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Review of literature Chapter (3) PHARMACOLOGY Propofol Propofol is the most frequently used IV anesthetic today. It is used for induction and maintenance of anesthesia and for sedation in and outside the operating room.(69) Chemical structure: Propofol (2, 6-diisopropylphenol) consists of a phenol ring with two isopropyl groups attached. Altering the side-chain length of this alkylphenol influences potency, induction, and recovery characteristics.(70) Propofol is not water soluble, but a 1% aqueous solution (10mg/mL) is available for intravenous administration as an oil-inwater emulsion containing soybean oil, glycerol, and egg lecithin. (71) This formulation can cause pain during injection (less common in elderly patients) that can be decreased by prior injection of lidocaine or by mixing lidocaine with propofol prior to injection (2mL of 1% lidocaine in 18 mL propofol). (72) Propofol formulations can support the growth of bacteria, so good sterile technique must be observed in preparation and handling.(73) 25 Review of literature Chapter (3) Mechanisms of Action: The mechanism by which propofol induces a state of general anesthesia may involve facilitation of inhibitory neurotransmission mediated by GABA.(74) Pharmacodynamics: I. Central nervous system Anaesthesia is induced within 20-40 s after IV administration in otherwise healthy young adults.(75)Transfer from blood to the sites of action in the brain is slower than with thiopental, and there is a delay in disappearance of the eyelash reflex, normally used as a sign of unconsciousness after administration of barbiturate anaesthetic agents. Over dosage of propofol, with exaggerated side-effects, may result if this clinical sign is used; loss of verbal contact is a better end-point.(76) Propofol reduces the duration of seizures induced by ECT in humans. However, there have been reports of convulsions following the use of propofol and it is recommended that caution be exercised in administration of propofol to epileptic patients.(77) Normally cerebral metabolic rate (CMR), cerebral blood flow (CBF) and intracranial pressure (ICP) are reduced.(78) Recovery of consciousness is rapid and there is a minimal 'hangover' effect even in the immediate post-anaesthetic period. (79) 26 II. Review of literature Chapter (3) Cardiovascular system In healthy patients, arterial pressure decreases to a greater degree after induction of anaesthesia with propofol than with thiopental; the reduction results predominantly from vasodilatation although there is a slight negative inotropic effect. In some patients, large decreases (> 40%) occur. The degree of hypotension is substantially reduced by decreasing the rate of administration of the drug and by appreciation of the kinetics of transfer from blood to brain.(77) The pressor response to tracheal intubation is attenuated to a greater degree by propofol than thiopental. Heart rate may increase slightly after induction of anaesthesia with propofol.(80) However, there have been occasional reports of severe bradycardia and asystole during or shortly after administration of propofol, and it is recommended that a vagolytic agent (e.g. glycopyrronium or atropine) should be considered in patients with a preexisting bradycardia or when propofol is used in conjunction with other drugs which are likely to cause bradycardia.(80) III. Respiratory system After induction, apnea occurs more commonly, and for a longer duration, than after thiopental. During infusion of propofol, tidal volume is lower and respiratory rate higher than in the conscious state. There is decreased ventilatory response to carbon 27 Review of literature Chapter (3) dioxide. As with other agents; ventilatory depression is more marked if opioids are administered.(81) Propofol has no effect on bronchial muscle tone and laryngospasm is particularly uncommon. The suppression of laryngeal reflexes results in a low incidence of coughing or laryngospasm when a laryngeal mask airway (LMA) is introduced, and propofol is regarded by most anesthetists as the drug of choice for induction of anaesthesia when the LMA is to be used.(82) IV. Skeletal muscle Tone is reduced, but movements may occur in response to surgical stimulation.(83) V. Gastrointestinal system Propofol has no effect on gastrointestinal motility in animals. Its use is associated with a low incidence of postoperative nausea and vomiting.