The study of the relationship between a drug's dose, tissue concentration, and elapsed time is called pharmacokinetics (how a body affects a drug).

The study of drug action, including toxic responses, is called pharmacodynamics (how a drug affects a body).

course of general anesthesia can be divided into three phases: (1) induction, (2) maintenance, and (3) emergence. Inhalation anesthetics are particularly useful in the induction of pediatric patients in whom it may be difficult to start an intravenous line. In contrast, adults usually prefer rapid induction with intravenous agents, although the nonpungency and rapid onset of sevoflurane have made inhalation induction practical for adults. Regardless of the patient's age, anesthesia is often maintained with inhalation agents. Emergence depends primarily upon the pulmonary elimination of these agents. Because of their unique route of administration, inhalation anesthetics have useful pharmacological properties not shared by other anesthetic agents. For instance, exposure to the pulmonary circulation allows a more rapid appearancePHARMACOKINETICS OF INHALATION ANESTHETICS unknown, it is assumed that their ultimate effect depends on attainment of a therapeutic tissue concentration in the central nervous system

FACTORS AFFECTING INSPIRATORY CONCENTRATION (FI) mixes with gases in the breathing circuit before being inspired by the patient. Therefore, the patient is not necessarily receiving the concentration set on the vaporizer depends mainly on the fresh gas flow rate, the volume of the breathing system, and any absorption by the machine or breathing circuit

FACTORS AFFECTING ALVEOLAR CONCENTRATION (FA)1. Uptake If no uptake of anesthetic agent by the body, the alveolar gas concentration (FA) would rapidly approach the inspired gas concentration (FI) Reality alveolar concentrations lag behind inspired concentrations (FA/FI< 1.0). The greater the uptake, the slower the rate of rise of the alveolar concentration and the lower the FA:FIratio Because the concentration of a gas is directly proportional to its partial pressure, the alveolar partial pressure will also be slow to rise. The alveolar partial pressure is important because it determines the partial pressure of anesthetic in the blood and, ultimately, in the brain. Similarly, the partial pressure of the anesthetic in the brain is directly proportional to its brain tissue concentration, which determines clinical effect. Therefore, the greater the uptake of anesthetic agent, the greater the difference between inspired and alveolar concentrations, and the slower the rate of induction. Three factors affect anesthetic uptake: solubility in the blood, i. Insoluble agents, such as nitrous oxide, are taken up by the blood less avidly than soluble agents, such ashalothane. As a consequence, the alveolar concentration of nitrous oxide rises faster than that of halothane, and induction is faster.ii. The higher the blood/gas coefficient, the greater the anesthetic's solubility and the greater its uptake by the pulmonary circulation. iii. As a consequence of this high solubility, alveolar partial pressure rises more slowly, and induction is prolonged. iv. Because fat/blood partition coefficients are greater than 1, it is not surprising that blood/gas solubility is increased by postprandial lipidemia and is decreased by anemia.v. Eg. Blood/gas for NO is 0.47, that means in same 1 ml volume of blood and alveolar gas, under same partial pressure, theres 0.47 unit of NO in blood, 1 unit of NO in alveolar gas. Things like halothane has much higer solubility, being 2.4. But why higher solubility takes longer to do induction? Concentration of gas is directly proportional to its partial pressure. Because with higher solubility, so achieve the same partial pressure, halothane has to dissolve 2.4 units in blood! alveolar blood flow, and i. cardiac output increases, anesthetic uptake increases, the rise in alveolar partial pressure slows, and induction is delayed.ii. Low-output states predispose patients to overdosage with soluble agents, as the rate of rise in alveolar concentrations will be markedly increased. the difference in partial pressure between alveolar gas and venous blood.i. depends on tissue uptakeii. If anesthetics did not pass into organs such as the brain, venous and alveolar partial pressures would become identical and there would be no pulmonary uptakeiii. transfer of anesthetic from blood to tissues is determined by three factors analogous to systemic uptake: tissue solubility of the agent (tissue/blood partition coefficient), tissue blood flow, and the difference in partial pressure between arterial blood and the tissue.iv. highly perfused vessel-rich group (brain, heart, liver, kidney,and endocrine organs) is the first to take up appreciable amounts of anesthetic.v. Anesthetic uptake produces a characteristic curve that relates the rise in alveolar concentration to timevi. initial steep rate of uptake is due to unopposed filling of the alveoli by ventilation. The rate of rise slows as the vessel-rich groupand eventually the muscle groupreach their capacityvii. 2. Ventilation lowering of alveolar partial pressure by uptake can be countered by increasing alveolar ventilation constantly replacing anesthetic taken up by the pulmonary bloodstream results in better maintenance of alveolar concentration. 2 situationsi. The effect of increasing ventilation will be most obvious in raising the FA/FIfor soluble anesthetics, as they are more subject to uptake.ii. the FA/FIis already high for insoluble agents, increasing ventilation has minimal effect.3. Concentration effects of uptake can also be reduced by increasing the inspired concentration. Interestingly, increasing the inspired concentration not only increases the alveolar concentration but also increases its rate of rise (ie, increases FA/FI) This has been termed the concentration effecti. The first is confusingly called the concentrating effect. If 50% of an anesthetic is taken up by the pulmonary circulation, an inspired concentration of 20% (20 parts of anesthetic per 100 parts of gas) will result in an alveolar concentration of 11% (10 parts of anesthetic remaining in a total volume of 90 parts of gas). On the other hand, if the inspired concentration is raised to 80% (80 parts of anesthetic per 100 parts of gas), the alveolar concentration will be 67% (40 parts of anesthetic remaining in a total volume of 60 parts of gas.). Thus, even though 50% of the anesthetic is taken up in both examples, a higher inspired concentration results in a disproportionately higher alveolar concentration. In this example, increasing the inspired concentration 4-fold results in a 6-fold increase in alveolar concentration. The extreme case is an inspired concentration of 100% (100 parts of 100), which, despite a 50% uptake, will result in an alveolar concentration of 100% (50 parts of anesthetic remaining in a total volume of 50 parts of gas).ii. The second phenomenon responsible for the concentration effect is the augmented inflow effect. Using the example above, the 10 parts of absorbed gas must be replaced by an equal volume of the 20% mixture to prevent alveolar collapse. Thus, the alveolar concentration becomes 12% (10 plus 2 parts of anesthetic in a total of 100 parts of gas). In contrast, after absorption of 50% of the anesthetic in the 80% gas mixture, 40 parts of 80% gas must be inspired. This further increases the alveolar concentration from 67% to 72% (40 plus 32 parts of anesthetic in a volume of 100 parts of gas). more significant with nitrous oxide than with the volatile anesthetics, as the former can be used in much higher concentrations. Nonetheless, a high concentration of nitrous oxide will augment (by the same mechanism) not only its own uptake but theoretically that of a concurrently administered volatile anesthetic. The concentration effect of one gas upon another is called the second gas effect, which is probably insignificant in the clinical practice of anesthesiology.FACTORS AFFECTING ARTERIAL CONCENTRATION (FA) Ventilation/Perfusion Mismatch Normally, alveolar and arterial anesthetic partial pressures are assumed to be equal, but in fact the arterial partial pressure is consistently less than end-expiratory gas would predict. Reasons for this may include venous admixture, alveolar dead space, and nonuniform alveolar gas distribution.FACTORS AFFECTING ELIMINATION Anesthetics can be eliminated by biotransformation, transcutaneous loss, or exhalation most important route for elimination of inhalation anesthetics is the alveolus Many of the factors that speed induction also speed recovery: elimination of rebreathing, high fresh gas flows, low anesthetic-circuit volume, low absorption by the anesthetic circuit, decreased solubility, high cerebral blood flow (CBF), and increased ventilation

