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08. NONVOLATILE ANESTHETIC AGENT

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Title: 08. NONVOLATILE ANESTHETIC AGENT


1
08. NONVOLATILE ANESTHETIC AGENT
2009.04.06 R1 ???
2
  • 1. PHARMACOLOGICAL PRINCIPLES Phmacokinetic
    Phamacodynamic 2. SPECIFIC NONVOLATILE
    ANESTHETIC AGENTS Babituates Benzodiazepins
    Opioids ketamine Etomidate Propofol
    Droperidol

3
PHARMACOLOGICAL PRINCIPLES PHARMACOKINETICS
  • Four parameters absorption, distribution,
  • biotransformation, excretion
  • Elimination biotransformation excretion
  • Clearance elimination ? rate

4
1. Absorption
  • Oral, sublingual, rectal, inhalation, transdermal
  • subcutaneous, IM, IV
  • Administration site ? Blood stream
  • characteristic of drug site of absorption
  • Bioavailability
  • unchanged drug? systemic circulation ? ???? ?

5
  • Oral administration
  • Unreliable Pts ?? ? first- pass hepatic
  • metabolism, gastric pH, enzymes,
  • motility, food, other drug ?? ??
    ??
  • Transdermal administration
  • with minimal total dose?? prolonged and
  • continuous absorption

6
  • Subligual, rectal, buccal administration
  • 1st pass hepatic metabolism ? bypass
  • Parenteral injection
  • Subcutaneous, IM, difffusion
  • IV completely bypass the process of absorption

7
2. Distribution
  • Major determinant of end-organ drug concentration
  • Clinical pharmacology ? Key role
  • Highly perfused organs large amount of drug

8
  • Plasma protein bounded drug uptake??
  • Albumin bind acidic drug
  • AAG bind basic drug
  • Plasma protein ? ?? , binding site? ?? ??? ??
  • ???? ??? tissue? uptake ?? free drug ? ??
  • Renal dis., liver dis., CHF, malig. alb.
    production ??
  • Trauma, infection, MI, chr. pain AAG ??
  • Redistribution
  • termination of effect of many anesthetic drugs

9
  • Vd. (volume of distribution)
  • Dose / Plasma concentration
  • A small Vd.
  • ??? intravascular space? ???? ??
  • High protein bounding, ionization
  • A large Vd.
  • total body water ? ??? ?? ?? ??
  • High solubility or binding of the drug in tissue
  • other than plasma

10
3. Biotransformation
  • Liver ? primary organ
  • ??? end product? water soluble, inactive
  • Kidney?? excretion? ??? ???
  • Phase I
  • Parent drug ? oxidation, reduction, hydrolysis
  • -gt more polaric

11
  • Phase II
  • Metabolic process
  • Parent drug? phase I ? metabolite? glucuronic
  • acid ?? conjugation ?? highly polar end product
  • ?? -gt urine?? ??
  • Hepatic clearance (ml/min)
  • Liver biotransformation??? ?? ???? drug? rate
  • Hepatic blood flow, hepatic excraction ratio ? ??

12
4. Excretion
  • The kidney principle organ
  • Non-protein bound drugs? ???? plasma ??
  • glomerular filtrate? cross
  • Non-ionized fraction? the renal tube?? ???
  • Ionized portion is excreted in urine urine pH ?
    ??
  • Renal clearance
  • kidney excretion? ?? drug? ???? rate
  • Renal failure ? drug? pharmacokinetics??
  • by altering protein binding, Vd, clearance
    rates

13
  • Biliary excretion
  • ?? intestine ?? ??? ??? urine?? ??.
  • Delayed toxic effect
  • The lungs
  • volatile agents ?? ??

14
5. Compartment Models
  • ???? drug distribution ? elimination ? ??
  • Plasma vessel rich group central compartment
  • Muscle, fat, skin, etc. pph. compartment
  • Compartment ? conceptual, actual tissue? ??
  • Two compartment model
  • Drugs? distribution ? elimination phase ? ? ???
  • Alpha phase (distribution phase)
  • Initial rapid decline in plasma conc.
    (redistribution)
  • Plasma, vessel rich group of the CNS
  • ? less perfused pph. tissue

15
  • Beta phase (elimination phase)
  • Less steep decline in plasma conc.
  • Elimination half-life of drug
  • Vd ? ??, rate of clearance ? ???