(84) VI. Uterus and placenta Propofol has been used extensively in patients undergoing gynecological surgery, and it does not appear to have any clinically significant effect on uterine tone.(85) Propofol crosses the placenta. Its safety to the neonate has not been established and its use in pregnancy (except for termination), in obstetric practice and in breastfeeding mothers is not recommended by the manufacturers.(86) 28 VII. Review of literature Chapter (3) Hepatorenal There is a transient decrease in renal function, but the impairment is less than that associated with thiopental.(87) Hepatic blood flow (HBF) is decreased by the reductions in arterial pressure and cardiac output (CO). Liver function tests are not deranged after infusion of propofol for 24 h.(88) VIII. Endocrine Plasma concentrations of cortisol are not decreased after administration of propofol and a normal response occurs to administration of Synacthen.(89) Pharmakokinetics: Propofol is highly protein-bound in vivo and is metabolized by conjugation in the liver.(90) Its rate of clearance exceeds hepatic blood flow, suggesting an extrahepatic site of elimination as well.(91) The half life of elimination of propofol has been estimated at between 2 and 24 hours. However, its duration of clinical effect is much shorter, because propofol is rapidly distributed into peripheral tissues. When used for IV sedation, a single dose of propofol typically wears off within minutes. Propofol is versatile; the drug can be given for short or prolonged sedation as well as for general anesthesia. Its use is not associated with nausea as is often seen with opioid medications. These characteristics of rapid onset and recovery along with its amnestic effects have led to its widespread use for sedation and anesthesia.(91) 29 Review of literature Chapter (3) Uses & dosage: Induction and Maintenance of Anesthesia Propofol is suitable for the induction and maintenance of anesthesia. The induction dose is 1 to 2.5 mg/kg. Physiologic characteristics that best determine the induction dose are age, lean body mass, and central blood volume.(92)Premedication with an opiate or a benzodiazepine, or both, markedly reduces the induction dose.(93) For induction in children, the ED95 (2 to 3 mg/kg) is increased, primarily because of pharmacokinetic differences.(94) Table 1: Uses and Doses of Intravenous Propofol (92) Induction of general 1-2.5 mg/kg IV dose reduced with anesthesia increasing age Maintenance of 50-150 µg/kg/min IV combined with N2O general anesthesia or an opiate Sedation 25-75 µg/kg/min IV Antiemetic 10-20 mg IV, can repeat every 5-10 min or start infusion of 10 µg/kg/min N2O, nitrous oxide. 30 Review of literature Chapter (3) Propofol, when used for induction of anesthesia in briefer procedures, results in a significantly quicker recovery and an earlier return of psychomotor function compared with thiopental or methohexital, regardless of the anesthetic used for maintenance of anesthesia. The incidence of nausea and vomiting when propofol is used for induction also is markedly less than after the use of other IV anesthetics, probably because of the antiemetic properties of propofol.(95) Because of its pharmacokinetics, propofol provides a rapid recovery and is superior to barbiturates for maintenance of anesthesia, and it seems to be equal to enflurane, isoflurane and sevoflurane.(96) Several infusion schemes have been used to achieve adequate plasma concentrations of propofol. After an induction dose, an infusion of 100 to 200µg/kg/min is usually needed. (97) The infusion rate is titrated to individual requirements and the surgical stimulus.(98) When combined with propofol, the required infusion rate and concentration of opiates, midazolam, clonidine, or ketamine is reduced. Because opioids alter the concentration of propofol required for adequate anesthesia, the relative dose of either opioid or propofol markedly affects the time from termination of drug to awakening and recovery.(98) Increasing age is associated with a decrease in propofol infusion requirements, whereas these requirements are higher in children and infants.(99) 31 Review of literature Chapter (3) Sedation Propofol has been evaluated for sedation during surgical procedures(100) and for patients receiving mechanical ventilation in the ICU.(101) Propofol by continuous infusion provides the ability to titrate to a desired level of sedation and provide a rapid recovery after infusion is terminated, regardless of the duration of the infusion.