and excitement and delirium may develop during recovery in the presence of pain.
Usual Dosage
For induction, adults, after a 2-ml test dose of a freshly prepared 2.5 % solution, 50 or 100 mg is injected intermittently every 30 to 40 seconds until the desired effect has been obtained, or a single injection of 3 to 5 mg/kg is given. For maintenance, 50 to 100 mg of a 2.5 % solution is injected as required.
Ketamine Hydrochloride
Actions and uses. Ketamine is a nonbarbiturate anesthetic that can be admimistered intravenously or intramuscularly. It induces a sedated, amnesic state in which the patient may appear to be awake but is dissociated from the environment, is immobile, and does not respond to pain. Induction of anesthesia is rapid, even after intramuscular injection. Like thiopental, the anesthetic action of an induction dose of ketamine is terminated by redistribution out of the central nervous system in approximately 10 minutes. Recovery from the postanesthetic psychic effects is more prolonged and may depend on elimination.
Because this anesthetic is rapidly effective when administered intramuscularly, it is particularly useful for repeated anesthesia in burn patients, for diagnostic studies, for sedating uncontrollable patients (eg, the mentally retarded), and for minor surgical procedures in young children.
Ketamine also may be of value to induce anesthesia, particularly when a barbiturate cannot be used or cardiovascular depression must be avoided (eg, shock, severe dehydration, severe anemia, constrictive pericarditis). In is particularly useful in the presence of bronchospasm. However, it is not satisfactory as the sole agent for abdominal or other major operations because skeletal muscle relaxation is inadequate and adverse effects occur.
An anticholinergic drug should be given for premedication to reduce secretions. Ketamine potentiates the neuromuscular blocking effects of tubocurarine but not of pancuronium or succinylcholine. Posoperative analgesia may be produced when ketamine is administered intraoperatively.
Adverse Reactions and Precautions
Muscular regidity, athetoid motions of the mouth and tongue, swallowing, random movements of the extremities, vocalization, laryngeal spasm, fasciculations, tremors, and generalized extensor spasm have occurred occasionally. Frank convulsions are extremely rare.
Although arrhythmias are seldom observed, ketamine usually increases heart rate and cardiac output, and the arterial pressure may increase as much as 25 %, principally from stimulation of the central sympathetic nervous system and inhibition of reuptake of released norepinephrine. The drug should be used with care in patients with mild, uncomplicated hypertension and is contraindicated when a significant elevation of blood pressure would constitute a serious hazard (in patients with aneurysms, angina, heart failure, cerebral trauma, or thyrotoxicosis). Tracheobronchial secretions are increased. Pre-existing bronchospasm usually is abolished by the smooth muscle relaxant action of ketamine.
Ketamine increases cerebrospinal fluid pressure and intracranial blood flow and should be used with extreme caution in patients with evidence of increased intracranial pressure or a space-occupying lesion.
Ketamine may cause vomiting, hypersalivation, lacrimation, shivering, and transient cutaneous reactions. These is some evidence that the drug may interact with thyroid medication to produce severe hypertension and tachycardia.
Recovery from ketamine anesthesia sometimes is prolonged up to several hours. Psychic disturbances during emergence (unpleasant dreams, irrational behavior, excitement, disorientation, illusions, delirium, hallucinations) may occur more frequently in adults (particularly women) than in children. The reported incidence varies between 3 % and 50 %. Several techniques can reduce the incidence of such reactions: (1) Oral premedication with diazepam 10 mg; (2) intravenous administration of diazepam 0.15 to 0.3 mg/kg at the end of anesthesia; (3) use of no more than 2 mg/kg as the induction dose and maintenance of anesthesia with doses of 0.5 to 1 mg/kg.
Usual Dosage
Tachyphylaxis has been observed when ketamine is given for repetitive operative, diagnostic, or therapeutic procedures.
Intravenous: For induction, single dose method, 2 mg/kg (range, 1 to 4.5 mg/kg) administered over a period of 60 seconds. Unconsciousness will persist for 10 to 15 minutes; analgesia will persist for an additional 30 minutes. For maintenance, one-half of the full induction dose, repeated as necessary.
Intramuscular: For induction, 6/5 to 13 mg/kg. For maintenance, one-half of the full induction dose, repeated as necessary. For analgesia (eg, burn patients), 2 mg/kg.
Propanidid
Propanidid produces anesthesia with about the same rapidity as thiopental. Recovery is more complete and accumulation less likely with propanidid than with thiopental, since it is rapidly degraded by cholinesterase into inactive methabolites.
Propanidid causes hypotension, chiefly due to peripheral vasodilatation and a negative inotropic effect on the heart. Because of rapid recovery, an apparent lack of cumulative effect, and minimal cardiorespiratory effects, propanidid was at one time considered a promising anesthetic. However, numerous adverse reactions have been reported: Major epileptiform convulsions occur occasionally in patients with or without epilepsy, severe hypotension with rash has occurred after injection, phlebitis and trombophlebitis.
