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11. pharmacology (autosaved)

  1. 1. Pharmacology of Commonly Used Drugs in Conscious Sedation PHARMACOLOGY OF COMMONLY USED DRUGS IN CONSCIOUS SEDATIONConscious Sedation 67
  2. 2. Pharmacology of Commonly Used Drugs in Conscious SedationBARBITURATES Barbiturates are those agents that may pharmacologically be described as “sedative-hypnotics”. Chemically, they are derivatives of barbituric acid or malonyl urea, which is acombination of malonic acid and urea. Barbituric acid itself has no hypnotic properties, butreplacement of hydrogen by various radicals produces many different drugs processing hypnoticcharacteristics. The new compounds are varied in their actions, both the potency and duration ofaction being markedly affected by the different substitutions. The barbiturates may be divided into two categories based on the chemical structure.Those compounds having oxygen attached to the carbon of the urea component are properlytermed barbiturates. They are frequently referred to as oxybarbiturates to distinguish them fromthose of the second category, the thiobarbiturates - which have a sulfur atom in place of theoxygen. Although the pharmacology of all barbiturates is essentially similar they differ inpotency, duration, and intensity of effect. Thiobarbiturates possess a greater degree of fatsolubility, and are more rapid in onset, have shorter duration of action, and are somewhat moretoxic than the oxybarbiturates. 93 The barbiturates are general depressants; they depress the activity of nerve, skeletalmuscle, smooth muscle, cardiac muscle, and the central nervous system. However, it must beemphasized that the central nervous system is exquisitely sensitive to depression by barbiturates;as a result, when these drugs are administered in therapeutic doses, the effects on other structuresare absent or negligible. All degrees of depression of the central nervous system are possible,ranging from mild sedation to general anesthesia or to coma.Conscious Sedation 68
  3. 3. Pharmacology of Commonly Used Drugs in Conscious Sedation Drugs in this category appear to act at all levels of neuraxis. There is a complex,interrelated group of pathways coursing through the reticular formation of the midbrain andmedulla and extending anteriorly into the thalamus and hypothalamus – the “reticular activatingsystem.” This system is very sensitive to the depressant effects of sedative hypnotic drugs. It istheir effect on the reticular system that seems to be responsible for the inability to maintainwakefulness under the influence of these compounds. The cerebral cortex is among structuresmost sensitive to these drugs, since they do depress cerebral function as evidenced by release ofinhibitions and the production of amnesia in the conscious patient. 93 Barbiturates can be classified based on the time of onset and duration of action intofour groups: 93 1. Ultra short acting: The ultra short acting barbiturates most commonly used are thiopental sodium, thiamylal sodium, and methohexital sodium. With the exception of thiopental these drugs are administered exclusively by the intravenous route for the production of conscious sedation. They possess the shortest duration of action and are also the most potent barbiturates available. With all drugs in this group the peak effect after intravenous administration will be realized in 30 to 60 seconds. Sedative effect will be present for 5 to 7 minutes for methohexital, the shortest acting and most potent barbiturate, and for 10 to 15 minutes with thiopental and thiamylal. Thiopental is the only agent in this group that may be administered by any route other than the intravenous. A rectal suspension is available that when instilled rectally in doses of no more than 10 to 14mg. per pound will produce sedation in 8 to 10 minutes. This method is particularly useful in apprehensive children. Duration will be about 30 to 60 minutes.Conscious Sedation 69
  4. 4. Pharmacology of Commonly Used Drugs in Conscious Sedation 2. Short acting barbiturates: The short acting barbiturates most commonly used are pentobarbital and secobarbital. They may be administered orally, intramuscularly, or intravenously. These drugs are particularly useful via the intravenous route for the production of conscious sedation, either as a sole agent or in combination with other central nervous system depressants. When used alone intravenous dose range usually is from 50 to 100 mg. lower doses must be employed when used these drugs are used in conjugation with psycho sedatives and / or narcotic analgesics. Duration of sedation via the intravenous route will range from 2 to 3 hours. Short acting barbiturates are also of value when administered via the oral route to provide the patient with a restful sleep the night before his dental appointment. Depending on the individual, the oral dose will range from 50 to 200 mg. the drug will require 30 to 45 minutes for its maximum effectiveness and will have duration of 4 to 6 hours. Providing the patient with a restful sleep the night before his appointment will allow him to arrive at the office well rested and thus with an elevated pain reaction threshold. 3. Intermediate acting barbiturates: The intermediate acting barbiturates most commonly used are amobarbital, aprobarbital, and butabarbital. They are administered via the oral route only and effective in 45minutes to one hour. Duration will range from 6 to 8 hours. They may be used to best advantage on the night before the appointment to aid the patient in obtaining a good night‟s rest. 4. Long acting barbiturates: The long acting barbiturates most commonly used are barbital sodium and Phenobarbital. These agents are indicated for oral administration only and,Conscious Sedation 70