(102) Infusion rates required for sedation to supplement regional anesthesia in healthy patients are half or less than the rates required for general anesthesia (i.e., 30 to 60µg/kg/min). In elderly patients (>65 years old) and in sicker patients, the infusion rates that are necessary are markedly reduced. It is important to titrate the infusion individually to the desired effect.(102) Although the pharmacokinetic profile and to a large extent the pharmacology of propofol make it an excellent choice for long-term (days) sedation, this always must be weighed against the hemodynamic effects, the often concomitant need for an analgesic, tolerance, and rare occurrences of hypertriglyceridemia (and potential pancreatitis) or propofol infusion syndrome. The recommended maximal dose of propofol infusion rate is 80 µg/kg/min (<5 mg/kg/hr).(103) Side Effects and Contraindications: Induction of anesthesia with propofol is associated with several side effects, including pain on injection, myoclonus, apnea, 32 Review of literature Chapter (3) hypotension, and, rarely, thrombophlebitis of the vein into which propofol is injected. Pain on injection is reduced by using a large vein, avoiding veins in the dorsum of the hand, and adding lidocaine to the propofol solution or changing the propofol formulation.(104) The most common side effect during induction of anesthesia is hypotension, which is augmented by the concomitant administration of opioids. Conversely, with laryngoscopy and endotracheal intubation, the changes in MAP, heart rate, and systemic vascular resistance are less significant after propofol compared with thiopental.(105) Propofol infusion syndrome is a rare but lethal syndrome associated with infusion of propofol at 5 mg/kg/hr or more for 48 hours or longer. It was first described in children, but subsequently has been observed in critically ill adults. The clinical features of propofol infusion syndrome are acute refractory bradycardia leading to asystole, in the presence of one or more of the following: metabolic acidosis (base deficit >10 mmol/L-1), rhabdomyolysis, hyperlipidemia, and enlarged or fatty liver.(106) Absolute contraindications: Airway obstruction and known hypersensitivity to the drug are probably the only absolute contraindications. Propofol should not be used for long-term sedation of children in the ICU because of a number of reports of adverse outcome.(107) 33 Review of literature Chapter (3) Sevoflurane Sevoflurane is a methyl propyl ether which was first synthesized in 1968 and reported in 1971. The initial development was slow because of some apparent toxic effects, which were later found to be caused by flawed experimental design. After its first use in volunteers in 1981, further work was delayed again because of the problems of biotransformation and stability with soda lime. The drug has been available for general clinical use in Japan since 1990, and by the end of 1993, 1 million patients had received sevoflurane.(108) Physical properties: It is non-flammable and has a pleasant smell. The blood/gas partition coefficient of sevoflurane is 0.69, which is about half of that of isoflurane (1.43) and closer to that of desflurane (0.42) and nitrous oxide (0.44). (109) The MAC value of sevoflurane in adults is between 1.7 and 2% in oxygen and 0.66% in 60% nitrous oxide.(110)The MAC, in common with other volatile agents, is higher in children (2.6% in oxygen and 2.0% in nitrous oxide) and neonates (3.3%) and it is reduced in the elderly (1.48%). It is stable and is stored in amber colored bottles. In the presence of water, it undergoes some hydrolysis and this reaction also occurs with soda lime.(111) 34 Review of literature Chapter (3) Pharmacokinetics: Uptake and distribution It has a low blood/gas partition coefficient and therefore the rate of equilibration between alveolar and inspired concentrations is faster than that for halothane, enflurane or isoflurane but slower than that for desflurane. It is non-irritant to the upper respiratory tract and therefore the rate of induction of anaesthesia should be faster than that with any of the other agents.(108) Because of its higher partition coefficients in vessel-rich tissues, muscle and fat than corresponding values for desflurane, the rate of recovery is slower than that after desflurane anaesthesia.(112) Metabolism Approximately 5% of the absorbed dose is metabolized in the liver to two main metabolites(113) : The major breakdown product is hexafluoroisopropanol: An organic fluoride molecule which is excreted in the urine as a glucuronide conjugate.