Toxicity
Hepatotoxicity (Halothane): Postoperative hepatitis is usually associated with factors such as blood transfusions, hypovolemic shock, and other surgical stresses rather than anesthetic toxicity. However, halocarbons can cause liver damage, and chloroform was identified as a hepatotoxin in the first decade of this century. Halothane was introduced into clinical practice in 1956; by 1963, several cases of postoperative jaundice and liver necrosis associated with halothane had been reported. The mechanism underlying hepatotoxicity may depend on the production of a reactive metabolite (eg, a free radical) that either causes direct hepatocellular damage or initiates an immune-response.
Nephrotoxicity (Methoxyflurane): In 1966, vasopressin-resistant polyuric renal insufficiency was first reported in 13 of 41 patients receiving methoxyflurane anesthesia for abdominal surgery. Subsequently, the causative agent was shown to be inorganic fluoride, an end product of the biotransformation of methoxyflurane.
Chronic Toxicity:
1. Mutagenicity – under normal conditions, most modern and many previously used inhaled anesthetics are not mutagens and probably not carcinogens, except halothane.
2. Carcinogenicity – Several epidemiologic studies have suggested an increase in the cancer rate in operating room personnel who may be exposed to trace concentrations of anesthetic agents. However, no study has demonstrated the existence of a cause-and-effect relationship between anesthetics and cancer. Many other factors might account for the questionably positive results seen after a careful review of epidemiologic data.
3. Effects on reproduction – The most consistent finding reported from surveys conducted to determine the reproductive performance of female operating room personnel has been a higher than expected incidence of miscarriages. The risk of abortion is also clearly higher. Another concern is that anesthetics during pregnancy may lead to an increased incidence of congenital anomalies.
Yawning, coughing, and laryngeal spasm may occur during induction of anesthesia with barbiturates. Hypotension may develop, particularly in hypovolemic patients or in those with diminished cardiac contractility. Undesirably light anesthesia due to rapid redistribution from the central nervous system can occur. Pronounced respiratory depression and apnea may occur immediately after rapid injection or overdosage. Shivering or excitement and delirium in the presence of pain may be observed during recovery.
The barbiturates may exacerbate acute intermittent porphyria and are contraindicated in patients with this disease. Care should be taken to avoid extravasation or intra-arterial injection of these drugs, for tissue necrosis and gangrene may occur.
Intravenous Anesthetics
Ultra-Short-Acting Barbiturates
Although there are several ultra-short-acting barbiturates, thiopental is the one most commonly used for induction of anesthesia, often in combination with inhaled anesthetics.
Following intravenous administration, thiopental crosses the blood-brain barrier and, if given in sufficient dosage, produces hypnosis in one circulation time. Plasma: brain equlibrium occurs rapidly (in approximately 1 minute) because of high lipid solubility. Thiopental rapidly diffuses out of the brain and other highly vascular tissues and is redistributed to muscle, fat, and eventually all body tissues. It is because of this rapid removal from brain that a single dose of thiopental is so short-acting.
Metabolism following thiopental administration is much slower than redistribution and takes place primarily in the liver. Less than 1 % of an administered dose of thiopental is excreted unchanged by the kidney. Thiopental is metabolized at the rate 12-16 % per hour in humans following a single dose.
With large doses, thiopental causes dose-dependent decreases in arterial blood pressure, stroke volume, and cardiac output. This is due primarily to its effects; there is little change in total peripheral resistance. However, thiopental also markedly increases venous vessel compliance, resulting in pooling of blood and impaired venous return to the heart.
Thiopental, like other barbiturates, is a potent lowering the sensitivity of the medullary respiratory center to carbon dioxide.
Cerebral methabolism and oxygen utilization are decreased after thiopental administration in proportion to the degree of cerebral depression. Cerebral blood flow is also decreased, but much less so than oxygen consumption. This makes thiopental a much more desirable drug for use in patients with cerebral swelling than the inhaled anesthetics, since intracranial pressure and blood volume are not increased.
Thiopental may reduce hepatic blood flow and glomerular filtration rate, but it produces no lasting effects on hepatic and renal function.
Сombination Anesthesia
Balanced Anesthesia
Components: Because of its low potency, nitrous oxide must be supplemented with other agents to produce conditions suitable for surgery. The intravenous use of an ultrashort-acting barbiturate, a narcotic analgesic, a neuromuscular blocking agent, and nitrous oxide to produce general anesthesia is termed “balanced anesthesia”. Meperidine (Demerol), morphine, and fentanyl (Sublimaze) are the most widely employed analgesics and, in combination with a barbiturate, supplement the hypnotic and analgesic effects of nitrous oxide. Meperidine was the first narcotic analgesic used in this manner but is not as satisfactory as fentanyl because of its tendency to produce myocardial depression in elevated dosage.
Commonly, a narcotic analgesic analgesic is included in the premedication and anesthesia is induced with a barbiturate and nitrous oxide. The narcotic then is given intravenously in increments over a period of five to then minutes until adequate analgesia has been produced. Additional small amounts may be required during surgery if the patient shows signs of reacting to painful stimuli (eg, increasing pulse rate and arterial pressure, pupillary dilation, sweating, muscle movement). If used judiciously in this manner and if avoided during the last one to two hours of prolonged surgery, adequate intraoperative analgesia usually can be achieved without the need for postoperative ventilatory support. If a neuromuscular blocking agent is used, controlled ventilation is mandatory during surgery. If a neuromuscular blocking agent is not used, spontaneous ventilation may be satisfactory during short procedures; however, controlled ventilation generally is advisable.