PHARMACODYNAMICS OF INHALATION ANESTHETICS

multitude of substances capable of producing general anesthesia is remarkable: inert elements (xenon), simple inorganic compounds (nitrous oxide), halogenated hydrocarbons (halothane), and complex organic structures (barbiturates) various agents probably produce anesthesia by different methods (agent-specific theory) The unitary hypothesis proposes that all inhalation agents share a common mechanism of action at the molecular level. This is supported by the observation that the anesthetic potency of inhalation agents correlates directly with their lipid solubility (MeyerOverton rule). The implication is that anesthesia results from molecules dissolving at specific lipophilic sites. Neuronal membranes contain a multitude of hydrophobic sites in their phospholipid bilayer. Anesthetic binding to these sites could expand the bilayer beyond a critical amount, altering membrane function (critical volume hypothesis) Anesthetic binding might significantly modify membrane structure. Two theories suggest disturbances in membrane form (the fluidization theory of anesthesia and the lateral phase separation theory) General anesthetic action could be due to alterations in any one of several cellular systems including ligand-gated ion channels, second messenger functions, or neurotransmitter receptors. For example, many anesthetics enhance-aminobutyric acid (GABA) inhibition MINIMUM ALVEOLAR CONCENTRATION is the alveolar concentration that prevents movement in 50% of patients in response to a standardized stimulus (eg, surgical incision) a useful measure because it mirrors brain partial pressure, allows comparisons of potency between agents, and provides a standard for experimental evaluations MAC values for different anesthetics are roughly additiveFactors which Increase Anesthetic RequirementsFactors which Decrease Anesthetic Requirements

