NONVOLATILE ANESTHETIC AGENT

1
NONVOLATILE ANESTHETIC AGENT
R1 ???
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PHARMACOLOGICAL PRINCIPLES
3
PHARMACOKINETICS
Absorption

• Oral, sublingual, rectal, inhalation,
  transdermal, subcutaneous, IM, IV
• Administrarion site ? Blood stream
• Affected by characteristic of drug, site of
  absorption
• Bioavailability
• Fraction of unchanged drug that reaches the
  systemic circulation
• Oral administration
• Convenient, economical, tolerant
• Unreliable ? Pts cooperation, 1st pass hepatic
  metabolism, gastric pH, enzymes, motility, food,
  other drug ?? ?? ?? ??
• Subligual, rectal, buccal administration
• 1st pass hepatic metabolism ? bypass
• Transdermal administration
• Prolonged and continuous absorption with minimal
  total dose
• Parenteral injection
• Subcutaneous, IM, ? blood flow, carrier vehicle
• IV ? completely bypass the process of absorption

4
PHARMACOKINETICS
Distribution

• Major determinet of end-organ drug concentration
• Highly perfused organs ? large amount of drug

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PHARMACOKINETICS
Distribution

• Plasma protein bounded drug ? unavailable for
  uptake
• Albumin ? bind acidic drug (eg. Barbiturate)
• AAG ? bind basic drug (eg. Local anesthetics)
• Plasma protein ? ?? ???, binding site ? ?? ??? ??
  occupied ?? ??? tissue? uptake ?? free drug ? ??
• Renal dz, liver dz, CHF, malignancy ? albumin
  production ??
• Trauma , infection, MI, Chr. Pain ? AAG ??
• Availability ??? ?? ?? ???? ?? drug uptake ? ??
• Permeation of CNS ? BBB? ionized drug? ??? ??
• Molecular size
• Lipid-solubility
• After the highly perfused organs are saturated
  during initial distribution, the greater mass of
  the less perfused organs takeup drug from the
  blood stream
• Plasma conc. ? ?? ? ?? drug? highly perfuse
  organ?? ???? equilibrium ??
• ??? redistribution ? ???? ?? ??? termination ? ??

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PHARMACOKINETICS
Distribution

• Vd
• Volume of distribution ? apparent volume into
  which a drug has been distributed
• Dose / Plasma concentration
• Drug elimination ? continual redistribution ? ??
• A small Vd
• relative confinement of the drug to the
  intravascular space
• High protein bounding, ionization
• A large Vd
• total body water ? ??? ?? ?? ??
• High solubility or binding of the drug in tissue
  other than plasma

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PHARMACOKINETICS
Biotransformation

• Metabolic process
• Liver ? primary organ
• ??? end product ? water soluble, inactive
• Kidney?? excretion ? ??? ??
• Phase I
• Drug ? oxidation, reduction, hydrolysis ??? ??
  more polar ? ??? ??
• Phase II
• Parent drug? phase I ? metabolite? conjugation
• Glucuronic acid ?? conjugation ?? highly polar
  end product ??
• Hepatic clearence
• Rate of elimination of a drug as a result of
  liver biotransformation
• mm/min
• Hepatic blood flow, hepatic excretion ratio ? ??
• Hepatic enzyme system capacity

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PHARMACOKINETICS
Excretion

• The kidney is the principle organ of excretion
• Non-protein bound drugs freely cross from plasma
  into the glomerular filtrate
• Non-ionizedfraction ? reabsorbed in the renal
  tube
• Ionized portion is excreted in urine ? urine pH ?
  ????
• Kidney active secrete some drug
• Renal clearance ? the rate of elimination of a
  drug from kidney excretion
• Renal failure ? changing pharmacokinetics of drug
  protein bounding, Vd, clearance rates
• Relatively few drugs depend on biliary excretion
• The lungs ? excretion of volatile agents

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PHARMACOKINETICS
Compartment Models

• A simple way to characterize the distribution and
  elimination of drug in the body
• Group of tissues that process similar
  pharmacokinetics
• Plasma vessel rich group ? central compartment
• Muscle, fat, skin, etc. ? pph. compartment
• Compartment ? conceptual ? not represent actual
  tissues
• Two compartment model
• Correlate well with the distribution and
  elimination phase of many drugs
• Alpha phase (distribution phase)
• Initial rapid decline in plasma conc.
  (redistribution)
• Plasma, vessel rich group of the CNS ? less
  perfused pph. tissue
• Beta phase (elimination phase)
• Less steep decline in plasma conc.
• Distribution slows ? elimination of drug from
  continued but less steep
• Elimination half-life of drug
• Vd ? ??, rate of clearance ? ???

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PHARMACOKINETICS
Compartment Models

• Three compartment model
• Central compartment 2 pph. Compartment
• Plasma conc. (Cp)
• Cp (t) Ae at Be bt Ce rt
• A, B, C ? fractional coefficient
• Alpha ? rapid distribution half-life, beta? slow
  distribution half life, gamma ? terminal
  distribution half life ? ???

• Rates of dustribution biotransformation
• First-order kinetics
• Constant fraction or percentage of drug is
  distributed or metabolized per unit of time
• Zero-order kinetics
• Drug ? ??? biotransformation capacity ? ????
  constant amount of drug ? ????? ?? ?? ??