The following combination is often used for short surgical procedures (15 to 20 minutes in adults): Fentanyl 0.1 mg intravenously and atropine 0.4 mg intravenously two minutes prior to induction, thiopental 4 mg/kg for induction, and maintenance anesthesia with 70 % nitrous oxide-30 % oxygen, plus supplemental doses of thiopental 2 to 3 mg/kg and fentanyl 0.5 to 1 mkg/kg. This regimen permits rapid recovery and is useful for outpatient surgery in adults.
Clinical experience and data from some controlled trials indicate that properly administered balanced anesthesia minimizes intraoperative cardiovascular depression and may increase peripheral resistance; there is an early return of consciousness, and the incidence of postoperative nausea, vomiting, excitement, and pain is low.
Neuroleptanalgesia and Neuroleptanesthesia
Neuroleptanalgesia historically refers to administration of the combination of a narcotic analgesicand droperidol (inapsine), a neuroleptic (antipsychotic) drug, to produce an altered state of consciousness and awareness. Alternative combinations used in investigational clinical studies include diazepam (valium), ketamine (ketaject, ketalar), or droperidol with the narcotic analgesics, meperidine (demerol), morphine, fentanyl (sublimaze), or pentazocine (talwin). Consciousness is not lost during neuroleptanalgesia and the appropriate combination may be of value for diagnostic and therapeutic procedures performed under local anesthesia (eg, cardiac catheterization, repeated burn dressings).
Wheitrous oxide is used to supplement these combinations, the descriptive term, neuroleptanesthesia, is employed. A muscle neuroleptanesthesia, is employed. A muscle relaxant also may be included. Neuroleptanesthesia often provides satisfactory general anesthesia, and it may be particularly valuable when the patient’s cooperation is required during the procedure, for consciousness should return soon after the flow of nitrous oxide is terminated.
The narcotic analgesic, fentanyl, has been used most commonly with the butyrophenone, droperidol, ieuroleptanesthesia. Droperidol and fentanyl are available as single-entity products or in fixed-dose combination (talamonal).
Droperidol and fentanyl citrate
Actions and uses. This fixed-dose combination contains the narcotic analgesic, fentanyl (0.05 mg/ml), and the neuroleptic butyrophenone, droperidol (2.5 mg/ml)/ These drugs usually provide satisfactory amnesia and analgesia, and the mi9xture has been used to produce neuroleptanalgesia and neuroleptanesthesia. As with all combinations, its use is appropriate only when both drugs are to be administered at the same time and in the dosage ratio present in the mixture; otherwise, the two drugs should be administered separately as necessary.
Droperidol and fentanyl can be administered safely to patients who have previously experienced malignant hyperpyrexia under general anesthesia.
Adverse reactions and precautions. Cardiac output is reduced and systemic vascular resistance is increased initially but return to normal as surgery continues. Arterial pressure and pulse rate tend to remain stable, but the heart rate may decrease. Ventricular arrhythmias are uncommon unless the sympathetic nervous system is stimulated by accumulation of carbon dioxide due to inadequate ventilation/ profound depression of the ventilatory rate and minute volume and apnea (caused by fentanyl) are to be expected. Apnea may result from central nervous system depression or peripheral muscle rigidity and can be treated by controlled ventilation. Muscle rigidity can be overcome by neuromuscular blocking agents.
Transient, slight abnormalities in the results of liver function tests similar to those observed after other anesthetic techniques have developed. Hyperglycemia occurs, but there is no evidence of metabolic acidosis. Pupils are constricted, intraocular tension is unchanged, and, provided hypercardia is avoided, cerebrospinal fluid pressure is reduced in patients with and without spaceoccupying lesions. In contrast, the volatile agents may increase pressure, even with normocardia.
Consciousness and spontaneous respiration return rapidly when nitrous oxide and controlled ventilation are stopped if large doses have not been administered repeatedly. Postoperative nausea, vomiting, and shivering due to hypothermia may occur, but restlessness and delirium are uncommon. Extrapyramidal reactions may develop if a large dose of droperidol has been used.
Narcotic and non-narcotic analgesics
Opiate agonists
History: References to the opium poppy exist as early as the third century BC with the Sumarians and Egyptians familiar with its analgesic and antidiarrheal properties. The opium poppy, papaver somniferum, actually contains more than 20 different alkaloids. Morphine was isolated in 1806 and followed by codeine in
Nalorphine, released in 1952 and used to treat opiate toxicity, is a stronger opiate antagonist than agonist. Nalorphine has since been discontinued due to the high incidence of psychometric side effects and the release of relatively “pure” opiate antagonists, naloxone (1971), naltrexone (1984), and nalmefene (1995).
With the confirmation of opiate receptors, the search began for endogenous opiates. In 1975, Hughes and colleagues[267] published their isolation of encephalin, a pentapeptide that was later determined to possess an amino acid sequence similar to a section of beta-endorphin. Both encephalin and beta-endorphin are now known to exert opiate-agonist properties.