  5. 5. Pharmacology of Commonly Used Drugs in Conscious Sedation because of their long duration of 8 to 10 hours, are seldom if ever indicated in dental practice.PENTOBARBITALPentobarbital is an oxybarbiturate and is one of the most frequently used barbiturates forpediatric sedation. Pentobarbital is a barbiturate with no inherent analgesic properties thatproduces profound sedation, hypnosis, amnesia, and anticonvulsant activity in a dose dependentfashion. With intravenous titration, sedation is evident in 3–5 min with duration of roughly 30–40 min. Like other barbiturates, pentobarbital can lead to respiratory depression and hypotension.In many centers, pentobarbital is the intravenous sedative of choice for diagnostic imaging inchildren, and is regarded as better than midazolam or chloral hydrate for this indication. 95METHOHEXITAL AND THIOPENTALWhen given intravenously, both methohexital and thiopental produce effective sedation within 1min and induce potent respiratory depression in the same manner as propofol and intimidate.Clinical recovery is rapid (about 15 min). The depth of sedation achieved in existing small seriesis not well described, but seems to be at or beyond levels consistent with deep sedation.Barbiturates are rapidly absorbed rectally and methohexital or thiopental given by this route canreliably produce anxiolysis and sedation suitable for CT or MRI scanning. Although respiratorydepression is unusual with typical doses, it can occur. When transporting patients who have received pentobarbital, methohexital, or thiopentalfrom a more controlled location such as the emergency department to a radiology suite, vigilanceis required to maintain adequate monitoring and to ensure that skilled personnel remain availableConscious Sedation 71
  6. 6. Pharmacology of Commonly Used Drugs in Conscious Sedationto manage airway complications. Barbiturates are rapidly absorbed rectally and methohexital orthiopental given by this route can reliably produce anxiolysis and sedation suitable for CT orMRI scanning. Although respiratory depression is unusual with typical doses, it can occur.95BENZODIAZEPENESMode of action:Binding of gamma – aminobutyric acid (GABA) to its receptor on the cell membrane triggers anopening of a chloride channel, which leads to an increase in chloride conductance. The influx ofchloride ions causes a small hyper polarization that moves the post- synaptic potential away fromits firing threshold and thus inhibits the formation of action potential away from its firingthreshold and thus inhibits the formation of action potentials. Benzodiazepines bind to specific,high affinity sites on the cell membrane, which are separate from but adjacent to the receptor forGABA.93 The benzodiazepine receptors are found only in the central nervous system, and theirlocation parallels that of the GABA neurons. The binding of benzodiazepines enhances theConscious Sedation 72
  7. 7. Pharmacology of Commonly Used Drugs in Conscious Sedationaffinity of GABA receptors for this neurotransmitter, resulting in a more frequent opening ofadjacent chloride channel. This in turn results in hyper polarization and further inhibition ofneuronal firing. Benzodiazepines and GABA mutually increase the affinity of their binding siteswithout actually changing the total number of sites. The clinical effects of the variousbenzodiazepines correlate well with each drug‟s binding affinity for the GABA receptor-chloride ion channel complex.93 At low doses, the benzodiazepines are anxiolytic. They are thought to reduce anxiety by selectively inhibiting neuronal circuits in the limbic system of the brain. All of the benzodiazepines used to treat anxiety have some sedative properties. At higher doses, certain benzodiazepines produce hypnosis.Uses:Primary therapeutic effects of benzodiazepines include sedation, anxiolysis, and anterogradeamnesia – all beneficial for the treatment of the fearful pediatric dental patient. These drugspossess muscle relaxant and anti-convulsant properties as well. 93Conscious Sedation 73
  8. 8. Pharmacology of Commonly Used Drugs in Conscious SedationAdverse Effects:Benzodiazepines demonstrate a wide margin of safety and a wide therapeutic index whichrepresents the dosage difference between an effective dose and a lethal dose. Its onset andduration of action are relatively short when compared with other orally administered sedatives.Minimal adverse reactions are associated with these drugs, and a reversible agent is available.Benzodiazepines administered alone can cause respiratory depression, an effect that is amplifiedwhen given in combination with opioids. Moreover, this synergistic effect causing significantrespiratory depression can also occur when benzodiazepines are administered in the presence ofother CNS depressants such as a patient‟s own medications. Physiological effects may include nausea, vomiting and/or unsteady movements(ataxia). This latter condition can manifest as a loss of head control, leading to a compromise ofthe patient‟s airway. Other undesirable responses may include a paradoxical or angry response,whereby the patient appears irritable, agitated and/or combative. Benzodiazepines should beavoided in patients with acute narrow angle glaucoma, and are contraindicated for patients with aknown allergy or hypersensitivity to them or any of their components. 93DIAZEPAMDiazepam is a benzodiazepine derivative. The chemical name of diazepam is 7-chloro-1, 3-dihydro-1-methyl-5-phenyl-2H-1, 4-benzodiazepin-2-one. It is a colorless to light yellowcrystalline compound. The empirical formula is C16H13ClN2O and the molecular weight is284.75. The structural formula is as follows:96Conscious Sedation 74