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PHARMACODYNAMICS
Dose-Response Curves

• Relationship between drug dose and
  pharmacological effect

• Relationship between drug dose and
  pharmacological effect
• X-axis ? steady-states plasma conc.
• Y-axis ? pharmacological
• Linear ? ??? logarithmic ? ??
• Curve position ? indication of drug potency
• Maximal effect of drug ? efficacy
• Slope of curve ? receptor binding character of
  the drug
• ED(50) median effective dose
• LD(50) median lethal dose
• Therapeutic index
• Ratio of LD 50ED 50

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PHARMACOKINETICS
Drug Receptor

• Macromollecules
• Protein embedded into cell membrane
• Endogeneous substance, exogenous eubstance
• Agonist ? receptor? ?? ?? cell function ? ??? ???
• Antagonist ? receptor ? ?? ???, cell ? direct
  effect ? ??
• ??? ??? agonist substance ? effect ? ??
• Competitive antagonist ? bind reversibly to
  receptor, can be displaced by higher conc. of
  agonist
• Non-competitive antagonist ? bind to the receptor
  with high affinity
• ?? ??? agonist ?? receptor blockade? reverse ??
  ??
• ?? cell function ? ??? ?? ??? ???, 2nd messenger,
  c-AMP ?? regulatory molecule? ?? ?? ??? ??

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SPECIFIC NONVOLATILE ANESTHETIC AGENTS
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BARBITURATES
Mechanism of action

• Depress reticular activating system
• Brain stem? complex polysynaptic network of
  neurons and regulatory centers
• Consciousness ? ??? ??? vital function? ??
• Axon ??? nerve synapse? ??? ??
• Excitatory neurotransmitters (Ach) ? suppress
  transmission
• Inhibitory neurotransmitters (GABA) ?enhance
  transmission

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BARBITURATES
Structure-Activity Relationship
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BARBITURATES
Pharmacokinetics

• Absorption
• IV route ? ??, ?? ??? induction ? ??? IV line? ??
  ???? ?? ?? ???? ??
• Rectal thiopental, methohexital
• ??? ??
• IM pentobarbital, secobarbotal
• Premedication for all age groups
• Distribution
• Highly lipid-soluble barbiturates(thiopental,
  thiamylal,methohexital)
• Duration of action ? redistribution ? ?? ??
• Thiopental ? highly protein bound, but great
  lipid solubility, highly nonionized fraction ?
  maximal brain uptake ? 30? ??
• ?? central compartment ? contracted(hypovolemia),
  low serum albumin level(LC), nonionized fraction
  ? ??(acidosis)
• ??? ??, brain? heart ? ?? ??? thiopental ? ??
• Redistribution
• pph. Compartment(?? muscle) ? 20-30? ??? peak
  level ? 10
• ????? ??? 30? ??? ??? ??, 20???? awake

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BARBITURATES
Pharmacokinetics

• Distribution

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BARBITURATES
Pharmacokinetics

• Distribution
• Induction dose
• BW ? age ? ?? (old age ? ?? dose ? ??)
• redistribution ? ??
• Elimination half-life ? 3-12 h
• Thiamylal, methohexital has similar distribution
  patterns
• Less lipid-soluble barbiturate
• Much longer distribution half life and duration
  of action
• Biotransformation
• Hepatic oxydation
• Inactive water soluble metabolites
• Methohexital ? ??, thiopental? ?? 3-4? hepatic
  clearnace? ??
• Single dose barbiturate ? awake ? ??
  redistribution ? ?? ?? ???, psychomotor function?
  full recover ? metabolism ? ?? ????

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BARBITURATES
Pharmacokinetics

• Excretion
• Highly protein bound ? decrease glomerular
  filtration
• Highly lipid solubility ? increase renal tubular
  reabsorption
• Renal excretion ? water-soluble hepatic
  metabolites??? ????
• Phenobarbital ? ??
• Methohexital ? ?? feces ? excretion

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BARBITURATES
Effects on Organ Systems

• Cardiovascular
• Induction dose of barbiturates
• Fall in BP, elevation HR
• Depression of the medullary vasomotor center ?
  pph. Capacitance vessel vasodilation , pph.
  Pooling of blood RA ?? venous return ??
• Tachycardia ? due to central vagolytic effect
• Sympathetic activity ? ?? resistance vessel ?
  constriction
• Increase pph. Vascular resistance
• ??? hypovolemia, CHF, BB ?? baroreceptor response
  ? ???? ??? cardiac output, ABP ? dramtically
  decreased
• ?? ??? ???? ?? pph. pooling effect ? direct
  myocardial depression
• Pt with poorly controlled HTN
• Induction ? BP? ?? wide swing
• Barbiturate ? vascular effect
• volume state, baseline autonomic tone,
  preexisting cardiovascular dz
• Slow rate of injection, preoperative hydration

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BARBITURATES
Effects on Organ Systems

• Respiratory
• Depression of medullary ventilatory center
• Decrease the ventilatory response to hypercapnia,
  hypoxia
• Barbiturate sedation
• Upper airway obx. ? apnea usually follows an
  induction dose
• Awakenning ? tidal volume, RR decreased
• Do not completely depress noxious airway reflex
• Bronchospasm ? asthma Pt.
• Laryngospasm ? lightly anesthetize Pt.
  (cholinergic nerve stimulation, histamine
  release, direct bronchial smooth m. contraction)
• ? Atropine premedication ?? ??
• Laryngospasm hiccuping are more common after
  use of methohexital

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BARBITURATES
Effects on Organ Systems