(114)Although this molecule is potentially hepatotoxic, conjugation of hexafluoroisopropanol occurs so rapidly that clinically significant liver damage seems theoretically impossible.(115) The second breakdown product is inorganic fluoride ion: The mean peak fluoride ion concentration after 60 min of anaesthesia at 1 MAC is 22µmol/L, which is similar to that produced 35 Review of literature Chapter (3) after enflurane anaesthesia and significantly higher than that after an equivalent dose of isoflurane.(114) Pharmacodynamics: I. Respiratory system The drug is non-irritant to the upper respiratory tract. It produces dose-dependent ventilatory depression.The ventilatory depression associated with sevoflurane may result from a combination of central depression of medullary respiratory neurones and depression of diaphragmatic function and contractility. It relaxes bronchial smooth muscle but not as effectively as halothane.(116) II. Cardiovascular system Sevoflurane have smaller effects on heart rate and causes less marked coronary vasodilatation. It decreases arterial pressure mainly by reducing peripheral vascular resistance, but cardiac output is well maintained over the normal anaesthetic maintenance doses. There is mild myocardial depression resulting from its effect on calcium channels.(117)Sevoflurane does not sensitize the myocardium to catecholamines. (118) It is a less potent coronary arteriolar dilator(119) and therefore does not appear to cause 'coronary steal'.(120) Sevoflurane is associated with lower heart rate and therefore helps to reduce myocardial oxygen consumption.(121) 36 III. Review of literature Chapter (3) Central nervous system Intracranial pressure increases at high inspired concentrations of sevoflurane but this effect is minimal over the 0.5-1.0 MAC range. It decreases cerebral vascular resistance and cerebral metabolic rate. It does not cause excitatory effects on the EEG.(122) IV. Renal system The peak concentration of inorganic fluoride after sevoflurane is similar to that after enflurane anaesthesia(113)and there is a positive correlation between duration of exposure and the peak concentration of fluoride ions.(123) However, renal toxicity does not appear to be related to inorganic fluoride concentrations following anaesthesia with sevoflurane as opposed to that associated with methoxyflurane. The apparent lack of renal toxicity with sevoflurane may be related to its rapid elimination from the body. This reduces the total amount of drug available for in vivo metabolism.(124) Renal blood flow is well preserved with sevoflurane.(108) V. Musculoskeletal system The drug potentiates non-depolarizing muscle relaxant. Sevoflurane can trigger malignant hyperthermia in susceptible patients and there have been cases reported in the literature.(125) VI. Obstetric use There are limited data on the use of sevoflurane in the obstetric population.(126) 37 Review of literature Chapter (3) Phenylephrine Clinical Considerations Phenylephrine is a noncatecholamine chemically known as 3hydroxy-alpha-[(methylamino)methyl] benzyl alcohol available as a (1:1) hydrochloride salt. It is a sympathomimetic amine that has primarily alpha 1-adrenergic activity causing peripheral vasoconstriction (high doses may stimulate α2- and β-receptors) (fig. 5).(127) The primary effect of phenylephrine is peripheral vasoconstriction with a concomitant rise in systemic vascular resistance and arterial blood pressure. It has no chronotropic or inotropic effect, however reflex bradycardia can reduce cardiac output. Coronary blood flow increases because any direct vasoconstrictive effect of phenylephrine on the coronary arteries is overridden by vasodilation induced by the release of metabolic factors.(128) Fig. 5: Phenylephrine.(129) 38 Review of literature Chapter (3) Pharmacokinetics/Dynamics Phenylephrine is a pure alpha-adrenergic agonist and leads to vasoconstriction without chronotropic or inotropic effects. Phenylephrine is poorly absorbed orally (<38%), but can be efficacious via the subcutaneous (SQ) or intramuscular (IM) route. The onset of action depends on the route of administration, with SQ and IM administration being 10–15 min, while IV administration is immediate.(128) The volume of distribution (Vd) can range from 184 to 543 L, and metabolism is extensive. Hepatic metabolism involves 50% deamination, but there is also a degree of sulfation and glucuronidation before the metabolites are excreted in the urine. The alpha half-life is about 5 min, but the terminal half-life is about 2–3 hours. The duration of action is about 1–2 hours if given IM, 50 min if given SQ, and 15–20 min if given IV.