16
  • 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

17
  • Rates of distribution biotransformation
  • First-order kinetics
  • ?? ??? ?? ???? ?? ??? ?? distributed or
  • metabolized
  • Zero-order kinetics
  • Drug ? ??? biotransformation capacity ?
  • ???? ?? ?? drug ? ????? ?? ?? ??

18
PHARMACODYNAMICS
  • Drug? therapeutic and toxic organ system
  • effect
  • Drug? efficacy, potency, therapeutic ratio ? ??

19
1. Dose-Response curves
  • drug dose and pharmacological effect ? ??

X-axis steady-states plasma conc.
Linear(A)? ??? logarithmic(B)? ?? Y-axis
pharmacological effect Curve position drug
potency Maximal effect of drug efficacy Slope
of curve receptor binding character ED(50)
median effective dose LD(50) median lethal
dose Therapeutic index Ratio of LD 50 ED 50
20
2. Drug Receptor
  • Macromollecules
  • Protein embedded into cell membrane
  • Agonist R.? ???? cell function ? ??? ?? ?
  • Antagonist R.? ?????, cell ? ?? ?? ??
  • ?????? agonist substance ? effect ? ??
  • Competitive antagonist R.? ??? ???? agonist?
  • higher conc. ? ??
    ????
  • Non-competitive antagonist R.? high affinity??
    ??
  • ?? ??? agonist?? R. blockade? reverse
    ?? ??
  • ?? cell function ? ??? ?? ??? ???, 2nd messenger
  • c-AMP ?? regulatory molecule? ?? ?? ??? ??

21
2. SPECIFIC NONVOLATILE ANESTHETIC AGENTS
22
BARBITURATES
1. Mechanism of action
  • Depress reticular activating system
  • Brain stem? ??, neurons and regulatory centers?
  • complex polysynaptic network
  • Consciousness ? ??? ? ?? vital function? ??
  • Axon ??? nerve synapse? ??? ??
  • Excitatory neurotransmitters(Ach)? transmission?
    ?
  • Inhibitory neurotransmitters(GABA)? transmission?
    ?

23
2. Structure-Activity Relationship
24
3. Pharmacokinetics
  • Absorption
  • IV route ? ?? ?? ??? induction ? ???,
  • IV line? ?? ???? ?? ?? ??
  • Rectal thiopental, methohexital ??? ??
  • IM pentobarbital, secobarbital premed.
  • Distribution
  • Highly lipid-soluble barbiturates
  • (thiopental, thiamylal, methohexital)
  • Duration of action ? redistribution ? ?? ??

25
  • Thiopental highly protein bound,
  • but great lipid solubility, highly
    nonionized
  • ? maximal brain uptake ? 30? ??
  • ?? central compartment ?
  • contracted (hypovolemia)
  • low serum albumin level (LC)
  • nonionized fraction ?? (acidosis)
  • -gt brain? heart ? ?? ??? thiopental ? ??
  • pph. compartment(?? muscle)? 20-30? ??? peak
    level ? 10? ??? redistribution
  • -gt ????? ??? 30? ??? ??? ??
  • 20? ??? awake

26
  • Induction dose Bwt.? age? ??
  • Elimination half-life 3-12 h
  • Repetitive administration
  • -gt saturate pph. compartment
  • -gt redistribution cannot occur

27
  • Biotransformation
  • Hepatic oxydation
  • -gt Inactive water soluble metabolites ??
  • Methohexital? ??, thiopental? ?? 3-4? hepatic
  • clearance? ??
  • Single dose awake? ?? redistribution? ?? ?????
  • methohexital? psychomotor function? full
    recover?
  • metabolism ? ?? ?? ??

28
  • Excretion
  • Highly protein bound -gt glomerular filtration
    ???
  • Highly lipid solubility -gt renal tubular
    reabsorption ??
  • Renal excretion
  • water-soluble hepatic metabolites ??? ????
  • Methohexital ? ?? feces ? excretion

29
4. Effects on Organ Systems
  • Cardiovascular
  • Induction dose of barbiturates
  • Fall in BP, elevation HR
  • medullary vasomotor center ??
  • pph. capacitance vessel vasodilation
  • pph. pooling of blood RA ?? venous return ??
  • Tachycardia central vagolytic effect
  • Sympathetic activity ? ?? resistance vessel ?
  • constriction increase pph. vascular resistance

30
  • hypovolemia, CHF, BB
  • 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 dis.??? ???
  • Slow rate of injection, preoperative hydration??
  • ?? ?? ? ??