Mechanism of Action: Opiate agonists and antagonists interact with stereospecific, saturable receptors in the brain and other tissues. These receptors are widely but unevenly distributed throughout the CNS. Opiate receptors include µ (mu), kappa (kappa), and delta (delta), which have been reclassified by an International Union of Pharmacology subcommittee as OP1 (delta), OP2 (kappa), and OP3 (µ). Distribution of these receptors varies according to the presence in the CNS. Mu receptors are located widely throughout the CNS, especially in the limbic system (frontal cortex, temporal cortex, amygdala, and hippocampus); thalamus; striatum; hypothalamus; and midbrain. Kappa receptors are located primarily in the spinal cord and cerebral cortex. Opiate receptors are coupled with G-protein (guanine-nucleotide-binding protein) receptors and function as modulators, both positive and negative, of synaptic transmission via G-proteins that activate effector proteins. Opiate agonists produce analgesia by inhibiting excitatory neurotransmission of substance P, acetylcholine, noradrenaline, dopamine, and GABA on a cellular level by blocking voltage-dependent calcium channels. Opiate agonists also have stimulatory effects oeurotransmission and neurotransmitter release; the exact mechanism of this stimulation has not been fully determined. Analgesia is mediated through changes in the perception of pain at the spinal cord (µ2-, delta-, kappa-receptors) and higher levels in the CNS (µ1- and kappa3 receptors). Opiate agonists also modulate the endocrine and immune systems. Opioids inhibit the release of vasopressin, somatostatin, insulin and glucagon.[1939] In addition to analgesia, stimulation at the µ-receptor produces euphoria, respiratory depression, and physical dependence.
Distinguishing Features: Pure opiate agonists may be categorized as phenanthrenes including codeine, hydromorphone, morphine, and oxycodone; phenylpiperidines (alfentanil, fentanyl, meperidine, and sufentanil) and diphenylheptanes (methadone, propoxyphene). Pure opiate agonists are generally referred to as either strong opiates (hydromorphone, morphine, methadone, and oxycodone) and weak opiate agonists (codeine, hydrocodone, and propoxyphene).
Naloxone, naltrexone, and nalmefene are antagonists at µ- and kappa-receptors. Administration of these agents to patients taking chronic opiate agonists will induce withdrawal symptoms and cause pain to recur.
Published tables vary in suggested equianalgesic doses of pure opiate agonists. Assessment of individual clinical response is necessary because there is not complete cross-tolerance among these agents.
Opiate Agonist Equianalgesic Chart – Adults and Children >=
Morphine (round-the-clock dosing)
•Oral 30 mg
•Parenteral 10 mg
Morphine (single or intermittent dosing)
•Oral 60 mg
•Parenteral 10 mg
Hydromorphone
•Oral 7.5 mg
•Parenteral 1.5 mg
Meperidine
•Oral 300 mg
•Parenteral 75-100 mg
Levorphanol
•Oral 4 mg
•Parenteral 1-2 mg
Oxycodone
•Oral 15-20 mg
Hydrocodone
•Oral 30 mg
Codeine
•Oral 200 mg (this dose is not recommended)
•Parenteral: This dosage form is not routinly used clinically as more potent and less toxic agents are available.
Some pharmacokinetic differences also exist. Opiate agonists may be administered via many routes including orally, parenterally, epidurally, intrathecally, and topically. Meperidine is a short-acting opiate agonist, while methadone is a long-acting opiate agonist. Levomethadyl, a drug for the management of opiate dependence, acts longer than methadone. Regarding opiate antagonists, both naloxone and nalmefene are administered intravenously, however, naloxone is short-acting (1-2 hours) and nalmefene is long-acting (10 hours). Naltrexone is administered orally and is long-acting.
Meperidine also possesses the unique ability to interrupt amphotericin-B-induced infusion reactions such as shaking chills. It is unclear how meperidine mediates this effect, since other opiate agonists are not known to be effective for this use.
Opiate dependence is considered a medical disorder requiring pharmacologic treatment. During addiction, the functioning of the opiate receptor is altered due to repeated opiate exposure. Methadone treatment normalizes neurologic and endocrine processes.
Opium is still available as a tincture or as camphorated opium tincture (Paregoric) that is used to control severe diarrhea. Paregaoric is 25 times less potent than opium tincture. According to the American Academy of Pediatrics, diluted tincture of opium is the preferred drug for the treatment of opioid withdrawal ieonates.
Adverse Reactions: The most significant and well-known adverse reaction to opiate agonists is respiratory depression. Death secondary to opiate overdose is nearly always due to respiratory depression. When opiate agonists are appropriately titrated, the risk of severe respiratory depression is generally small as tolerance rapidly develops to this effect. True allergy to opiate agonists is uncommon, despite the claims of many patients. Opiate agonists can cause histamine release, which can induce rash and pruritus. The most common GI effects include nausea/vomiting and constipation. Nausea/vomiting is more common at the initiation of therapy or when increasing doses and usually resolves within a few days. Constipation is an ongoing concern with chronic opiate therapy and requires prophylactic treatment. Codeine is often associated GI intolerance, which some patients incorrectly identify as an allergic reaction.