• Cerebral
• Constrict the cerebral vasculature
• Decreasing in cerebral blood flow, ICP
• ?? ICP ? cerebral ABP ?? ???? cerebral perfusion
  pressure ? ??
• CPP ? cerebral artery pressure (greater of
  cerebral venous pressure or ICP)
• ??? ??? cerebral blood flow ? ??? ???? ??
• Barbiturate ? cerebral oxygen consumption ? 50
  ?? ??
• EEG changes
• Small dose ? low-voltage fast activity
• High dose ( bolus of 15-40 mg/kg, thiopental) ?
  electrical silence (suppression)
• ??? effect ? transient episode of focal ischemia
  (cerebral embolism) ? ?? pretect
• ??? global ischemia (cardiac arrest, etc) ???
  not protectove
• ??? EEG suppression dose ?
• Prolonged awakening, delayed extubation,
  inotropic support need

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BARBITURATES
Effects on Organ Systems

• Cerebral
• Degree of CNS depression ? mild sedation to
  unconsciousness
• Depending on the dose
• Garlic or onion sensation during induction with
  thiopental
• Unlike opioids, do not selectively impair the
  perception of pain
• ?? ???? antianalgesic effect (lowering the pain
  threshold)
• Small dose ? ??? excitement, disorientation
• Do not produce muscle relaxation,
• some induce involuntary skeletal m. contraction

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BARBITURATES
Effects on Organ Systems

• Cerebral
• Small dose of thiopental (50-100mg, iv)
• ???? grand mal seizure ? ??
• Acute tolerance, physiologic dependence on the
  sedative effect
• Renal
• Reduce renal blood flow and GFR
• in proportion to the fall in BP
• Hepatic
• Hepatic blood flow is decreased
• Chr. exposure ? opposing effect on drug
  biotransformation
• Induction of hepatic enzyme
• Increase rate of metabolism of some drug (eg,
  digoxin)
• Combination with the CYT P-450 enzyme system
• Interfere with the biotransformation of other
  drug (eg, TCA)
• Formation of porphyrin ? ??
• Porphyria ??

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BARBITURATES
Effects on Organ Systems

• Immunological
• Anaphylactic and anaphylactoid allergic reactions
  are rare
• Thiobarbiturates ? mast cell histamine release in
  vitro
• Some anesthesiologist
• Prefer methohexital over thiopental or thiamylal
  in asthmatic pt.

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BARBITURATES
Drug Interaction

• Contrast media, sulfonamides, etc
• Same protein-binding site as thiopental ?
  increase the amount of free drug
• Potentiate the organ system effect
• Ethanol, opioid, antihistamine, other CNS
  depressant
• Potentiate the sedative effects of barbitura
• Common clinical impression
• chr. Alcohol abuse ? increased thiopental
  requirements
• Lacks scientific proof

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BENZODIAZEPINES
Mechanism of Action

• Interact with specific receptors in CNS, cerebral
  cortex
• Inhibitory effect of various neurotransmitters
• Ficilitate GABA-receptor binding ? increase
  membrane conductance of chloride ions ? membrane
  polarization change? inhibits normal neuronal
  function
• Flumazenil
• Specific benzodiazepine-receptor antagonist that
  effectively reverse most of the CNS effects of
  benzodiazepines

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BENZODIAZEPINES
Structure-Activity Relationships

• Include benzene rings and a seven-member
  diazepine rings

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BENZODIAZEPINES
Pharmacokinetics

• Absorption
• Benzodiazepines ? ?? PO, IM, IV ??? ??
• Sedation ? ?? ??? induction
• Diazepam, lorazepam ? GI tract ?? well absorbed
• Peak plasma level ? 1-2 ?? ?? ??
• Oral midazolam ? FDA ?? ???? ????, ???
  premedication ? ?? ??
• Intranasal(0.2-0.3mg/kg), buccal(0.07mg/kg),
  sublingual(0.1mg/kg)
• Effective preoperative sedation
• IM injection of diazepam is painful and
  unreliable
• Midazolam, lorazepam ? well absorbed, peak level
  ? 30-90? ??
• Midazolam ? ??? ????? induction ? IV
  administration ??

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BENZODIAZEPINES
Pharmacokinetics

• Distribution
• Diazepam ? lipid soluble ? BBB ? ?? ??
• Midazolam ? low pH ?? water soluble
• But physiologic pH ? increase lipid solubility
• Lorazepam ? modest lipid solubility
• Slower brain uptake and onset of action
• Redistribution of benzodiazepines
• Rapid ( initial distribution half life is 3-5
  min)
• Responsible for awakening
• Midazolam ? ?? induction agent ? ???
• ??? thiopental ? rapid onset? short duration of
  action ? ?? ? ?? ??
• Benzodiazepines are highly protein bound (90-98)
  

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BENZODIAZEPINES
Pharmacokinetics

• Biotransformation
• Rely on liver ? water-soluble glucuronide end
  products
• Phase I metabolites of diazepam are
  phramacologically active
• Slow hepatic extraction and a large Vd result in
  a long elimination half-life for diazepam (30h)
• Lorazepam also has a low hepatic extraction
  ratiio
• Lower lipid solubility limits its Vd, shorter
  elimination half-life(15h)
• Clinical duration of lorazepam ? too long due to
  a high affinity
• Midazolam ? ?? diazepam ? Vd? ?? ??? high hepatic
  extraction ratio ? ???? half life ? ?? (2h)

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BENZODIAZEPINES
Pharmacokinetics

• Excretion
• Chiefly in the urine
• Enterohepatic circulation produce 2nd peak in
  diazepam plasma conc. (6-12h after
  administration)
• Renal failure ? prolonged sedation in Pt
  receiving midazolam
• Accumulation of a conjugated metabolite