  9. 9. Pharmacology of Commonly Used Drugs in Conscious Sedation A benzodiazepine that is lipid soluble and water insoluble. It is readily absorbed from thegastro intestinal tract, reaching peak levels at 2 hours. Biotransformation of the drug occurs quiteslowly and it has a half life of 20 to 50 hours. The drug has three active metabolites, one ofwhich is also very lipophilic and has a half life of 96 hours. These metabolites are anxiolytic thansedative. After intravenous administration, diazepam is redistributed within 30 to 45 minutes,and the patient seems not to be sedated although free from anxiety. The patient should not beconsidered recovered from the drug. It has simply been redistributed. In fact stored drug can beredistributed to the CNS by a fatty meal consumed sometime later and the patient will suddenlyfeel resedated. This is referred to as rebound effect. Diazepam has strong anticonvulsant activity and provides some prophylaxis against thisadverse reaction of other drugs during the operative procedure. Diazepam can be administeredorally, rectally, or parenterally. If the intravenous route is selected, use of a large vein and slowadministration is recommended because the drug‟s propensity to cause irritation of the vein, withresultant thrombophlebitis. In addition rapid administration may result in apnea. Ataxia andprolonged CNS effects are the only common adverse reactions that can be anticipated whendiazepam is used for conscious sedation. 97Conscious Sedation 75
  10. 10. Pharmacology of Commonly Used Drugs in Conscious SedationDosage: Oral or rectal – 0.2to 0.5 mg/kg to a maximum single dose of 10mg Intravenous – 0.25mg/kgSupplied as: Tablets – 2, 5, and 10 mg Suspension- 5mg/mlMIDAZOLAMMidazolam HCL first was synthesized by Fryer and Walser in 1976. Midazolam is a short-acting, water-soluble benzodiazepine. It has anxiolytic, sedative, hypnotic, anticonvulsant,muscle-relaxant, and anterograde amnesic effects. The drug has been used as a preanestheticsedative in adults, and more recently in children. Chemically, midazolam HCl is 8-chloro-6-(2-fluorophenyl)-1-methyl-4 H -imidazo [1, 5-a] [1, 4] benzodiazepine hydrochloride. Midazolamhydrochloride has the molecular formula C18H13ClFN3•HCl, a calculated molecular weight of362.25 and the following structural formula: 96 Midazolam is imidazo benzene with unique properties when compared with otherbenzodiazepines. It is water soluble in its acid formulation but is highly lipid soluble in vivo.Midazolam also has a relatively rapid onset of action and high metabolic clearance whenConscious Sedation 76
  11. 11. Pharmacology of Commonly Used Drugs in Conscious Sedationcompared with other benzodiazepines. The drug produces reliable hypnosis, amnesia, and antianxiety effects when administered orally, intramuscularly, or intravenously. There are many usesfor midazolam in the peri operative period including premedication, anesthesia induction andmaintenance, and sedation for diagnostic and therapeutic procedures. Clinical advantages ofmidazolam are: 98 1. Water soluble 2. Rapid onset 3. Short acting 4. Anticonvulsant, muscle relaxant 5. Anterograde amnesia 6. Clinically inactive metabolites 7. Relatively high margin of safety 8. Reversal agent available 9. May be administered intra nasally Like most drugs, its onset of action varies greatly depending upon its route ofadministration. Intravenous administration will result in the most rapid onset of action due to itsimmediate deposit into a patient‟s circulation. However, when administered orally, the drug isexposed to metabolic clearance mechanisms in the intestine and liver, and will take longer toproduce its pharmacological effects pending its eventual deposit into the circulatory system andaction at receptors. For pediatric dental patients, it is commonly administered orally, in doses of 0.25 –0.75 mg/kg, with an upper limit of up to 1.0 mg/kg. An effective dose is usually 0.5 mg/kg andshould not exceed the maximally recommended dose of mg. In obese children, the dose shouldConscious Sedation 77
  12. 12. Pharmacology of Commonly Used Drugs in Conscious Sedationbe calculated based on ideal body weight. When supplied as an oral formulation, the bitter tasteoften requires an accompanying flavoring agent, (i.e. apple juice) for patient acceptance. In orderto enhance analgesia, the sedative can be mixed with an acetaminophen elixir, at a dosage of 15mg/kg. The oral form of midazolam has a cherry flavored vehicle that can be mixed withchildren‟s flavored aspirin or acetaminophen to increase the palatability.84 Intravenous midazolam is highly lipid soluble and redistributes rapidly.Consequently intravenous midazolam can be titrated to effect with fractionated doses of 0.05-0.1mg/kg that may be repeated at intervals of 3 to 4 minutes. As opposed to the oral route ofadministration, intravenous midazolam reaches peak effect in 2 to 3 minutes. Slow intravenousadministration is recommended with close observation for respiratory depression. Whencombined with intravenous opioids for painful procedures, midazolam has potent sedative effectsand the use of cardio-respiratory monitoring is imperative. A maximum intravenous dose of 0.05 88mg/kg has been recommended when combining the drug with narcotics. Anterograde amnesia is even more prominent than when the drug is used orally.Slurred speech has been shown to coincide with the onset of anterograde amnesia. Certainunderlying conditions or medications may prolong the effects of midazolam. Heparin decreasesprotein binding and increases the free fraction. Hepatic metabolism is inhibited by cimetidine,which prolongs the elimination half-life. Intravenous midazolam is an excellent agent forsedation and anxiolysis in patients for minor procedures when an intravenous line is in place. Itprovides complementary sedation for patients receiving opioids for very painful procedures dueto synergy but extreme caution is warranted when combining the drugs due to respiratorydepression.Conscious Sedation 78