(130) Indications/Dosage/Administration Phenylephrine may be used to maintain adequate BP during anesthesia use, shock, or shock-like states. It may also be used to overcome paroxysmal supraventricular tachycardia from prolonged spinal anesthesia and as a vasoconstrictor in regional anesthesia.(131) Phenylephrine can be given as a 100–500 µg bolus dose every 10–15 min, if needed. IV infusions should start at a dose of 100–180 µg/min (or 0.5 µg/kg/min) and be titrated to maintain a low-normal SBP of 80–100 mm Hg or MAP 60 mm Hg. Tachyphylaxis occurs 39 Review of literature Chapter (3) with phenylephrine infusions requiring upward titration of the infusion. Concentrations of phenylephrine should range from 0.04 to 0.2 µg/mL, and can be mixed with dextrose, saline, or lactated Ringer’s solutions. (132) Adverse Effects Adverse reactions include reflex bradycardia, hypertension, metabolic acidosis, and gastric irritation and nausea. Phenylephrine use may lead to anxiety, headache, parasthesias, tremors, and weakness. Extravasation necrosis at the injection site is a serious complication that can be minimizedvby dilution and administration through a large vein.(133) Drug Interactions Phenylephrine interacts with tricyclic antidepressants (eg, amitriptyline, clomipramine, and imipramine), atomoxetine, and MAO inhibitors with clinical increases in alpha-adrenergic effects.(132) Availability Phenylephrine is available in 10 mg/mL vials of 1 and 5 Ml. (130) 40 Review of literature Chapter (3) Sodium Nitroprusside Mechanism of Action Sodium nitroprusside relaxes both arteriolar and venous smooth muscle. Its primary mechanism of action is shared with other nitrates (eg, hydralazine and nitroglycerin). As these drugs are metabolized, they release nitric oxide,(134) which activates guanylyl cyclase. This enzyme is responsible for the synthesis of cyclic guanosine 3',5'-monophosphate (cGMP), which controls the phosphorylation of several proteins, including some involved in control of free intracellular calcium and smooth muscle contraction.(135) Nitric oxide, a naturally occurring potent vasodilator released by endothelial cells (endothelium-derived relaxing factor), plays an important role in regulating vascular tone throughout the body. Its ultrashort half-life (< 5 s) provides sensitive endogenous control of regional blood flow.(136) Clinical trials have shown that inhaled nitric oxide is a selective pulmonary vasodilator that may be beneficial in the treatment of reversible pulmonary hypertension. By improving perfusion only in ventilated areas of the lung, inhaled nitric oxide may improve oxygenation in patients with acute respiratory distress syndrome (ARDS) or during one-lung ventilation. Nitric oxide may also have antiinflammatory effects that could promote lung healing.(137) 41 Review of literature Chapter (3) Clinical Uses Sodium nitroprusside is a potent and reliable antihypertensive. It is usually diluted to a concentration of 100 µg/mL and administered as a continuous intravenous infusion (0.5–10 µg/kg/min). Its extremely rapid onset of action (1–2 min) and fleeting duration of action allow precise titration of arterial blood pressure. (138) A bolus of 1–2 µg/kg minimizes blood pressure elevation during laryngoscopy but can cause transient hypotension in some patients. The potency of this drug requires frequent blood pressure measurements or, preferably, intraarterial monitoring and the use of mechanical infusion pumps. Solutions of sodium nitroprusside must be protected from light because of photodegradation. (139) Metabolism After parenteral injection, sodium nitroprusside enters red blood cells, where it receives an electron from the iron (Fe2+) of oxyhemoglobin. This nonenzymatic electron transfer results in an unstable nitroprusside radical and methemoglobin (Hgb Fe3+). The former moiety spontaneously decomposes into five cyanide ions and the active nitroso group. (140) The cyanide ions can be involved in one of three possible reactions: binding to methemoglobin to form cyanmethemoglobin; (140) undergoing a reaction in the liver and kidney catalyzed by the enzyme rhodanase (thiosulfate + cyanide ---> thiocyanate); 42 (141) or Review of literature Chapter (3) binding to tissue cytochrome oxidase, which interferes with normal oxygen utilization. (142) The last of these reactions is responsible for the development of