31
  • 2) Respiratory
  • medullary ventilatory center??
  • Decrease the ventilatory response to
  • hypercapnia hypoxia
  • Barbiturate sedation
  • Upper airway obx. ? induction dose? apnea??
  • Awakening tidal volume, RR decreased
  • Do not completely depress noxious airway reflex
  • Bronchospasm asthma Pt. (cholinergic n. ??)
  • Atropine premedication ?? ?? ??
  • Laryngospasm lightly anesthetize Pt.
  • Methohexital ??? Laryngospasm hiccuping ??

32
  • Cerebral
  • Small dose of thiopental (50-100mg, iv)
  • ???? grand mal seizure ? ??
  • Renal
  • BP ??? ??? renal blood flow and GFR ?? ?
  • Formation of porphyrin ? ??
  • Porphyria ??

33
  • Hepatic
  • Hepatic blood flow is decreased
  • Chr. exposure ? drug biotransformation? opposing
  • effect
  • Induction of hepatic enzyme
  • Increase rate of metabolism of some drug
  • Combination with the CYT P-450 enzyme system
  • Interfere with the biotransformation of other
  • drug (eg, TCA)

34
Drug Interaction
  • Contrast media, sulfonamides, etc
  • thiopental ? same protein-binding site
  • free drug, systemic effect ??
  • Ethanol, opioid, antihistamine, other CNS
    depressant
  • potentiate the sedative effects of barbiturate

35
BENZODIAZEPINES
1. Mechanism of Action
  • Interact with specific receptors in CNS
  • Inhibitory effect of various neurotransmitters
  • Facilitate GABA-receptor binding
  • increase membrane conductance of chloride ions
  • membrane polarization change
  • inhibits normal neuronal function
  • Flumazenil
  • Specific benzodiazepine-receptor antagonist
  • Effectively reverse most of the CNS effects

36
2. Structure-Activity Relationships
  • benzene rings and a seven-member diazepine rings

37
3. Pharmacokinetics
  • Absorption
  • Sedation ? ?? ?? induction ? ?? PO, IM, IV ??? ??
  • Diazepam lorazepam GI tract?? well absorbed
  • peak plasma level? 1-2 ?? ?? ??
  • Oral midazolam? ??? premedication ? ?? ??
  • IM injection of diazepam is painful and
    unreliable
  • IM midazolam, lorazepam? peak level? 30-90? ??
  • Midazolam? ??? ????? induction? IV administration

38
  • Distribution
  • Diazepam? lipid soluble ? BBB ? ?? ??
  • Midazolam low pH ?? water soluble
  • 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? ?? ?
  • Benzodiazepines are highly protein bound (90-98)

39
  • Biotransformation
  • ??? water-soluble glucuronide end products? ??
  • Phase I metabolites are phramacologically active
  • Diazepam slow hepatic extraction, large Vd
  • long elimination half-life(30h)
  • Lorazepam low hepatic extraction ratio
  • Lower lipid solubility limits its Vd
  • -gt shorter elimination half-life(15h)
  • Clinical duration prolong due to a high affinity
  • Midazolam diazepam ? Vd? ?? ??? high hepatic
  • extraction ratio? ???? half-life ? ?? (2h)

40
  • Excretion
  • Chiefly in the URINE
  • Enterohepatic circulation produce 2nd peak
  • in diazepam plasma conc.
  • Renal failure? prolonged sedation
  • due to accumulation of a conjugated metabolite

41
Effects on Organ Systems
  • Cardiovascular
  • Minimal cardiovascular dep. effect at induced
    doses
  • ABP, cardiac output, pph. V. resistance decline
    slightly
  • HR? ??? ??
  • Midazolam? cardiovascular effect? diazepam?? ??.
  • Midazolam?? ?? HR change? decreased vagal tone

42
  • Respiratory
  • Depress ventilatory response to CO2
  • IV? ???? ??? ?? respiratory depressants
  • ??? ?? ??
  • Barbiturate ? ?? apnea? less common
  • small dose of diazepam midazolam? IV????
  • respiratory arrest ? ????
  • careful titration to avoid overdosage apnea