Some health care professionals avoid opiate agonists therapy for the treatment of pain due to concerns of physical and psychological dependence and tolerance. It is important to differentiate physiologic dependence, the onset of a withdrawal syndrome upon abrupt discontinuation of the drug from psychological dependence. Psychological dependence is a behavioral syndrome characterized by drug craving, overwhelming concern with acquisition of the drug and other drug-related behaviors such as drug selling and seeking the drug from multiple sources. Tolerance is the need for increasing opiate doses to maintain initial pain relief. Typically, tolerance presents as a decrease in the duration of analgesia and is managed by increasing the opioid dose or frequency. There is no limit to tolerance; thus, some patients may require very large doses of opiate analgesics to control their pain. When increasing doses of analgesia are required causes may be multi-factorial including tolerance, progression of disease or psychological distress.
Clinicians should be aware of a CNS-excitatory metabolite of meperidine and propoxyphene. When administered in high doses, especially to patients with renal disease, these agents can cause CNS disturbances including seizures.
ixed opiate agonists/antagonists
History: In an effort to develop opioid analgesics with little or no abuse potential, agents with both opiate agonist and antagonist activities have been developed. With the introduction of pentazocine (1967), butorphanol (1978), nalbuphine (1979), and buprenorphine (1981), the group of mixed agonist-antagonist opiate analgesics was born. The first marketed mixed agonist/antagonist, nalorphine (1952) is no longer available due to an unacceptable incidence of psychotomimetic effects. Investigational mixed opiate agonists/antagonists include meptazinol, profadol, and propiram.
Mechanism of Action: Opiate agonists and antagonists interact with stereospecific, saturable receptors in the brain and other tissues. Opiate receptors include µ (mu), kappa (kappa), and delta (delta), which have been reclassified by an International Union of Pharmacology subcommittee as OP1 (delta), OP2 (kappa), and OP3 (µ). These receptors are widely but unevenly distributed throughout the CNS. Mu receptors are located in all areas of the CNS, especially in the limbic system (frontal cortex, temporal cortex, amygdala, and hippocampus); thalamus; striatum; hypothalamus; and midbrain. Kappa receptors are located primarily in the spinal cord and cerebral cortex. Opiate receptors are coupled with G-protein (guanine-nucleotide-binding protein) receptors and function as modulators, both positive and negative, of synaptic transmission via G-proteins activated effector proteins. Analgesia is mediated through changes in the perception of pain at the spinal cord (µ2-, delta-, kappa-receptors) and higher levels in the CNS (µ1- and kappa3 receptors). In addition to analgesia, stimulation at the µ-receptor produces euphoria, respiratory depression, and physical dependence. The opiate agonists/antagonists are thought to bind to µ-receptors and compete with pure opiate agonists, but either exert no action (competitive antagonism) or limited effects (partial agonist) at this receptor. It is possible that an opioid may function as an antagonist at the µ-receptor but still have analgesic effects by functioning as an agonist at kappa-receptors.
Distinguishing Features: Mixed opiate agonists/antagonists exhibit a variety of actions at the three receptors, although all are antagonists at the µ-receptor and most are either full or partial agonists at kappa-receptors. The mixed opiate agonists/antagonists may be divided into two groups based upon their adverse effects and abstinence syndromes. Morphine-type opiate agonists/antagonists have low intrinsic µ-agonist activity but have a high affinity for the µ-receptor. Buprenorphine, which has partial µ-agonist activity, and the investigational agents, meptazinol, profadol and propiram, are members of this group. Buprenorphine produces analgesia and other CNS effects that are qualitatively similar to morphine. The withdrawal syndrome associated with buprenorphine is less severe than that of morphine. Nalorphine-type opiate agonists/antagonists have varying affinity and intrinsic activity at all three opiate receptors, but all are competitive antagonists at the µ-receptor with agonist activity at kappa-receptors. Members of this group include butorphanol, nalbuphine, and pentazocine. These agents are associated with a higher incidence of psychotomimetic effects.
Unlike pure opiate agonists, these agents have a ceiling effect in regard to analgesic effects and respiratory depression. Mixed opiate agonists/antagonists are generally not considered agents of choice in patients with chronic pain. These agents can precipitate withdrawal symptoms in patients who are taking chronic opiate agonists.
Adverse Reactions: The abuse potential of the mixed opiate agonists/antagonists is less than propoxyphene and codeine. The respiratory depressive effects of the mixed opiate agonists/antagonists seem to have a ceiling effect as opposed to pure opiate agonists where this effect is proportional to the dose. Buprenorphine-induced respiratory depression is not readily reversed by usual doses of naloxone; large doses of naloxone must be used. High doses of pentazocine are associated with respiratory depression, hypertension, tachycardia and psychotomimetic effects including anxiety, nightmares, and hallucinations. The hemodynamic effects of mixed opiate agonists/antagonists are varied. The incidence of biliary tract effects with these agents is usually lower than the incidence of biliary side effects with morphine.
Tolerance may develop to the analgesic and certain adverse effects of mixed agonists/antagonists, although not to the degree of that seen with pure opiate agonists.
Narcotics
Those drugs which possess both an analgesic (pain relieving) and sedative properties.