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BENZODIAZEPINES
Effects on Organ Systems

• Cardiovascular
• Minimal cardiovascular depressant effect at
  induced doses
• ABP, cardiac output, pph. Vascular resistance
  decline slightly
• HR ? ??? ??
• Midazolam ? cardiovascular effect ? diazepam ??
  ??.
• Midazolam ???? HR change? decreased vagal tone ?
  ??
• Respiratory
• Depress ventilatory response to CO2
• Usually insignificant unless the drug are
  administered IV or in association with other
  respiratory depressants
• Barbiturate ? ?? apnea ? less common ???, small
  dose of diazepam midazolam ? IV???? respiratory
  arrest ? ????
• Steep dose-response curve, slightly prolonged
  onset and high potency of midazolam
• Careful titration to avoid overdosage apnea
• IV benzodiazepines ? ?? ?? ?? ??? ventilation
  monitoring ??? ??, ?? ?????? ??? ???? ?

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BENZODIAZEPINES
Effects on Organ Systems

• Cerebral
• Reduce cerebral oxygen consumption, cerebral
  blood flow, ICP
• Barbiturate ? ?? ??? ??
• Grand mal seizure ? ???
• Oral sedative dose ? often antegrade amnesia,
  useful premedication
• Mild muscle relaxant property of these drugs is
  mediated at the spinal cord level, not the NM
  junction
• Low dose ? antianxiety, amnesic, sedative effect
• Induction dose ? stupor and unconsciousness
• Thiopental ? ????, benzodiazepines ? ?? induction
• Slower loss of consciousness and longer recovery
• No direct analgesic properties

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BENZODIAZEPINES
Drug Interactions

• Cimetidine binds to CYT P-450, reduce metabolism
  of diazepam
• Erythromycin inhibits metabolism of midazolam
• Cause 2-3 fold prolongation and intensification
  of effects
• Heparin displaces diazepam from protein-binding
  site
• Increase drug conc. (200 increase after 1000
  units of heparin)
• Combination of opioids and diazepam
• Markedly reduces ABP, pph. Vascular resistance
• Pronounced in Pt with ischemic heart dz, or
  valvular heart dz
• Benzodiazepines reduce the MAC of volatile agents
  (30)
• Ethanol, barbiturates, other CNS depressants
  potentiate the sedative effects of the
  benzodiazepines

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BENZODIAZEPINES
Uses and Dosee of Commonly used Benzodiazepines
37
Opioids
Mechanisms of action

• Specific receptors located CNS other tissues
• Mu, kappa, delta, sigma

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Opioids
Mechanisms of action

• Provide some degree of sedation,
• Most effective at analgesia
• Binding ?? receptor? ??, affinity, receptor
  activation? ??? ?? pharmacodynamic property ? ??
• Agonist ?? receptor activation
• Agonist-antagonist (nalbuphine, nalophine,
  butorphanpl, pentazoxin) ?? ???? receptor ??
  opposite action? ??
• Naloxone ? pure opioid antagonist
• Opioid receptor ? ???? endogenous peptides
• Endorphins, enkephalins, dynorphins
• ??
• Opiate receptor activation? excitatory
  neurotransmitter (Ach, substance P) ??
  presynaptic release ? postsynaptic response ? ??
• Potassium, calcium ion conduction ? ??

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Opioids
Mechanisms of action

• ??
• Pain impulse? dorsal horn of the spinal cord
  level ??, intrathecal, epidural ?? opioid ??? ??
  ???
• ?? periaqueductal gray ?? nucleus raphae ? ????
  dorsal horn?? ???? ??? ?? descending inhibitory
  pathway ? modulation ? ??? ??? ?
• CNS ?? ???, somatic, sympathetic pph. Nerve ???
  opiate receptor ? ??

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Opioids
Structure-Activity Relationships

• Opiate-receptor interaction? ????? ??? group?
  compound ? ?? ???
• ??? common structural characteristics ? ??
• ??? molecular change ? ???? agonist ? antagonist
  ? ???? ??
• L-isomer ? d-isomer ?? more potent

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Opioids
Pharmacokinetics

• Absorption
• IM morphine, meperidine
• Rapid absorption, (20-60min)
• Fentanyl citrate , oral transmucosal
• Analgesia, sedation (10???)
• Children (15-20 micrograms/kg), adult (200-800
  micrograms)
• Fentanyl
• ?? ???, ?? lipid solubility
• Transdermal absorption ??
• Surface area? ??, local skin condition ?? ?? ??
• Upper dermis ? reservoir of drug
• ?? ??? ???? ?? ??? ???
• Serum conc ? 14-24h ? plateau ??,72?? ?? ??
• High incidence of nause, variable blood level

42
Opioids
Pharmacokinetics

• Distribution
• Half-life ? 5-20 ? ,?? ??
• Morphine ? ??, fat solubility ? ?? BBB ??? ??,
  onset of action? ??? ?? ?? ??
• Fentanyl ? sufentanil ? ?? ?? ???? ??, rapid
  onset ? short duratio
• Alfentanil ? fentanyl? ?? ?? ???? ???, nonionized
  fraction ? ??? onset ? duration ? ??.
• Lipid soluble opioid? liver ?? retained (1st-pass
  uptake),
• ??, ?? systemic circulation??
• Pul. Uptake ? ??????
• Smoking, ?????
• ???? ??
• ?? drug ? ?? accumulation ???
• Redistribution small dose of drug ?
  termination,??? ?? ?? drug ? biotransformation ?
  ?? termination