Chronic ETOH Infant (highest MAC at 6 mo.) Red hair Hypernatremia Hyperthermia Acute ETOH Elderly Patients Hyponatremia Hypothermia Anemia (Hgb < 5 g/dL) Hypercarbia Hypoxia Pregnancy

One of the most striking is the 6% decrease in MAC per decade of age, regardless of volatile anesthetic.MAC is relatively unaffected by species, sex, or duration of anesthesia

Example of inhalation anasesthetics

Inorganic VS organic

1. NITROUS OXIDE N2O; laughing gas is the only inorganic anesthetic gas in clinical use colorless and essentially odorless gas at room temperature and ambient pressure relatively inexpensive anesthetic, however, concerns regarding its safety have led to continued interest in alternatives such asxenon Effects on organs CVS: stimulate the sympathetic nervous system Resp: increases respiratory rate (tachypnea) and decreases tidal volume as a result of central nervous system stimulation and, perhaps, activation of pulmonary stretch receptors Brain: By increasing CBF and cerebral blood volume, nitrous oxide produces a mild elevation of intracranial pressure MSK: In contrast to other inhalation agents, nitrous oxide does not provide significant muscle relaxation. Problems Although nitrous oxide is insoluble in comparison with other inhalation agents, it is 35 times more soluble than nitrogen in blood. Thus, it tends to diffuse into air-containing cavities more rapidly than nitrogen is absorbed by the bloodstream. Examples of conditions in which nitrous oxide might be hazardous include air embolism, pneumothorax, acute intestinal obstruction, intracranial air (tension pneumocephalus following dural closure or pneumoencephalography), pulmonary air cysts, intraocular air bubbles, and tympanic membrane grafting. Because the relatively high MAC of nitrous oxide prevents its use as a complete general anesthetic2. HALOTHANE halogenated alkane Halothane is the least expensive volatile anesthetic, and because of its safety profile (see below), continues to be used worldwide Effects on organs CVS: dose-dependent reduction of arterial blood pressure is due to direct myocardial depression; 2.0 MAC ofhalothaneresults in a 50% decrease in blood pressure and cardiac output Resp: causes rapid, shallow breathing MSK: relaxes skeletal muscle and potentiates nondepolarizing neuromuscular-blocking agents (NMBA) Problems Halothanehepatitisis extremely rare (1 per 35,000 cases) Contraindicated in patients with unexplained liver dysfunction following previous exposure halothane hepatitis appears to affect primarily adults and children past puberty, some anesthesiologists choose other volatile anesthetics in these patients3. ISOFLURANE nonflammable volatile anesthetic with a pungent ethereal odor4. DESFLURANE non-flmammable fluorinated methyl ethyl ether5. SEVOFLURANE Like desflurane, sevoflurane is halogenated with fluorine

NONVOLATILE ANESTHETIC AGENTS: INTRODUCTION

Nothing much to say. Divide into groups like opioid, non-opioid.

Neuromuscular Blocking AgentsKEY CONCEPTSIt is important to realize that muscle relaxation does not ensure unconsciousness, amnesia, or analgesia.Depolarizing muscle relaxants act asacetylcholine(ACh) receptor agonists, whereas nondepolarizing muscle relaxants function as competitive antagonists.Because depolarizing muscle relaxants are not metabolized by acetylcholinesterase, they diffuse away from the neuromuscular junction and are hydrolyzed in the plasma and liver by anotherenzyme, pseudocholinesterase (nonspecific cholinesterase, plasma cholinesterase, or butyrylcholinesterase).With the exception of mivacurium, nondepolarizing agents are not significantly metabolized by either acetylcholinesterase or pseudocholinesterase. Reversal of their blockade depends on redistribution, gradual metabolism, and excretion of the relaxant by the body, or administration of specific reversal agents (eg, cholinesterase inhibitors) that inhibit acetylcholinesterase enzyme activity.Muscle relaxants owe their paralytic properties to mimicry of ACh. For example,succinylcholineconsists of two joined ACh molecules.Compared with patients with low enzyme levels or heterozygous atypical enzyme in whom blockade duration is doubled or tripled, patients with homozygous atypical enzyme will have a very long blockade (eg, 46 h) following succinylcholine administration.Succinylcholine is considered contraindicated in the routine management of children and adolescents because of the risk of hyperkalemia, rhabdomyolysis, and cardiac arrest in children with undiagnosed myopathies.Normal muscle releases enough potassium during succinylcholine-induced depolarization to raise serum potassium by 0.5 mEq/L. Although this is usually insignificant in patients with normal baseline potassium levels, a life-threatening potassium elevation is possible in patients with burn injury, massive trauma, neurological disorders, and several other conditions.As a general rule, the more potent the nondepolarizing muscle relaxant the longer its speed of onset.Doxacurium,pancuronium,vecuronium, and pipecuronium are partially excreted by the kidneys, and their action is prolonged in patients with renal failure.Cirrhotic liver disease and chronic renal failure often result in an increased volume of distribution and a lower plasma concentration for a given dose of water-soluble drugs, such as muscle relaxants. On the other hand, drugs dependent on hepatic or renal excretion may demonstrate prolonged clearance. Thus, depending on the drug, a greater initial dosebut smaller maintenance dosesmight be required in these diseases.Atracuriumandcisatracuriumundergo degradation in plasma at physiological pH and temperature by organ-independent Hofmann elimination. The resulting metabolites (a monoquaternary acrylate and laudanosine) have no intrinsic neuromuscular blocking effects.Mivacurium, like succinylcholine, is metabolized by pseudocholinesterase. It is only minimally metabolized by true cholinesterase.Hypertension and tachycardia may occur in patients given pancuronium. These cardiovascular effects are caused by the combination of vagal blockade and catecholamine release from adrenergic nerve endings.Long-term administration of vecuronium to patients in intensive care units has resulted in prolonged neuromuscular blockade (up to several days), possibly from accumulation of its active 3-hydroxy metabolite, changing drug clearance, or the development of a polyneuropathy.Rocuronium(0.91.2 mg/kg) has an onset of action that approaches succinylcholine (6090 s), making it a suitable alternative for rapid-sequence inductions, but at the cost of a much longer duration of action.