OPIOID
refer to drugs in a generic sense, natural or synthetic, with morphine- like actions
Classification of OPIOIDS
natural
semisynthetic
synthetic
Natural
phenanthrene
morphine 10%
codeine 0.5%
thebaine 0.2%
benzylisoquioline
papaverine
noscopine
narceine
Semisynthetic
heroin
oxymorphone
hydromorphone
Synthetic
meperidine
methadone
morphinians
benzamorphans
Morphine
pentacyclic alkaloid (five ring structure)
oxygen bridge at 4,5 position
three major rings (a, b, c)
phenolic groups (s/a hydroxyl, alcoholic, OH) at position 3 and 6
modifications at those positions changes pharmacokinetics and potency of drug
nitrogen at 16 position (n16)
changing it by adding an alkyl group converts it to naloxone (i.e. go from a agonist to an antagonist)
OPIOID receptors (located in CNS)
Receptor Stimulation
mu
physical dependence
euphoria
analgesia (supraspinal)
respiratory depression
kappa
sedation
analgesia (spinal)
miosis
delta
analgesia (spinal & supraspinal)
release of growth hormone
sigma
dysphoria (opposite of euphoria)
hallucination
respiratory and vasomotor stimulation
mydriasis
OPIOID receptors in CNS, their distribution is not uniform they are at areas concerned with pain receptor locations beginning with highest concentration areas
1. cerebral cortex
2. amygdala
3. septum
4. thalamus
5. hypothalamus
6. midbrain
7. spinal cord
Sigma receptor also known as the “pcp receptor” since pcp will bind there
Mu receptor high in areas of pain perception and at medulla (area for respiration)
Amino acid sequence of OPIOID peptides
In early 1950’s, it was thought that since morphine from poppy plant had relieved pain then it was likely that their was an endogenous substance for pain relief first found the receptor and then found the peptide which are enkephalins
Enkephalins
they are 5 amino acids long
also have met enkephalin (methionine at 5′ position) and leu enkephalin (leucine at 5′ position enkephalins are neuromodulators since they are small peptides, it was found that they came from larger peptides (pro enkephalins) proenkephalin gene codes for peptide 276 amino acid in length cleavage of proenkephalin gives 4 to 5 pieces of activated enkephalins
Runners high enkephalins let a runner not feel the knee pains caused by running
Endorphin 30 amino acid peptide
last 5 amino acids are the same sequence as enkephalins
endorphins are neurohormones
conservation between species
little difference in humans
Proopomelanocortin
various proteins that can come from this gene
gamma MSH, ACTH, beta LPH, alpha MSH, beta MSH, met Enk
Pharmacokinetics
absorption
readily absorbed from GI tract, nasal mucosa, lung subcutaneous, intramuscular, and intravenous route
distribution
bound free morphine accumulates in kidney, lung, liver, and spleen
CNS is primary site of action (sedation)
metabolism/excretion
metabolic transformation in liver
conjugation with glucuronic acid
excreted by kidney
half life is 2.5 to 3 hours (does not persist in body tissue)
morphine 3 glucuronide in main excretion product
lose 90% in first day
duration of 10 mg dose is 3 to 5 hours
Morphine administration
oral morphine not given due to erratic oral availability
significant variable first pass effect from person to person and have intraspecies effect (same dose will vary in person day to day)
IV morphine acts promptly and its main effect is at the CNS
CNS is primary site of action of morphine
analgesia
sedation
euphoria
mood change
mental cloudiness
Morphine strongest analgesic today as a natural substance
Morphine analgesia
changes our reaction and our perception of pain
i.e. if person steps on your foot, still perceive somebody stepped on foot, but have lesser of a sensation where paiot blocked, but your reaction changes where your pain threshold has increased (i.e. can tolerate pain more)
severe cancer pain is tolerated more when person is given morphine
relieves all types of pain, but most effective against continuous dull aching pain
sharp, stabbing, shooting pain also relieved by morphine
Morphine sedation
morphine causes sedation effect, but no loss of consciousness
person easily go asleep, but easily aroused unlike when on barbiturates where person goes into coma
Morphine euphoria
sense of well being
reason why morphine is abused
Morphine given to a pain free individual
first experience is dysphoria
not experienced in person in pain
Initial Injection of opioid makes person sick, have anxiety, apathetic, lethargic, inability to concentrate, nausea, vomiting, and drowsiness Morphine mood change person who is lively will become dull when using morphine
Morphine mental cloudiness difficulty in concentration and have apathy
Effects of morphine on respiration there is a primary and continuous depression of respiration related to dose decrease rate decrease volume decrease tidal exchange mu receptor activation produces respiratory depression; with increase in dose, further respiratory depression Morphine CNS becomes less responsive to pCO2 thereby causing a build up of CO2
Depression on medulla affect brain center on rhythm and responsiveness gives irregular breathing patterns. As increase dose, one will see periods of apnea Respiratory centers less responsive to pCO2 as well as medullary centers for responsiveness to CO2 in blood so irregular breathing (short breath) normal response 2 to 3 hours after normal dose Morphine initially stimulates chemoreceptor trigger zone (CTZ)and then it will depress CTZ (antiemetic effect) this may be one of the reasons for the dysphoria in pain free people
Morphine nausea and vomiting
morphine initially stimulates the CTZ -> emetic
later effect is antiemetic
cough reflex
antitussive effect due to direct depression of cough center in the medulla
pupil size