43
Opioids
Pharmacokinetics

• Biotransformation
• Primarily on the liver
• High hepatic extraction ratio, clearance ?
  hepatic blood flow ? ?? ??
• Alfentanil ? small Vd, ? short elimination
  half-life (1.5h)
• Morphine ? glucuronic conjugation
• Meperidine ? N-demethylated to normeperidine,
  active metabolite,
• Fentanyl, alfentanil, sufentanil
• Inactive metabolite
• Remifentanil
• Ultrashort-acting opioid with a terminal
  elimination half-life of less than 10min ?
  non-specific esterase in blood, tissue ? ??
  hydolysis
• Duration of remifentanyl infusion ? wake-up time
  ? ?? ??? ??? ??
• Context/sensitive half-time (infusion ?, ??? ??
  ??? 50? ????? ??? ??)
• ? 3?, infusion ? duration ? ???? ??

44
Opioids
Pharmacokinetics

• Biotransformation
• Remifentanil ? repeated bolus, prolonged
  infusion, ? ???? accumulation ?? ? ?? ??
• ?? opioid ?? ?? ??
• Extra hepatic metabolism
• Metabolic toxicity ? ?? ??,hepatic dysfunction
  ??? ???? ????
• Pseudocholinesterase deficiency ? ???? normal
  response

45
Opioids
Pharmacokinetics

• Excretion
• End product of morphine and meperidine
  ?eliminated by kidney
• 10 ??? biliary excretion
• 5-10 ? morphine ? unchanged ??? kidney ? ??
• Renal failure ? ??? duration ??
• Accumulation of morphine metabolite in renal
  failure
• Narcosis, ventilatory depression
• ??? metabolite ? more potent opioid receptor
  agonist
• Normeperidine ( metabolite of meperidine)
• CNS excitatory effects
• Myoclonic activity, seizure ??
• Not reversed by naloxone
• Fentanyl
• IV 4??? late 2nd peak in plasma level
• Enterohepatic recirculation, mobilization of drug
• Sufentanil ? metabolite ? urine ? bile ? ??
• Remifentanil ? metabolite ? effect ? ?? ??
• Severe liver disease pt ? ???? pharmacodynamics ?
  pharmakokinetics ? ?? ??? ??

46
Opioids
Effects on Organ systems

• Cardiovascular
• ?? opioids ? ??? ???? ?? ??? ??
• Meperidine ? HR ?? (atrophine ? ??? ??), high
  dose of morphine, fentanyl, sufentanil,
  remifentanil , alfentanil ? vagus mediated
  bradycardia ??
• Meperidine ? ?? ??, ?? opioid ? cardiac
  contractility ? depression ??? ??
• ???, ABP ? bradycardia, venodilation, decrease
  sympathetic reflex ? ?? ????
• Meperidine, morphine ? ?? ??? ??, histamine
  release ??
• Systemic vascular resistance ?, ABP ? ??? ??
• Slow infusion, ??? intravascular volume ??, H1,
  H2 histamine antagonist ? pretreatment ? ??
• Intraoperative HTN during opioid anesthesia
• ?? morphine, meperidine? ?? ??? ?? ??
• ?? ?? ??? ??? ???? vasodilater ? ?? ???? ??? ????
• Opioid ? ?? ???? (nitrous oxide, benzodiazepines,
  barbiturates, volatile agents) ? ?? ??? ???
  myocardial depression? ?? ? ? ??

47
Opioids
Effects on Organ systems

• Respiratory
• Depress ventilation, particularly respiratory
  rate
• Resting PaCO2 ? ??, PaCO2 ??? ?? response ? ??
• CO2 response curve ? downward and to the right
• Brainstem ? respiratory center ? ??
• Apneic threshold ? ??, hypoxic drive ? ??
• ??? ??? more depressed
• Morphine, meperidine
• Histamine-induced bronchospasm
• Opioids, particularly fentanyl, shfentanil,
  alfentanil
• Chest wall rigidity ?? ? ventilation ? ??
• ?? large bolus dose ? ?? ??
• ????? ????? ????
• Opioids ? ????? bronchoconstrictive response ? ??
  (intubation ?)

48
Opioids
Effects on Organ systems

• Cerebral
• Cerebral perfusion ? ICP ? ?? ??? variable
• Cerebral oxygen consumption, cerebral blood flow,
  ICP ? ??
• Barbiturate ? benzodiazepines ? ?? ??? ??
• Artificail ventilation ??? normocarbia ??
• Opioids bolus ? Brain tumor ? head trauma ? ?????
  ??? cerebral blood flow velocity ? ICP ? ??? ??
  ??? ?
• Opioids ? mild ? MAP ??
• CPP ? ?? ? abnormal intracranial elastance ? ???
  ????? ??? ???? ?? ? ? ??
• Opioid ? mild ? ICP ?? ??
• ??? ???? ??? intubation ??? ?? ICP ??? ???? ??
• Stimulation of the medullary chemoreceotor
  trigger zone
• High incidence of nausea and vomiting
• Physical dependence
• ???? ?? ? incidence ??