Skeletal muscle relaxation can be produced by deep inhalational anesthesia, regional nerve block, or neuromuscular blocking agents (commonly calledmuscle relaxants) neuromuscular junction blocking agents produce paralysis, not anesthesia. In other words, muscle relaxation does not ensure unconsciousness, amnesia, or analgesia NEUROMUSCULAR TRANSMISSION As a nerve's action potential depolarizes its terminal, an influx of calcium ions through voltage-gated calcium channels into the nerve cytoplasm allows storage vesicles to fuse with the terminal membrane and release their contents ofacetylcholine(ACh) structure of ACh receptors varies in different tissues and at different times in development. Each ACh receptor in the neuromuscular junction normally consists of five protein subunits, twosubunits and single,, andsubunits. Only the two identicalsubunits are capable of binding ACh molecules Cations flow through the open ACh receptor channel (sodium and calcium in; potassium out), generating anend-plate potential. contents of a single vesicle, a quantum of ACh (104molecules per quantum), produce a miniature end-plate potential ACh is rapidly hydrolyzed into acetate and choline by the substrate-specificenzymeacetylcholinesterase. This enzyme (also called specific cholinesterase or true cholinesterase) is embedded into the motor end-plate membrane immediately adjacent to the ACh receptors

Table 91. Depolarizing and Nondepolarizing Muscle Relaxants.

DepolarizingNondepolarizing

Short-actingShort-acting

Succinylcholine Mivacurium

Intermediate-acting

Atracurium

Cisatracurium

Vecuronium

Rocuronium

Long-acting

Doxacurium

Pancuronium

Pipecuronium

Similar to ACh, all neuromuscular blocking agents are quaternary ammonium compounds whose positively charged nitrogen imparts an affinity to nicotinic ACh receptors Depolarizing muscle relaxants very closely resemble ACh and therefore readily bind to ACh receptors, generating a muscle action potential. Unlike ACh, however, these drugs arenotmetabolized by acetylcholinesterase, and their concentration in the synaptic cleft does not fall as rapidly, resulting in a prolonged depolarization of the muscle end-plate Continuous end-plate depolarization causes muscle relaxation because opening of the lower gate in the perijunctional sodium channels is time limited After the initial excitation and opening, these sodium channels close and cannot reopen until the end-plate repolarizes. The end-plate cannot repolarize as long as the depolarizing muscle relaxant continues to bind to ACh receptors; this is called a phase I block. After a period of time, prolonged end-plate depolarization can cause ionic and conformational changes in the ACh receptor that result in a phase II block, which clinically resembles that of nondepolarizing muscle relaxants. Nondepolarizing muscle relaxants bind ACh receptors but are incapable of inducing the conformational change necessary for ion channel opening. Because ACh is prevented from binding to its receptors, no end-plate potential develops. Neuromuscular blockade occurs even if only onesubunit is blocked use of peripheral nerve stimulators to monitor neuromuscular function Four patterns of electrical stimulation with supramaximal square-wave pulses are considered:1. Tetany: A sustained stimulus of 50100 Hz, usually lasting 5 s.2. Twitch: A single pulse 0.2 ms in duration.3. Train-of-four: A series of four twitches in 2 s (2-Hz frequency), each 0.2 ms long.4. Double-burst stimulation (DBS): Three short (0.2 ms) high-frequency stimulations separated by a 20-ms interval (50 Hz) and followed 750 ms later by two (DBS3,2) or three (DBS3,3) additional impulses