morphine produces miosis (pinpoint pupils)
tolerance does not develop to miosis
excitatory and spinal reflexes
high doses of many OPIOID cause convulsions
Central trigger zone
in postrema of medulla
stimulation by stretch receptors causes nausea and vomiting
has afferents from gut and ear
involved in motion sickness
Codeine in cough syrup
it has an antitussive effect
Morphine and all OPIOID
they cause miosis (pinpoint pupils)
kappa receptor effect
gives indication that patient has OPIOID overdose
pinpoint pupils responsive to bright light
if block kappa receptor (causes miosis), see mydriasis from sigma effect
oculomotor nerve (CN3) is stimulated by kappa receptor site
start at edenmeyeroff nucleus. see parasympathetic discharge at oculomotor nerve giving pin point pupils
atropine only blocks effect indicating parasympathetics only partially explains the miosis
High doses (overdose situation) of morphine
can cause convulsions
this is stimulation at sigma receptor
at really high doses, sigma receptor overwhelmed
Summary of CNS effects of morphine
1. analgesia
analgesia, sedation, euphoria, mood change, mental cloudiness
2. respiration
depression
3. nausea and vomiting
emetic, and antiemetic (main effect)
4. cough reflex
antitussive
5. pupil size
miosis (stimulation of cranial nerve 3)
6. excitatory spinal reflexes
stimulation produces convulsions (high doses)
Cardiovascular effects of morphine lead to vasodilation
morphine causes the release of histamine
suppression of central adrenergic tone
suppression of reflex vasoconstriction
Morphine effects on the vasculature
morphine by itself has no direct effect on heart since no OPIOID receptor on heart, but indirectly it causes vasodilation lowering blood pressure
orthostatic hypotension from lying to sitting position test due to suppression of vasoconstriction reflex due to less sensitivity of pCO2 in CNS, cerebral artery also dilates and have increased intracranial pressure
Morphine effects on the gastrointestinal system
increase in tone and decrease in mobility leading to constipation
decreased concentration of HCl secretion
increased tone in stomach, small intestine, and large intestin
Reason for constipation produced by morphine
delay of passage of food (gastric contents) so more reabsorption of water
**tolerance does not develop (i.e. same amount of effect each time) to this constipation effect
Morphine increases tone of smooth muscle
Morphine effects on various smooth muscles
biliary tract
marked increase in the pressure in the biliary tract
10 fold increase over normal (normal is
increase due to contraction of sphincter of oddi
urinary bladder
tone of detrusor muscle increased
feel urinary urgency
have urinary retention due to increased muscle tone where sphincter closed off
bronchial muscle
bronchoconstriction can result
**contraindicated in asthmatics, particularly before surgery
uterus
contraction of uterus can prolong labor
Morphine
due of increased muscle tone, it gives biliary tract pain that resembles biliary colic
Tolerance to morphine (therefore, must increase dose)
nausea
analgesia
sedation
respiratory depression
cardiovascular
euphoric
not to:
miosis
constipation
OVERVIEW OF THE EFFECTS OF MORPHINE
Toxicity of morphine
acute overdose
respiratory depression
pinpoint pupils (miosis)
coma
Treatment
1. establish adequate ventilation
2. give OPIOID antagonist (naloxone)
Naloxone
it has no agonist activity
it displaces morphine from all receptors, reverses all of the effects of morphine
its effects are immediate (3-5 min)
duration is 30-45 minutes so have to reinject it
Heroin
its effects can last 3-5 hours
Therapeutic uses of morphine
relief of pain
terminal illness
preoperative medications
postoperative medications
acute pulmonary edema
constipating effect
cough
obstetrical analgesia
Morphine for relief of pain don’t give morphine for severe head injuries since it dilates cerebral blood vessels causing an increase in intracranial pressure
Morphine for terminal illness used for the pain relief only , no effect to cure person, but makes their life tolerable with morphine
Morphine for preoperative medication morphine alleviates some of that pain use morphine, papaverine, fentanyl (generic name)
Fentanyl
lasts 30 minutes
short duration
quick onset
OPIOID give smooth induction into anesthesia
pain relieving
reduces restlessness and anxiousness
reduces cough reflex
decreases pain
allows us to reduce amount of general anesthetic necessary
Disadvantage of using morphine in preoperative medications
prolongs awakening time
spasms in smooth muscle
wheezing in asthmatic patients
nausea and vomiting can occur
constipation and urinary retention
hypotension due to vasodilation
respiratory depression
Morphine for postoperative medication
controls pain and discomfort after surgery
lets person breathe deeply
Disadvantage of using morphine in postoperative medications
GI effect
constipation
urinary retention
cough
cough good for clearing bronchial tree, but morphine reduces coughing
Morphine for acute pulmonary edema with left sided heart failure
related to anxiety level
high anxiety
not breathing well
pooling effect in heart
morphine relieves anxiety
breathing more deeply and pulmonary edema relieved
Morphine for severe dysentery (ie. shigella)
due to morphine’s constipation effect
Codeine
drug of choice for cough
morphine would be too strong of a medication
Morphine for obstetrical analgesia
not used much since morphine crosses placental barrier
baby born with respiratory depression
meperidine is drug of choice for obstetrical analgesia
Contraindications of morphine
biliary colic
due to increased pressure in biliary tract
acute head injuries
due to increased intracranial pressure
asthmatics
Drug interactions with OPIOIDS