49
Opioids
Effects on Organ systems

• Cerebral
• Do not produce amnesia
• Barbiturate ? benzodiazeoines ? ??, pt ?
  unconscious ?? ??? ???? ??? large dose ? opioid?
  ??
• IV meperidine (25 mg) ? shivering? ?????? ?? most
  effective ? opioid
• Gatrointestinal
• Reducing peristalsis
• Slow gastric emptying time
• Biliary colic
• Opioid-induced contraction of Sphincter of Oddi
• Biliary spasm ? naloxone ? ?? reversed
• Long term opioid therapy ??? ??
• Constipation ? ??? ???? side effect ? tolerance

50
Opioids
Effects on Organ systems
51
Opioids
Effects on Organ systems

• Endocrine
• Stress response to surgical stimulation
• Secretion of cathecholamine, ADH, cortisol
• Opioids ? ????? ?? ??? ??? ?? ??? ???? ??? ??
• ?? more potent opioids? fentanyl, alfentanil,
  sufentanil, remifentanil ?? ??? ??? ?????.
• Ischemic heart dz ???? ??? stress response ? ??
  ??? benifitial

52
Opioids
Drug Interactions

• Combination of opioids (particulary meperidine)
  and MAO inhibitor
• Respiratory arrest, Hypertension, hypotension,
  coma, hyperpyrexia ? ?? ??
• Barbiturate, benzodiazepines, other CNS
  depressants
• Synergistic cardiovascular , respiratory,
  sedative effect with opioid
• Alfentanil ? ?? erythromycin ?? ? prolonged
  sedation, respiratory depression effect

53
KETAMINE
Mechanisms of action

• Multiple effects on CNS
• Spinal cord ? blocking polysynaptic reflex
• Brain ? inhibiting excitatoryneurotransmitter
• Barbiturate ? depression of the reticular
  activationg system
• Ketamine ? functionally dissociate the thalamus
  from the limbic cortex
• Some brain neurons inhibited but others are
  tonically excited
• This state of dissiciative anesthesia cause the
  patient to appear conscious (eye eye opening,
  swallowing, muscle contracture) , but unable to
  process or respond to sensory input

54
KETAMINE
Structure-Activity Relationships

• Analogue of phencyclidine
• One-tenth s potent, retain many of
  phencyclidines psychotomimetic effects
• Subtherapeutic dose
• Can cause hallucinogenic effects

55
KETAMINE
Pharmacokinetics

• Absorption
• IV or IM
• Peak plasma level ? 10-15min after IM injection
• Distribution
• Thiopental ? ?? more lipid soluble, less protein
  bound
• Increase in cerebral blood flow, cardiac output
• Rapid brain uptake, subsequent redistributin
  (distribution half life 10-15 min)
• Awakening is due to redistribution to pph
  compartment

56
KETAMINE
Effects on Organ Systems

• Cardiovascular
• Increase ABP, HR, Cardiac output
• Central stimulation of the sympathetic nervous
  system, inhibition of the reuptake of
  norepinephrine
• Increase in pulmonary artery pressure, myocardial
  work
• Avoided in coronary artery dz, uncontrolled HTN,
  CHF, arterial aneurysm
• Direct myocardial depressant effect of large
  doses of ketamine
• Inhibition of calcium transients (unmasked by
  sympathetic blockade)
• Exhaustion of catechlolamine store (eg. Severe
  end-stage shock)
• Indirect stimulatory effecs
• Often benificial to Pt with acute hypovolemic
  shock

57
KETAMINE
Effects on Organ Systems

• Respiratory
• Ventilatory drive is minimally affected
  (customary induction dose)
• Rapid IV bolus, pretreatment with opioids
  occasionally produce apnea
• Ketamine is a potent bronchodilator
• Good induction agent for asthmatic Pt
• Upper airway reflex remain largely intact
• ??? aspiration Pn. Risk ? ?? ??? ?? ???
  intubation
• Ketamine ? ?? salivation ??
• Premedication with an anticholinergic agent

58
KETAMINE
Effects on Organ Systems

• Cerebral
• Increase cerebral oxygen consumption, cerebral
  blood flow, ICP
• Space-occupying intracranial lesions ? ??? ??
• Myoclonic activity ? increased subcortical
  electrical activity
• Undesirable psychotomimetic side effects
• Illusions, disturbing dreams, delirium during
  emergence and recovery
• Less common in chlidren and in Pt with
  benzodiazepines premedication
• Of the nonvolatile agents, ketamine may be the
  closet to being a complete anesthetic as it
  induce analgesia, amnesia, and unconsciousness

59
KETAMINE
Effects on Organ Systems
60
KETAMINE
Drug Interactions

• Nondepolarizing neuromuscular blocking agnets are
  potenciated by ketamine
• Theophylline ? ketamine ? ?? ??? seizure ? ????
  ??
• Diazepam ? ketamine? cardiostimulatory effects ?
  ?? ??? elimination half life ? ??
• Propranolol, phenoxybenzamine, ?? ?? sympathetic
  antagonist ? ketamine? direct myocardial
  depressant effect ? unmasking
• Halothane ? ?? ??? ???? ketamine ??? ??
  myocardial depression ? ??

61
ETOMIDATE
Mechanisms of Action

• Depress the reticular activating system and
  mimics the inhibitory effects of GABA
• Bind to a subunits of the GABA type A receptor
• Barbiturate ?? ?? extrapyramidal motor activity ?
  inhibitory effect ? ??
• ? disinhibition ? 30-60 ? myoclonus incidence ?
  ??