  13. 13. Pharmacology of Commonly Used Drugs in Conscious Sedation Midazolam may be given as an intramuscular bolus of 0.08-0.1 mg/kg. Goodsedation and cooperation scores were recorded at 15 minutes after this dose in one study.Persistent sedation is minimal 60 minutes after the dose. Midazolam gives reliable sedation afterintramuscular dosing - a useful alternative for children who will not accept oral medications,particularly where residual sedation is a concern.84 Midazolam may be given by the intranasal route at doses of 0.2-0.4mg/kg. Onsettime is intermediate between the oral and intravenous routes of administration (10-15 minutes).The effectiveness of this route of administration is well established as a pre - medicant foranesthesia but its use is limited by burning on application to the nasal mucosa which mostchildren find very objectionable, as well as the bitter taste of midazolam reaching theoropharynx. Adverse effects including respiratory depression and synergy with opioids aresimilar to those mentioned above. For sedation and anxiolysis in young children who eitherrefuse or cannot take an oral dose of midazolam. Onset is reliable but most children will onlyaccept this route of administration once.97 Midazolam may be administered rectally at doses of 0.3-0.75 mg/kg. A dose of 0.3mg/kg has been shown to give reliable levels of sedation with a mean time of 16 minutes tomaximal blood level. Rectal administration is generally not as well tolerated in children > 3 yearsof age. After thirty minutes, blood levels were generally low but sedation and anxiolysis effectsremain.84Dosage: Oral – 0.25 to 1.0 mg/kg to a maximum single dose of 20mg; Intramuscular – 0.1 to 0.15 mg/kg to a maximum dose of 10 mg; Intravenous – slow titration;Conscious Sedation 79
  14. 14. Pharmacology of Commonly Used Drugs in Conscious SedationSupplied as: Syrup-2mg/ml; Injectable – 1- and 5mg/ml vialsBENZODIAZEPINE ANTAGONIST: FLUMAZENILOne of the benefits of using benzodiazepines is the ability to reverse possible undesirable effectssuch as oversedation. Flumazenil is a benzodiazepine antagonist, acting competitively at thebenzodiazepine site of the GABA receptor, but without altering its morphology. Chemically,flumazenil is ethyl 8-fluoro-5, 6-dihydro-5-methyl-6-oxo-4H-imidazo [1, 5-a] (1, 4)benzodiazepine-3-carboxylate. Flumazenil has an imidazobenzodiazepine structure, a calculatedmolecular weight of 303.3, and the following structural formula: 96Flumazenil is a white to off-white crystalline compound with an octanol: buffer partitioncoefficient of 14 to 1 at pH 7.4. It is insoluble in water but slightly soluble in acidic aqueoussolutions. This reversal agent is typically administered intravenously and its onset of action isusually within 1 minute. The first dose administered is 0.01 mg/kg with a maximum dose of 0.2mg. Doses should be administered slowly over 15-30 seconds, and may be repeated every minuteat 0.01 mg/kg for up to 5 doses or a maximum cumulative dose of 1.0 mg. The duration of actionof flumazenil is about 30 minutes, less than the half life of the benzodiazepine being reversed.Therefore, the patient should be carefully monitored after its administration for any signs ofConscious Sedation 80
  15. 15. Pharmacology of Commonly Used Drugs in Conscious Sedationresedation and hypoventilation. If such undesirable signs occur, another dose may be required oran infusion may need to be initiated.97 For reversal of sedation, the initial dose should be 0.01 mg/kg (up to 0.2 mg) given over15 seconds. If the desired level of consciousness does not occur after waiting an additional 45seconds, another dose of 0.01 mg/kg (up to 0.2 mg) should be administered and dosing repeatedat 60-second intervals to a maximum total dose of 0.05 mg/kg or 1 mg, whichever is lower. Mostpatients respond to doses in the range of 0.6 to 1.0 mg. A series of injections is preferable to asingle bolus to titrate to a desired end point and thus manage the problem with the minimallyeffective amount of drug. Onset of reversal is usually seen within 1 to 2 minutes. 88 The duration and degree of reversal are related to dose and plasma concentration ofthe sedating benzodiazepine, as well as that of the antagonist given. This coupled with the factthat the duration of effect is shorter for flumazenil than for most benzodiazepines, means thatresedation can occur. Patients should be carefully monitored for re-sedation and respiratorydepression throughout that period of reversal. The longer the period of sedation, the longer thatperiod required for monitoring and surveillance for re-sedation. If re-sedation occurs, repeateddoses of flumazenil at no less than 20-minute intervals may be used.Dosage: intravenous – as described aboveSupplied as: 5-and 10ml multiple-use vials containing 0.1 mg/ml in boxes of 10CHLORAL HYDRATEChloral hydrate, the oldest member of the hypnotic group of drugs, was discovered by Liebig in1832.It is produced by the hydration of chloral (trichloroacetalydhyde -CC, CHO). The chloralhydrate produced is a crystalline substance readily soluble in oil or water. Chloral Hydrate isConscious Sedation 81
  16. 16. Pharmacology of Commonly Used Drugs in Conscious Sedationclassified as a non-barbiturate, a hypnotic that has been widely used as a sedative in pediatricdentistry for decades.96 Its mechanism of action is unknown, yet its depressant effects on the C.N.S. areprimarily due to its active metabolite, trichloro ethanol (TCE), a carcinogen in mice. Followingoral administration, chloral hydrate is absorbed into the bloodstream and the major portion ofthis drug is reduced by liver alcohol dehydrogenase to trichoroethanol. The trichloroethanol maythen be conjugated to glucoronides of urochloralic acid and excreted in the urine and bile. Asmall portion of the chloral hydrate as well as a small portion of trichloroethanol is oxidized inthe kidney and liver by a DPNH-dependent enzyme system to the inactive metabolite,trichloroacetic acid. It may be administered orally at a dose of 25-50 mg/kg, with a maximal total dose of1,000 mg. Its onset of action is 30-60 minutes and duration of up to 5 hours. A majordisadvantage of this medication is that of all the orally administered sedative medications, it mayhave the worst taste. Moreover, its liquid concentration is a mucosal irritant that can causenausea, vomiting or even laryngospasm. 84 Compared with other agents, other notable side effects include its delayed onset, prolongedrecovery, possible cardio-irregularity at higher doses, and no analgesic properties. Chloralhydrate depresses genioglossus activity causing hypotonicity of the tongue which can lead to itfalling backward against oropharyngeal structures, depressing respiration and compromising thepatient‟s airway. Moreover, it has no reversal agent.88Conscious Sedation 82