**in general, the coadministration of CNS depressants with OPIOID often produces at least an additive depression (potentiation)
OPIOID and phenothiazines
produces an additive CNS depression as well as enhancement of the actions of OPIOID (respiratory depression)
this combination may also produce a greater incidence of orthostatic hypotension
OPIOID and tricyclics antidepressants
can produce increased hypotension
meperidine and MOA inhibitors
results in severe and immediate reactions that include excitation, rigidity, hypertension, and severe respiratory depression
OPIOID and barbiturates
increased clearance
morphine and amphetamine
enhanced analgesic effect
Morphine
at 3 hydroxyl and 6 hydroxyl positions have changes that change the potency and pharmacokinetics
Codeine
change in the methyl group on 3 position (substituted for the hydroxyl group)
one tenth the potency (analgesic properties) of morphine
absorbed readily from GI tract
the absorption is more regular than morphine and more predictable
given orally
metabolized like morphine through glucuronic acid
physical dependence is necessity of drug so you don’t go through withdrawal tolerance and physical dependence is protracted from morphine since potency of codeine is low
withdrawal from codeine is mild in relation to morphine
antitussive drug for cough
Heroin (diacetylmorphine)
at 3 and 6 hydroxy positions, there are acetyl groups instead of hydroxyl groups
it is anywhere from 3 to 4 times the analgesic potency of morphine
heroin is the most lipophilic of all the OPIOID
morphine is the least lipophilic of all the OPIOID
when heroin is ingested, it crosses the blood brain barrier rapidly (morphine crosses slow) where it is hydrolyzed to monoacetyl morphine (acetyl group got cleaved off) and then it is hydrolyzed to morphine making more of the drug in the brain making it 3 to 4 times more potent
withdrawal symptoms of heroin similar to morphine, but more intense
mydriasis
diarrhea
vasoconstriction
dysphoria
etc.
OPIOID withdrawal is NOT fatal , person won’t die; but with barbiturates, withdrawal can be fatal
withdrawal from OPIOID is called going cold turkey (goose bumps on skin) and also called kicking the habit due to leg motions
as a general rule, a drug that is more potent as analgesic than morphine will have more intense drug withdrawal symptoms
Hydromorphone (trade name is dilaudid)
have ketone at 6 hydroxyl position of morphine
also strong agonist
9 times more potent than morphine
more sedation than morphine so less euphoric feeling so not abused much
less constipation
does not produce miosis
tolerance and physical dependence is more intense than morphine because of its high potency
respiratory depression same as morphine
Fentanyl (sublimaze, china white)
synthetic drug
different structure than morphine
80 to 100 times more potent than morphine
rapidly acting drug
used as preoperative medication
short acting (30-45 min)
onset of action is 5 minutes
high potency
highly abused ,known as china white as street name
Meperidine
produced in 1940’s
wanted drug with less addictive liability than morphine, but it has same addictive liability as morphine
same CNS actions as morphine
sedation, analgesia, respiratory depression
potency same as morphine
unlike morphine:
more respiratory depression
more bronchoconstriction activity
less constipation
no antitussive activity
**it causes mydriasis (not miosis)
toxic effects similar to atropine
dry as a bone, blind as a bat, red as a beet, mad as a hatter
have dry mouth
drug absorbed orally
drug most abused by health care professionals due to its availability
withdrawal similar to morphine
Diphenoxylate (lomotil)
can be OTC drug now
therapeutic use is antidiarrhea drug (treats diarrhea)
meperidine type drug
has very little analgesic properties at therapeutic dose
no antitussive effect
at high doses it has analgesic problems
causes respiratory depression and euphoria at high doses
Methadone
pharmacological activity similar to morphine
long duration of activity
absorbed well orally
lasts long time
16 to 20 hour duration of action
used in maintenance program for narcotic treatment
all OPIOID are cross tolerant to each other since all act on same receptor site
want to replace heroin from receptor site (short duration of action of 2 hours) with methadone (16 to 20 hour duration of action) to get people off of heroin while preventing withdrawal
powerful pain reliever
same potency as morphine
Antagonism of Morphine
two drugs: naloxone and naltrexone (pure antagonist)
Naloxone
no analgesic activity at all
competitive antagonist at mu, kappa, and sigma receptor
displaces morphine and other OPIOID from receptor site
reverses all actions of the OPIOID and does it rather quickly
it will precipitate withdrawal
person on heroin, thealoxone will precipitate withdrawal, but naloxone effects are seen in the first five minutes and it only lasts for 30 minutes:
increased blood pressure
diarrhea
reversible respiratory depression
metabolized same as morphine through glucuronic acid and excreted through kidney
after naloxone, when person wakes up, person will be very irritable and agitated; after 30-45 minutes coma will return so closely supervise patients; give another dose after drug wears off.
Naltrexone
same effect of naloxone except it is used orally so can’t use it if for person with acute toxicity
long duration of activity
single dose block action of heroin effects for 24 hours
used for emergency treatment
once stabilized, give patient naltrexone
patient get no euphoric effect from heroin so person gets off heroin (negative reinforcement)
approved for use by the FDA
also used for treatment of alcoholism
1. http://www.youtube.com/watch?v=oKHQJc5mG8Y&feature=related