62
ETOMIDATE
Structure-Activity Relationships

• Carboxylated imidazole ? ????? ?? anesthetic
  agents ? ??? ?? ??? ??
• Imidazole ring
• Water solubility in acidic solution, lipid
  solubility at physiologic pH
• Ethmidate ? propylene glycol ? ??? ??
• Cause pain on injectin
• Reduced by a prior injection of lidocaine

63
ETOMIDATE
Pharmacokinetics

• Absorption
• Only for intravenous administration
• Used primarily for induction of general
  anesthesia
• Distribution
• Highly protein bound, ??? ?? lipid soulubility,
  large nonionized fraction(at physiologic pH) ???
  ?? ?? onset ? ??
• Redistribution
• Awakening level ?? plasma concentration ? ??
• Biotransformation
• Hepatic microsomal enzymes and plasma esterases
• Rapidly hydrolyze etomidate to an inactice
  metabolite
• Biotransformation rate ? barbiturate ? ? 5?
• Excretion
• ?? kidney ?? metabolite ? ??

64
ETOMIDATE
Effects on Organ Systems

• Cardiovascular
• Minimal effects on the cardiovascular system
• Mild reduction in pph. vascular resistance
• Slight decline in ABP
• Myocardial contractility, cardiac output
• Usually unchanged
• Dose not release histamine
• Respiratory
• Affected less with ethmidate than with
  barbiturates or benzodiazepines
• Induction dose ?? ?? apnea ? ?? ?? ??
• Opioids ? ?? ??? apnea ?? ??

65
ETOMIDATE
Effects on Organ Systems

• Cerebral
• Decrease cerebral metabolic rate, cerebral blood
  flow, ICP
• Same extent as thiopental
• Cardiovascular effects ? ?? ??? CPP? intact
• Postoperative nausea, vomiting
• More common than barbiturate induction
• Can be minimized by antiemetic medication
• Sedative-hypnotic but lacks analgesic properties
• Endocrine
• Transiently inhibit enzymes involved in cortisol
  and aldosterone synthesis
• Long-term infusions lead to adrenocortical
  supression
• Critically ill Pt ?? mortality rate ??

66
ETOMIDATE
Drug Interaction

• Frentanyl increase the plasma level and prolong
  the elimination half-life of etomidate
• Opioid decrease the myoclonus characteristic of
  an etomidate induction

67
PROPOFOL
Mechanisms of Action

• Involce facilitation of inhibitory
  neurotransmission mediated by GABA

68
PROPOFOL
Structure-Activity relationships

• Phenol ring with two isopropyl groups attached
• Altering the side-chain length of this
  alkylphenol influence potency, induction,
  recovery characteristics
• Not water soluble, 1 aqueous solution (10mg/mm)
• Soybean oil, glycerol, egg lecithin ? ??? oil-in
  water emulsion ??? IV ? ????
• History of egg allergy
• Non CIx of propofol ???? egg allergy ? ?? egg
  white ? ???? albunin? ??
• Egg lecithin ? egg york ?? ??
• ??? pain ??
• Elderly ? ?? pain ? ??
• Prior lidocaine injection, mixing with lidocaine
  (2ml of 1 lidocaine 18ml propofol)

69
PROPOFOL
Structure-Activity Relationship

• Support the growth of bacteria
• So good sterile technique is needed
• Cleaning the rubber stopper or ample neck with an
  alcohol swab
• Ample ??? 6?? ?? ??? ??? ?? ?
• 0.025 sodium metabisulfite ? ????
• ???? ??? ??

70
PROPOFOL
Pharmacokinetics

• Absorption
• Only for IV administration for induction of GA
  and for moderate to deep sedation
• Distribution
• High lipid-solubility
• Onset of action almost as rapid as that of
  thiopental
• Awakening from single bolus dose rapid
• Very short initial distribution half-life(2-8
  min)
• Good agent for outpatient anesthesia
• Thiopental, etomidate ?? ?? recovery ? ??? ?????
  ??
• Lower induction dose is recommended in elderly
  patient
• Elderly pt ? ?? Vd ? ?? ??
• Women may require a higher dose of propofol

71
PROPOFOL
Pharmacokinetics

• Biotransformation
• Clearance of propofol ? hepatic blood flow ? ???
• Implying the existence of extrahepatic metabolism
• High clearance rate (thiopental ? 10? )
• Relatively rapid recovery after a continuous
  infusion
• Liver conjugation ? inactive metabolite ? kidney
  ?? elimination
• Do not affected by moderate cirrhosis
• Long term sedation of critically ill children,
  neurosurgical pt, (young adult)
• long-term propofol infusion ? lipemia, metabolic
  acidosis, death ??
• Excretion
• Primarily excreted in the urine, but CRF ? ?? ??
  ??

72
PROPOFOL
Effects On Organ System

• Cardiovascular
• Decrease in ABP systemic vascular resistance ??
  (inhibition of sympathetic vasoconstrictor
  activity), cardiac contractility, preload ??
• Thiopental ? ?? hypotension ? ????
• ??? laryngoscopy, intubation ??? ?? ?? reversed
• Hypotension ? ?? ?? factor
• Large dose, rapid injection, old age
• Markdly impair the normal arterial baroreflex
  response to hypotension- ?? normocarbia ?
  hypocarbia ?
• Marked drop in preload ? vagally mediated
  bradycardia
• ??? HR, cardiac output ? ??? health pt ? ?? ???
  ??? ??, ? ???? ???, ??? ???? (?? ????, negative
  chronotrophics ???, oculocardiac reflex ? ???
  surgical procedure ?) asystole ?? ?? ? ???? ??
• Impaired ventricular function ? ventricular
  filling pr., contractility ?? ??? ???? cardiac
  output ??