  17. 17. Pharmacology of Commonly Used Drugs in Conscious Sedation Nordenberg, et al., reported that the recommended hypnotic dose of chloral hydratedepresses the cerebral hemispheres and induces sleep without significant changes in respiration,blood pressure or heart rate. With higher doses the respiratory rate may be depressed and theblood pressure reduced due to medullary depression and peripheral cutaneous vasodilation.However, because of its therapeutic ratio, these and other known untoward effects are not seenfollowing the ingestion of sedative quantities. It is particularly effective for non-painful procedures requiring sedation or sleep inchildren younger than 2 years of age who do not require an intravenous catheter. Somepractitioners recommend sleep deprivation for children prior to giving chloral hydrate. Chloralhydrate should be given in a quiet, calm and dimly lit environment to be most effective. Chloral hydrate is well established as a sedative for painless procedures such as forradiographs, CT and MRI scans. Usefulness in painful procedures is limited by patientmovement and agitation that occurs during a painful procedure even when the child may appearto be much sedated. The long elimination half-life of chloral hydrate (trichloroethanol) often isan indication for prolonged supervision prior to discharge.84PROPOFOLPropofol is 2, 6 diisopropylphenol, a phenol derivative with sedative, hypnotic and anestheticproperties. 96Conscious Sedation 83
  18. 18. Pharmacology of Commonly Used Drugs in Conscious Sedation Propofol is a clear colourless insoluble phenolic compound supplied in an isotonic, oil-in-water, Intra-lipid emulsion that came into use as a useful, short acting, IV anaesthetic in 1984. Itis unrelated, chemically, to any other anaesthetic agent, but behaves rather like ketamine (q.v.).Recovery from propofol is, however, rather more rapid, and „hangovers‟ are less common. Thedrug is rapidly redistributed into fat and other body tissues and more than half leaves thecirculation within 10 minutes even after neonatal IV administration. It is then conjugated andmetabolized in the liver, the elimination half life being 5–10 hours although, with sustained use,elimination from deep stores may take 2–3 days.96 Propofol‟s primary mechanism of action is through the GABAA receptor. Throughthis mechanism propofol results in neuronal cell membrane hyper polarization, inhibition of theaction potential and a reduction in cell activity. Propofol is not teratogenic or fetotoxic inanimals but crosses the placenta readily, and the manufacturers do not recommend use duringpregnancy or delivery, although no problems have been encountered with use for Caesareandelivery.97 Propofol can be administered by either bolus dosing or bolus dosing followed by acontinuous infusion. Because of propofol‟s short duration, procedures exceeding 15 to 20minutes are often best managed by a bolus dose followed by continuous infusion to maintain thedesired plasma concentration and clinical effect. As noted above onset of action is extremelyrapid and induction of sedation or anesthesia may be achieved with 2-3 mg/kg in 95% of patientswithin 60-90 seconds. Typical induction doses for sedation include infusing propofol at 0.5-2mg/kg/min until the child is asleep. Infusion of 100-150 mcg/kg/min maintain sleep in close to100% of patients. Doses of propofol following induction can be used at 0.5-1 mg/kg if the patient 84awakens.Conscious Sedation 84
  19. 19. Pharmacology of Commonly Used Drugs in Conscious Sedation The three properties of propofol that make it such a useful sedative-hypnotic are highlipid solubility, large volume of distribution and high metabolic clearance. In fact clearance ofpropofol exceeds hepatic blood flow. Propofol is metabolized by the liver throughglucuronidation pathways to inactive conjugated metabolites. It is highly protein bound. Itspharmacokinetics is summarized best by a 3-compartment model. Infants have a larger volumeof distribution and a greater metabolic clearance than older children. Consequently bolus dosesrequired to achieve clinical effect is higher in infants. Similarly because the metabolic clearanceis higher in infants, continuous infusions rates are greater. Propofol is particularly effective as a sole agent for noninvasive radiologic procedures. ForMRI and CT scans infusions of 100-150 mcg/kg results in a very high success rate. Propofol isalso very effective either as a sole agent or combined with opioids/ketamine for brief painfulprocedures. As a single agent propofol is effective for invasive oncology procedures89,90 andgastrointestinal procedures84KETAMINEKetamine is chemically related to phencyclidine (PCP) and cyclohexamine; it has a molecularweight of 238 and a pKa of 7.5. Although ketamine hydrochloride is water soluble, ketamineslipid solubility is ten times that of thiopentone. The molecular structure (2-(O-chloropheny l)-2-methylamino cyclohexanone) contains a chiral centre at the C-2 carbon of the cyclohexanonering so that two enantiomers of the ketamine molecule exist: s (+) ketamine and r (-) ketamine.96Conscious Sedation 85