acute cyanide toxicity, characterized by metabolic acidosis, cardiac arrhythmias, and increased venous oxygen content (as a result of the inability to utilize oxygen). Another early sign of cyanide toxicity is the acute resistance to the hypotensive effects of increasing doses of sodium nitroprusside (tachyphylaxis). (143) Cyanide toxicity can usually be avoided if the cumulative dose of sodium nitroprusside is less than 0.5 mg/kg/h. Patients with cyanide toxicity should be mechanically ventilated with 100% oxygen to maximize oxygen availability. The pharmacological treatment of cyanide toxicity depends on increasing the kinetics of the two reactions by administering sodium thiosulfate (150 mg/kg over 15 min) or 3% sodium nitrate (5 mg/kg over 5 min), which oxidizes hemoglobin to methemoglobin. (144) Hydroxocobalamin, an experimental drug, combines with cyanide to form cyanocobalamin (vitamin B12). (143) Thiocyanate is slowly cleared by the kidney. Accumulation of large amounts of thiocyanate (eg, in patients with renal failure) may result in a milder toxic reaction that includes thyroid dysfunction, muscle weakness, nausea, hypoxia, and an acute toxic psychosis. The risk of cyanide toxicity is not increased by renal failure, however. (141) Methemoglobinemia from excessive doses of sodium nitroprusside or sodium nitrate can be treated with methylene blue 43 Review of literature Chapter (3) (1–2 mg/kg of a 1% solution over 5 min), which reduces methemoglobin to hemoglobin. Effects on Organ Systems Cardiovascular The combined dilation of venous and arteriolar vascular beds by sodium nitroprusside results in reductions of preload and afterload. Arterial blood pressure (ABP) falls due to the decrease in peripheral vascular resistance. (145) Although cardiac output is usually unchanged in normal patients, the reduction in afterload may increase cardiac output in patients with congestive heart failure, mitral regurgitation, or aortic regurgitation.(134) In contrast to the pure afterload reduction produced by hydralazine, sodium nitroprusside primarily reduces preload, which decreases myocardial work and the likelihood of ischemia. In opposition to any favorable changes in myocardial oxygen requirements are reflex-mediated responses to the fall in arterial blood pressure. These include tachycardia (less pronounced than with hydralazine) and increased myocardial contractility. In addition, dilation of coronary arterioles by sodium nitroprusside may result in an intracoronary steal of blood flow away from ischemic areas that are already maximally dilated. (145) Cerebral Sodium nitroprusside dilates cerebral vessels and abolishes cerebral autoregulation. Cerebral blood flow is maintained or 44 Review of literature Chapter (3) increases unless arterial blood pressure is markedly reduced. The resulting increase in cerebral blood volume tends to increase intracranial pressure, particularly in patients with reduced intracranial compliance (eg, brain tumors). This intracranial hypertension can be minimized by slow administration of sodium nitroprusside and institution of hypocapnia. (147) Respiratory The pulmonary vasculature also dilates in response to sodium nitroprusside infusion. Reductions in pulmonary artery pressure may decrease the perfusion of some normally ventilated alveoli, increasing physiological dead space. By dilating pulmonary vessels, sodium nitroprusside may prevent the normal vasoconstrictive response of the pulmonary vasculature to hypoxia (hypoxic pulmonary vasoconstriction). Both these effects tend to mismatch pulmonary ventilation to perfusion and decrease arterial oxygenation. (148) Renal In response to decreased arterial blood pressure, renin and catecholamines are released during administration of nitroprusside. This hormonal response, which can lead to a pressure rebound after discontinuation of the drug, is blocked by propranolol or a high epidural block (T1 level). Renal function is fairly well maintained during sodium nitroprusside infusion despite moderate drops in arterial blood pressure and renal perfusion. (149) 45 Review of literature Chapter (3) Drug Interactions Sodium nitroprusside does not directly interact with neuromuscular blocking agents. Nonetheless, a decrease in muscle blood flow caused by arterial hypotension could indirectly delay the onset and prolong the duration of neuromuscular blockade.(150) By inhibiting phosphodiesterase, aminophylline increases cGMP and potentiates the hypotensive effects of these agents.(151) 46