43
  • Cerebral
  • Reduce oxygen consumption, blood flow, ICP
  • Grand mal seizure? ???
  • Oral sedative dose
  • ? antegrade amnesia, useful premedication
  • Mild muscle relaxant property is mediated
  • at the spinal cord level, not the NM junction
  • Low dose antianxiety, amnesic, sedative effect
  • Induction dose stupor and unconsciousness
  • Benzodiazepines? ?? induction
  • slower loss of consciousness and longer
    recovery
  • No direct analgesic properties

44
Drug Interactions
  • Cimetidine binds to CYT P-450
  • -gt reduce metabolism of diazepam
  • Erythromycin inhibits metabolism of midazolam
  • -gt 2-3 fold prolongation and intensification of
    effects
  • Heparin? diazepam ? protein-binding site?? ????
  • -gt increase drug conc.
  • Combination of opioids and diazepam
  • -gt markedly reduces ABP pph. vascular
    resistance

45
  • Benzodiazepines reduce the MAC of volatile agents
  • Ethanol, barbiturates, other CNS depressants
  • -gt potentiate the sedative effects

46
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47
Opioids
1. Mechanisms of action
  • Specific receptors located CNS other tissues
  • mu, kappa, delta, sigma
  • Binding ?? receptor? ??, affinity, receptor
    activation
  • ??? ?? pharmacodynamic property? ??
  • Agonist?? receptor activation
  • Agonist-antagonist (nalbuphine, nalophine,
    butorphanol,
  • pentazoxin) ?? ?? ?? receptor?? opposite action?
    ??
  • Opioid receptor ? ???? endogenous peptides
  • Endorphins, enkephalins, dynorphins

48

49
  • Opiate receptor activation? excitatory
    neurotransmitter
  • (Ach, substance P) ?? presynaptic release ?
  • postsynaptic response ? ??
  • Potassium, calcium ion conduction ? ???? ??
  • Pain impulse? dorsal horn of the spinal cord
    level ??
  • intrathecal, epidural ?? opioid ??? ?? ???
  • CNS ?? ??? somatic, sympathetic pph. nerve??
  • opiate receptor? ??

50
2. Structure-Activity Relationships
  • Opiate-receptor
  • interaction? ?????
  • ??? group?
  • compound ? ?? ???

51
3. 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)
  • ?? ???, ?? lipid solubility transdermal ?? ??
  • Surface area? ??, local skin condition ?? ?? ??
  • Upper dermis? reservoir of drug?? ??? ?? ???
  • ???? ?? ??? ? ??
  • Serum conc. ? 14-24h ? plateau ??, 72?? ?? ??
  • High incidence of nausea, variable blood level

52
  • Distribution
  • Half-life 5-20 ? ,?? ??
  • Morphine fat solubility ? ?? BBB ??? ??
  • onset? ??? ?? ?? ??
  • Fentanyl sufentanil ?? ?? ???
  • -gt rapid onset ? short duratio??
  • Alfentanil ? fentanyl? ?? ?? ???? ???
  • nonionized fraction ? ??? onset? duration? ??
  • Lipid soluble opioid? lung?? retained (first-pass
  • uptake)?? ??, ?? systemic circulation??
  • Pul. Uptake? ?? Smoking, ?????
  • ?? ?? drug? ?? accumulation

53
?? ?? drug dose? redistribution? ?? termination
?? ?? ?? drug? biotransformation? ?? plasma level
???
54
  • 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 ?? normeperidine?
  • Fentanyl, alfentanil, sufentanil
  • inactive metabolite? biotransformation

55
  • Remifentanil
  • Ultrashort-acting opioid ? terminal elimination
  • half-life ? 10min??
  • blood, tissue? non-specific esterase ?? hydolysis
  • remifentanyl infusion? duration ? wake-up time?
  • ?? ??? ??? ??
  • Context/sensitive half-time (infusion ?, ??? ??
  • ??? 50? ????? ??? ??)
  • ? 3? (infusion ? duration ? ?? ?? ??)

56
  • Remifentanil ? repeated
  • bolus, prolonged infusion,
  • ? ???? accumulation
  • ??? ?? ??
  • ?? opioid ?? ?? ??
  • Extra hepatic metabolism
  • Metabolic toxicity? ??
  • ??, hepatic dysfunction
  • ??? ???? ????
  • Pseudocholinesterase
  • deficiency? ????
  • normal response


57
  • 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 R. agonist

58
  • 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? ??
  • Sufentanil ? metabolite? urine? bile? ??
  • Remifentanil ? metabolite? effect? ?? ??
  • Severe liver disease pt.? ????
  • pharmacodynamics? pharmakokinetics? ??
  • ??? ??