  20. 20. Pharmacology of Commonly Used Drugs in Conscious SedationThe mechanism of action of Ketamine includes:99 1. Noncompetitive antagonist of the central nervous system NMDA receptors a. NMDA receptor is a calcium-gated channel receptor b. NMDA receptor agonists are excitatory amino acids: glutamic acid, aspartic Acid and glycine c. Agonist binding to receptor results in opening of ion channel and depolarization Of the neuron d. NMDA receptor is involved in sensory input at the spinal, thalamic, limbic, and Cortical levels e. Ketamine blocks sensory input and impairs limbic functions 2. Agonist at α- and β-adrenergic receptors 3. Antagonist at muscarinic receptors of the central nervous system 4. Blocks reuptake of catecholamines 5. Agonist at opioid sigma receptor Ketamine is one of the most versatile sedative-analgesic agents and results in anumber of desired clinical effects that are dose-dependent.At the lowest of doses anxiolysis andConscious Sedation 86
  21. 21. Pharmacology of Commonly Used Drugs in Conscious Sedationanalgesia occur. Antegrade amnesia occurs at slightly higher doses and is often accompanied byperceptual changes. Higher doses result in a sedated state that is described as a “dissociativesedation”. Typically spontaneous respirations and airway reflexes are maintained although maynot be totally normal. Ketamine generally causes an increase in heart rate, blood pressure andcardiac output. 100 Because of concerns of potentially increasing intracranial pressure, ketamine should beused with caution in patients with suspected increased intracranial pressure as well as open globeinjuries. Ketamine‟s neuropsychiatric effects include visual hallucinations that may beaccompanied by emergence phenomena and agitation. Oral secretions are typically only mildlyincreased but may require antisialogogues. The single most severe adverse effect with ketaminesedation is laryngospasm. Ketamine is clinically effective by a number of different routes.Oral/Rectal Ketamine:Oral and rectal doses of ketamine are 4-10 mg/kg. Onset of sedation occurs in 15-30 minutes andeffects may be prolonged by the oral or rectal route lasting 3 to 4 hours. Ketamine‟s activemetabolite norketamine predominates with oral/rectal administration typically in a ratio ofnorketamine to ketamine of 5 to 1 and 3 to 1 respectively. Norketamine is approximately one-third as potent as ketamine. Following oral administration (10 mg/kg), peak effects occurred in30 to 40 minutes in children undergoing painful cancer procedures. Typically, higher doses oforal ketamine (8-10 mg/kg) are more effective as a premedication than lower doses (3-6mg/kg).84Intramuscular (IM) Ketamine:Intramuscular ketamine reaches peak blood levels and clinical effect in five minutes after 3 to 10mg/kg. Recovery from dissociation occurs within 15 to 30 minutes with coherence andConscious Sedation 87
  22. 22. Pharmacology of Commonly Used Drugs in Conscious Sedationpurposeful neuromuscular activity returning in 30-120 minutes. A smaller dose of 3 mg/kg hasbeen employed to facilitate intravenous catheter placement or acceptance of a mask foranesthesia induction, with no delay in discharge compared to control patients after 60 minutes. The 100 mg/ml formulation of ketamine is preferred for IM administration in olderchildren to minimize volume related injection site discomfort. Experience with intramuscularketamine is extensive. Sedation is accompanied by the excellent analgesia. Intramuscularadministration of ketamine is an excellent means of sedating the “out of control” patient for IVplacement or mildly painful procedures. Deep sedation may occur. 84Intravenous Ketamine:Ketamine is typically given in doses of 0.5 to 1 mg/kg although doses of 2 mg/kg can be used.Peak concentrations occur within 1 to 2 minutes and rapid absorption by the highly perfusedcerebral tissues allows almost immediate induction of clinical effects. Ketamine then slowlyredistributes into the peripheral tissues; thus decreasing central nervous system levels thatcorrelate with return of coherence, generally 10-15 minutes if no additional doses are given.Deep levels of sedation may be achieved. Remarkably painful procedures are tolerated wellfollowing administration of ketamine because of its profound analgesic effects as well as thedissociative sedation it affords. Intravenous ketamine is well established as a safe and efficacious agent in pediatricpatients. Because of higher blood levels with intravenous use, ketamine administered by thisroute may have more problems than oral or intramuscular administration. Oral secretions may beavoided by the administration of an antisialogogue (atropine 0.01-0.02 mg/kg or glycopyrrolate0.005 mg/kg intravenous). 84Conscious Sedation 88
  23. 23. Pharmacology of Commonly Used Drugs in Conscious Sedation Although patients will continue to breath and maintain airway tone, silent pulmonaryaspiration of oral contents has been reported with deep levels of sedation. Patients may continueto move during sedation and eyes remain open. Emergence delirium is much less common inchildren than adults and may be prevented or treated by the administration of a small dose of abenzodiazepine or preparing the patient by discussing the clinical effects of ketamine prior toadministration. Ketamine alone is particularly effective for procedures with moderate to severediscomfort and pain. Initial doses of 0.5 mg/kg followed by repeat doses of 0.25-0.5 mg/kg wereeffective for 97% of pediatric patients undergoing invasive emergency department procedures. Incombination with midazolam, ketamine doses of 0.5-1.5 mg/kg was superior in efficacy andsafety to an opioid-midazolam combination in children undergoing painful pediatric oncologyprocedures. Similarly the combination of propofol and ketamine 1 mg/kg resulted in less restlessnessduring burn dressing changes compared to a propofol-fentanyl combination. Ketamine should beused cautiously if at all in individuals with intracranial hypertension, systemic hypertension orneuropsychiatric disorders and/or any child with visual or auditory. 84NARCOTICS Narcotics are the “heavy artillery” of pediatric sedation. They are not employed with anygreat consideration for their analgesic properties. They do produce sedation and euphoria to agreater degree in children than in adults. Local anesthesia is still required for intra-operative paincontrol. Local anesthetics are also CNS depressants.Conscious Sedation 89