73
PROPOFOL
Effects On Organ System

• Respiratory
• Barbiturate ? ????? profound respiratory
  depression
• cause apnea following induction dose
• Conscious sedation ? ??subanesthetic dose ??
  hypoxic ventilatory drive ? ???? hypercarbia ? ??
  normal response? ??
• ??? ??? technique ? trained doctor ? ???? ????? ?
• Upper airway reflex depression
• Thiopental ? ?? ?? ?? ?? ? helpful during
  intubation, or laryngeal mask placement
• Can cause histamine release
• ??? barbiturate? etomidate ? ?? asthma ???, ???
  ???? ?? wheezing ? incidence ? ??
• Asthma ??? ??? propofol? ??? ???.

74
PROPOFOL
Effects On Organ System

• Cerebral
• Cerebral blood flow, ICP ??
• ICP ?? ? ??? ??, ?? MAP ? ???? ?? ?? ?? ??
  propofol ? CPP ? ???? ?? ?? ? ??
• Propofol ? thiopental ? ??? ??? focal ischemia ?
  ?? protection ??
• Antipruritic, antiemetic effect
• Outpatient anesthesia ? ???? ??
• Induction ? muscle twitching, spontaneous
  movement, opisthotonus, hiccupping ?? excitatory
  phenomena ? ??
• Subcortical gylcine antagonism
• But ??? ??? , tonic-clonic seizure ? ?????
  propofol ? anticonvulsant effect ? ??, status
  epilepticus ? ???
• Intraocular pr ? ????
• Long-term infusion ??? tolerance ???? ??

75
PROPOFOL
Drug Interactions

• Nodipolarizing neuromuscular blocking agent ? ??,
  ??? propofol fomula (Cremophor ??) ? ??,
  propofol? effect? potentiate (??? ??? fomula ? ??
  ??? ??? ??)
• Fentanyl, alfentanil ? ??? propofol ? ???? ??? ??
• ?? ???? ?? Propofol induction ?, midazolam ?
  pretreatment (30 micrograms / kg)? synergistic
  effect ? ?? ??? ??
• ???, ??? coinduction technique? questionable
  efficacy

76
DROPERIDOL
Mechanisms of Action

• Antagonism of dopamine receptors
• CNS system ?? caudate nucleus, medullary
  chemoreceptor zone?? ????
• Serotonin, norepinephrine, GABA ?? ??
  transmission ? ??
• Tranquilizer, antiemetic properties
• Pph alpha-adrenergic blockade

77
DROPERIDOL
Structure-Activity Relationships

• Droperidol,(butyrophenone ) ? ????? haloperidol ?
  ??
• ? ??? drug ? ???? ??
• Haloperidol neuroleptic
• Droperidol antipsychotic

78
DROPERIDOL
Pharmacokinetics

• Absorption
• Premedication ? IM inj. ?? ??? ??? ??? IV ? ??
• Distribution
• Repid distribution phase (? 10?) ? ????, sedative
  effect ? ?? molecular weight, extensice protein
  binding ?? ?? delayed
• Duration of action ? 3-24h ??? ??
• Biotransformation
• Extensively metabolized in the liver
• Hepatic clearance ? ketamine, etomidate ?? ????
  ?? ??
• Excretion
• Biotransformation ? end product? urine ?? ??

79
DROPERIDOL
Effects On Organ System

• Cardiovascular
• Mild alpha agonist blocking effecs
• Decrease ABP, pph vasodilation
• Hypovolemic pt ? ??, ??? ABP decline effect ? ??
  ????
• ??? alpha agonist blocking effect ?
  antiarrhythmatic effect ? ???? ???, ?? QT
  interval prolongation, torsades de pointes ?? ???
  ??
• Droperidol ?? ?? ?? 12 lead ECG ? ?? ??? ?
• ?? QT interval ? 440 ms (men), 450 ms (women)
  ???? droperidol ? ??? ?? ??? ?
• QT interval ? ???? droperidol ? ??? ?? ??, ECG
  monitoring (2-3h) ??? ?
• Pheochromocytoma Pt
• Droperidol ? ??? adrenal medulla ?? catecholamine
  release ? induce ?? severe HTN ??
• ??? droporidol ? ??? ??

80
DROPERIDOL
Effects On Organ System

• Respiratory
• Droperidol ? ??? resiration ? ??? depression ? ??
  ?? ??
• Cerebral
• Decrease cerebral blood flow, ICP ? by inducing
  cerebral vasoconstriction
• Barbiturate, benzodiazepines, etomidate ?? ??
  cerebral oxygen consumption ??? ??
• Droperidol is potent antiemetic
• Delayed awakening
• Antidopaminergic activity of droperidol rarely
  precipitates extrapytamidal reactions (eg,
  oculogyric crises, torticollis, agitation)
• Pakinson dz, restless leg syndrome,
  neurologically mediated movement disorder pt ? ??
  droperidol ??? ??? ?
• Premedication ? apprehensive, fearful
• ???? premedication ? ??? ?
• Opioid ? ?? ??? dysphoria ? incidence ? ??

81
DROPERIDOL
Effects On Organ System

• Cerebral
• droperidol is a tranqulilizer
• Does not produce analgesia, amnesia, or
  unconscious at usual dose
• Combination of fentanyl and droperidol
• Analgesia, immobility, variable amnesia
  (neuroleptanalgesia)
• Nitrous oxide ? hypnotic agent ? ?? ??? ketamine
  ? ??? disscociative state ? ???? unconsciousness
  ? GA ??

82
DROPERIDOL
Drug Interactions

• Antagonize the effects of levodopa, precipitate
  parkinsonian symptoms
• Dopamine ? renal effect ??
• Clonidine ? alpha adrenergic action? antagonize
• Ketamine ? cardiovascular effects ? ??