59
  • 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? ?? ?? ??

60
  • Meperidine, morphine? ?? ??? ??, histamine
  • release ??
  • Systemic vascular resistance ?, ABP? ??? ??
  • Slow infusion, ??? intravascular volume ??
  • H1, H2 histamine antagonist? pretreatment? ??
  • opioid anesthesia ? Intraoperative HTN
  • ?? morphine, meperidine? ?? ??? ?? ??
  • ?? ?? ??? ??? ???? vasodilater?
  • ?? ???? ??? ????
  • Opioid? ?? ????(nitrous oxide, benzodiazepines,
  • barbiturates, volatile agents)? ?? ??? ???
  • myocardial depression? ?? ? ? ??

61
  • Respiratory
  • Ventilation respiratory rate??
  • Resting PaCO2? ??
  • PaCO2 ??? ?? response? ??
  • CO2 response curve ? ????? ??
  • Brainstem? respiratory center? ??
  • Apneic threshold? ??, hypoxic drive? ??


62
  • Morphine, meperidine Histamine-induced
    bronchospasm ????
  • Opioids, particularly fentanyl, sufentanil,
    alfentanil
  • chest wall rigidity ?? ? ventilation? ?? ?? large
    bolus dose ? ?? ?? ????? ????? ????
  • Opioids? ????? bronchoconstrictive response?
  • ?? (intubation?? ?)

63
  • Cerebral
  • Cerebral perfusion ? ICP ? ?? ??? variable
  • oxygen consumption, blood flow, ICP ? ??
  • Barbiturate ? benzodiazepines ? ?? ??? ??
  • Artificail ventilation ??? normocarbia ??
  • Opioids bolus ? Brain tumor ? head trauma ?
  • ????? ??? cerebral blood flow velocity ?
  • ICP ? ??? ?? ??? ?
  • Opioid ? mild ? ICP ?? ??

64
  • medullary chemoreceotor trigger zone ?? ??
  • high incidence of nausea and vomiting
  • Physical dependence
  • ???? ?? ? incidence ??
  • Do not produce amnesia
  • Barbiturate ? benzodiazeoines? ??, pt?
    unconscious
  • ?? ??? ???? ??? large dose? opioid? ??
  • IV meperidine (25 mg) ? shivering? ?????? ??
  • most effective ? opioid

65
  • 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

66
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67
  • 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

68
Drug Interactions
  • Combination of opioids(particulary meperidine)
    MAOi
  • 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

69
KETAMINE
Mechanisms of action
  • Multiple effects on CNS
  • Spinal cord polysynaptic reflex ??
  • Brain excitatory neurotransmitter ??
  • Ketamine functionally dissociate the thalamus
    from the limbic cortex
  • Some brain neurons inhibited but others are
    tonically excited
  • This state of dissociative anesthesia cause the
  • patient to appear conscious (eye eye opening,
  • swallowing, muscle contracture) , but unable to
  • process or respond to sensory input

70
Structure-Activity Relationships

71
Pharmacokinetics
  • Absorption
  • IV or IM
  • Peak plasma level
  • 10-15min after IM injection
  • Distribution
  • Thiopental ? ?? more lipid soluble less prot.
    bound
  • Rapid brain uptake, subsequent redistribution
  • (distribution half life 10-15 min)
  • Awakening is due to redistribution to pph
    compartment

72
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73
Effects on Organ Systems
  • Cardiovascular
  • Increase ABP, HR, Cardiac output
  • Central stimulation of the sympathetic nervous
    system,
  • norepinephrine reuptake??
  • Increase in pulmonary artery pressure, myocardial
    work
  • Avoided in coronary artery dz, uncontrolled HTN,
    CHF,
  • arterial aneurysm

74
  • Direct myocardial depressant effect of large
    doses of ketamine
  • Inhibition of calcium transients
  • (unmasked by sympathetic blockade)
  • catecholamine store??
  • (ex. Severe end-stage shock)
  • Indirect stimulatory effects
  • acute hypovolemic shock ???? ??? ???