  24. 24. Pharmacology of Commonly Used Drugs in Conscious Sedation A significant drug-drug and drug-physiologic interaction can occur when narcotics orother drugs that depress respiration are combined with local anesthetics. In usual doses, localanesthetics are CNS depressants and will provide additive depression when combined with otherCNS depressants. In addition, when drugs that depress respiration are used (particularlynarcotics), varying degrees of hypercarbia can occur, with a resultant decrease in serum pH. Asthe respiratory depression continues to deepen, respiratory and metabolic acidosis results in anincrease in the availability of lidocaine to the CNS. This occurs as a result of less serum proteinbinding of lidocaine along with central vasodilation and an increase in blood flow to the CNS innan acidotic state. 97 Consequently the threshold for CNS lidocaine toxicity is lowered. Lidocaine toxicityresults in CNS excitation and seizures and ultimately coma and death. As a result, the maximumdosage of local anesthetic must be reduced when used in combination with a CNS and/orrespiratory depressant. This very important and significant interaction is often overlooked and isthe cause of many of the adverse incidents reported in pediatric sedation. The maximum localanesthetic does in children may allow for the use of only one or two dental cartridges, which isquite different than for adult patients. Combination with other sedative drugs, including nitrous oxide-oxygen, reduces the needfor larger doses of narcotics and thus reduces the potential for unwanted effects from thesepotent drugs. A practitioner employing narcotics should be thoroughly familiar with their actionsand interactions and should have had some supervised experience in their use as well as inmanagement of the airway and patient resuscitation procedures.88Conscious Sedation 90
  25. 25. Pharmacology of Commonly Used Drugs in Conscious SedationFENTANYLFentanyl is a synthetic opiate agonist in the same chemical class as meperidine. It is a potentnarcotic analgesic. A dose of 0.1 mg is approximately equivalent to 10 mg of morphine or 75 mgof meperidine. Fentanyl has a rapid action, and after a submucosal or intramuscular injection theonset occurs in 7 to 15 minutes; duration of effects is 1 to 2 hours. The drug is metabolized bythe liver and is excreted in the urine.97 Fentanyl produces little histamine release and has much less emetic effect than morphineor meperidine. Fentanyl can be administered by the intramuscular, intravenous, or submucosalroute. When it is used with other CNS depressants, the dose should be reduced. The drug workswell with orally administered diazepam and nitrous oxide-oxygen. It is not recommended for usein children younger than 2 years of age. The oral transmucosal preparation of fentanyl has never become popular for proceduralsedation and analgesia because titration is difficult, effectiveness is variable, and the incidence ofemesis is high (31–45%).89 Like all opioids, fentanyl can cause respiratory depression. Becauseof the lack of histamine release with fentanyl, nausea and vomiting are less common than withmorphine or meperidine. In the absence of substantial ethanol intoxication, hypovolaemia, orconcomitant drug ingestion, hypotension is rare, even with very large doses of fentanyl (doses of50 _g/kg are common in adult and pediatric cardiac surgery). A common reaction to fentanyl isisolated nasal pruritus.97 A widely-described but rare adverse effect of fentanyl with potential for respiratorycompromise is chest-wall rigidity. This complication is associated with much higher doses (_5Conscious Sedation 91
  26. 26. Pharmacology of Commonly Used Drugs in Conscious Sedation_g/kg as a bolus dose) than those used for procedural sedation and analgesia; indeed, this adverseevent has not been reported in this setting.Dosage: 0.002 to 0.004 mg/kg Supplied: 0.05 mg/mL in 2-and 5-mL amplesMEPERIDINEMeperidine is a synthetic opiate agonist. It is water soluble but is incompatible with many otherdrugs in solution. Meperidine may be administered orally or by subcutaneous, intramuscular, orintravenous injection. It is least effective by mouth. It is bitter and requires taste masking by aflavoring agent. By the oral route, peak effect occurs in 1 hour and lasts about 4 hours. Parenteraladministration shortens the time of onset and duration. High doses that lead to an accumulationof normeperidine, a primary metabolite of meperidine, have resulted in seizures. Meperidineshould be used with extreme caution in patients likely to accumulate or be sensitive to thismetabolite (e.g., patients with hepatic or renal disease, or history of seizures). Dosage: Oral, subcutaneous, or intramuscular-1.0 to 2.2 mg/kg, not to exceed 100mgwhen given alone or 50 mg when in combination with other CNS depressants 97Supplied: Oral tablets-50 and 100 mg; Oral syrup-50mg/5mL; Parenteral solution-25, 50, 75, and 100 mg/mL.Conscious Sedation 92
  27. 27. Pharmacology of Commonly Used Drugs in Conscious SedationNARCOTIC ANTAGONISTA semi synthetic opiate antagonist used for the sole purpose of reversing the effects of narcoticdrugs. Naloxone is a pure antagonist, with no agonist activity even in large doses. It acts in 2 to 5minutes after subcutaneous or intramuscular injection and 1 to 2 minutes intravenously. Afterintravenous administration the duration of reversal about 45 minutes; it is slightly longer whenthe drug is administered intramuscularly or subcutaneously. This is an important difference,because the duration of reversal is about 45 minutes; it is slightly longer when the drug isadministered intramuscularly or subcutaneously. This is an important difference, because theduration of effect of the opiate is in all likelihood longer than that of the antagonist. Consequently, patients undergoing reversal of sedation with naloxone should be keptunder continual surveillance until it has been determined that the narcotic will not produce arebound effect. The time period will vary depending on the duration of action of the narcotic.Repeated doses of naloxone may be necessary to establish patient stability. If the decision hasbeen made to administer an antagonist, other resuscitative measures must be available and mustbe used as necessary. Naloxone administration should never take precedence over basicresuscitative measures. There is no evidence to support the contention that naloxone will reverserespiratory depression but not the sedative action of the opiate.97 Adverse reactions include nausea, vomiting, sweating, hypotension, hypertension,ventricular tachycardia and fibrillation, and pulmonary edema. None of these effects, however,has been reported with its use in pediatric conscious sedation.Dosage: Intravenous, subcutaneous, intramuscular-initial dose: 0.01 mg/kg; subsequent doses:0.1 mg /kg (2 mg maximum) every 2 to 3 minutesConscious Sedation 93
  28. 28. Pharmacology of Commonly Used Drugs in Conscious SedationSupplied: Parenteral solution-0.02, 0.4, 1.0 mg/kgNITROUS OXIDENitrous oxide is an inorganic inhalation agent that is colourless, odorless to sweet-smelling, andnon-irritating to the tissues. It is non-flammable but will support combustion. It is slightlyheavier than air, with a specific gravity of 1.53, and has a blood: gas partition coefficient of 0.47.Because of its low solubility in blood, it has a very rapid onset and recovery time. Nitrous oxide has multiple mechanisms of action. The analgesic effect of nitrous oxideappears to be initiated by neuronal release of endogenous opioid peptides with subsequentactivation of opioid receptors and descending Gamma-amino butyric acid type A (GABAA)receptors and noradrenergic pathways that modulate nociceptive processing at the spinal level.The anxiolytic effect involves activation of the GABAA receptor either directly or indirectlythrough the benzodiazepine binding site. Unlike other anaesthetics, nitrous oxide produces a mild analgesic effect at subanestheticconcentrations. The mechanism for this effect most likely involves an interaction with theendogenous opioid system because it is abolished by administration of the opioid antagonist,naloxone. The strongest evidence is that nitrous oxide stimulates release of enkephalins, whichbind to opioid receptors that trigger descending noradrenergic pathways. Inhaled nitrous oxide provides anxiolysis and mild analgesia and sedation. It is commonlydispensed at concentrations between 30% and 70% with oxygen composing the remainder of themixture. Nitrous oxide has rapid onset (30–60 s), maximum effect after about 5 min, and rapidConscious Sedation 94
  29. 29. Pharmacology of Commonly Used Drugs in Conscious Sedationrecovery upon discontinuation. At typical procedural sedation and analgesia concentrations thereis preservation of hemodynamic status, spontaneous respirations, and protective airway reflexes.Nitrous oxide has an excellent safety profile; however as a sole agent it does not reliably produceadequate procedural conditions, and in many cases is supplemented with an opioid or local orregional anesthesia. Administration can also be useful for intravenous access or venipuncture infrightened children. The safest method of nitrous oxide administration is via a self-administered demand-valvemask, which needs negative inspiratory pressure to activate gas flow. If the patient becomessomnolent, the mask will fall from their face and gas delivery will cease. The main limitation ofself-administration is that it is ineffective in uncooperative patients, including most frightenedyoung children. Continuous-flow nitrous oxide has been used in this population with a mask strapped overthe nose, or over the nose and mouth producing moderate or deep sedation and necessitating anadditional physician dedicated to continuous gas titration. This technique is associated withmore frequent emesis than self-administration (0% vs. 4%), posing a potential hazard when amask is strapped over the child‟s mouth. Several minor adverse effects can be evident, including nausea, dizziness, voicechange, euphoria, and laughter. Because of its high diffusibility, nitrous oxide should be avoidedin patients with potential closed-space diseases such as bowel obstruction, middle ear disease,pneumothorax, or pneumocephaly. A scavenging system must be in place to ensure compliancewith occupational safety regulations as occupational exposure to nitrous oxide has beenassociated with increased rates of spontaneous abortions.Conscious Sedation 95
  30. 30. Pharmacology of Commonly Used Drugs in Conscious SedationANTIHISTAMINESHYDROXYZINEHydroxyzine hydrochloride is designated chemically as 2-[2-[4-(p-Chloro-?-phenylbenzyl)-1-piperazinyl] ethoxy] ethanol dihydrochloride. Hydroxyzine hydrochloride occurs as a white,odorless powder which is very soluble in water 96 Hydroxyzine is an antihistamine with mild sedative and antiemetic properties. Innormal doses, it has no cardio vascular or respiratory depressant effects. It is rapidly absorbedfrom the gastrointestinal tract with clinical effect seen in 15 to 30 minutes, peak levels occur at 2hours, and mean half-life is 3 hours. Administration is preferably by the oral route. Intramuscularinjections must be deep in a large muscle mass. The drug should not be injected subcutaneouslyor intravenously because of potential tissue necrosis and hemolysis. Adverse reactions includeextreme drowsiness, dry mouth and hypersensitivity.97Dosage: Oral-1 to 2mg/kg; Intramuscular-1.1mg/kgSupplied as: Tablets-10, 25, 50 and 100mg; Syrup- 10mg/5ml; Injectable-25 or 50mg/ml;Conscious Sedation 96
  31. 31. Pharmacology of Commonly Used Drugs in Conscious SedationDRUGS USED FOR PROCEDURAL SEDATION AND ANALGESIAConscious Sedation 97