75
  • Respiratory
  • Ventilatory drive is minimally affected
  • Rapid IV bolus, pretreat. with opioids produce
    apnea
  • Ketamine is a potent bronchodilator
  • good induction agent for asthmatic pt.
  • Upper airway reflex remain largely intact
  • aspiration pn. risk? ?? ??? ?? ??? intubated
    state
  • Ketamine ? ?? salivation ??
  • Premedication with an anticholinergic agent

76
  • 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

77
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78
Drug Interactions
  • Nondepolarizing neuromuscular blocking agnets?
  • 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? ??

79
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 ?
    ??

80
Structure-Activity Relationships
  • Imidazole ring
  • Water solubility in acidic solution,
  • lipid solubility at physiologic pH
  • Etomidate? propylene glycol? ??? ??
  • Cause pain on injectin
  • Reduced by a prior injection of lidocaine

81
Pharmacokinetics
  • Absorption
  • Only for IV 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? ??

82
  • Biotransformation
  • Hepatic microsomal enzymes and plasma esterases
  • Rapidly hydrolyze etomidate to an inactive
    metabolite
  • Biotransformation rate? barbiturate? ? 5?
  • Excretion
  • ?? kidney?? metabolite? ??

83
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 etomidate than with
    barbiturates or benzodiazepines
  • Induction dose?? ?? apnea ? ?? ?? ??
  • Opioids ?? ?? ? apnea ?? ??

84
  • Cerebral
  • Decrease cerebral metabolic rate, blood flow, ICP
  • 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 ??

85
Drug Interaction
  • Frentanyl increase the plasma level and prolong
    the
  • elimination half-life of etomidate
  • Opioid decrease the myoclonus characteristic of
    an
  • etomidate induction

86
PROPOFOL
Mechanisms of Action
  • Involve facilitation of inhibitory
    neurotransmission
  • mediated by GABA

87
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/ml)
  • 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)

88
  • 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 ? ????
  • ???? ??? ??

89
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 ? ??? ?????
    ??

90
  • Lower induction dose is recommended in elderly
    patient
  • Elderly pt ? ?? Vd ? ?? ??
  • Women may require a higher dose of propofol
  • Biotransformation
  • 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) -gt long-term
    propofol infusion ? lipemia, metabolic acidosis,
    death ??
  • Excretion
  • ?? urine?? ??, but CRF ? ?? ?? ??

91
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

92
  • 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 ???) asystole ?? ?? ? ???? ??
  • Impaired ventricular function ventricular
    filling pr., contractility ?? ??? ???? cardiac
    output ??

93
  • 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? ??? ???.

94
  • 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? ??
  • But ??? ??? , tonic-clonic seizure ? ?????
  • propofol ? anticonvulsant effect ? ??, status
  • epilepticus ? ???
  • Intraocular pr. ? ????
  • Long-term infusion ??? tolerance ???? ??

95
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

96
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

97
Structure-Activity Relationships
  • Droperidol,(butyrophenone ) ? ????? haloperidol ?
    ??
  • ? ? ?? drug ? ???? ??
  • Haloperidol neuroleptic
  • Droperidol antipsychotic

98
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 ?? ??

99
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) ??? ?

100
  • Pheochromocytoma Pt
  • Droperidol ? ??? adrenal medulla ??
  • catecholamine release ? induce ??
  • severe HTN ??
  • ??? droporidol ? ??? ??
  • Respiratory
  • Droperidol ? ??? resiration ? ??? depression ? ??
    ?? ??

101
  • 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
  • Pakinson dz, restless leg syndrome,
    neurologically
  • mediated movement disorder pt ? ?? droperidol
    ??
  • ??? ?

102
  • Premedication ? apprehensive, fearful
  • -gt ???? premedication ? ??? ?
  • Opioid ? ?? ??? dysphoria ? incidence ? ??
  • droperidol is a tranqulilizer
  • Does not produce analgesia, amnesia, or
  • unconscious at usual dose
  • Combination of fentanyl and droperidol
  • Analgesia, immobility, variable amnesia
  • Nitrous oxide ? hypnotic agent ? ?? ???
  • ketamine ? ??? disscociative state ? ????
  • unconsciousness ? GA ??

103
Drug Interactions
  • Antagonize the effects of levodopa, precipitate
    parkinsonian symptoms
  • Dopamine ? renal effect ??
  • Clonidine ? alpha adrenergic action? antagonize
  • Ketamine ? cardiovascular effects ? ??
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