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ANPH 500 - Pharmacology - McCarver > Week 3 - Pharmacokinetics of Inhaled Anesthetics > Flashcards

Week 3 - Pharmacokinetics of Inhaled Anesthetics Flashcards

1
Q

Inhaled anesthetics pharmacokinetics involve what?

A

ADME
Absorption - uptake from alveoli to pulmonary blood
Distribution - to CNS, VRG (vessel rich group), skeletal muscle, fat
Metabolism - variable % of metabolism of volatile agents (sevo 3-5%)
Elimination - Lung primary site for elimination

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2
Q

Aging does what to inhaled pharmacokinetics?

A

Alters pharmacokinetics due to

  1. Decreased lean body mass
  2. Increased % body fat
  3. Increased Volume of distribution (Vd)
  4. Decreased Hepatic function
  5. Decreased Pulmonary gas exchange
  6. Decreased Cardiac output (the lower the CO, the more rapid the onset via inhalation) - per Lewis is counterintuitive
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3
Q

Partial pressure gradients propel inhaled anesthetics across what?

A

(NOT AN ATP REQUIRING PROCESS)

  1. Anesthesia machine/circuit - absorbs minimal amounts of agent.
  2. Alveoli - anesthesia is very concerned with this.
  3. Capillaries
  4. Cell membranes
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4
Q

All tissues (given enough time) will equilibrate with what?

A

Partial pressures of inhaled anesthetics. (not likely to see this in single case.) If you do “you’ve had a bad day”

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5
Q

PA = Pbr

A 
Pa = arterial partial pressures
PA = Alveolar partial pressures (imagine this is a capital LITTLE a)
Pbr = brain partial pressures
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6
Q

Given enough time, Arterial blood partial pressures equilibrate with what?

A

alveolar partial pressures

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7
Q

Where is the first place that IA’s go once it gets into arterial blood?

A

The Brain

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8
Q

Equilibration between Pa & PA means what?

A

The partial pressures are the same in both phases.

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9
Q

PA and Pbr are determined by what?

A 
Input 
  -  PI - inhaled partial pressures
  -  Alveolar ventilation
  -  Delivery system
  -  FRC
Uptake
  -  Anesthetic solubility in tissue - BGPC
  -  CO - cerebral blood flow
  -  Alveolar to venous partial pressure differences (A-vD)
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10
Q

Alveolar concentration = ??

A

Brain concentration

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11
Q

BGPC is what?

A

Blood gas partition coefficient

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12
Q

Inspiratory concentrations of IA’s are ALWAYs ___ than expiratory concentrations.

A

higher

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13
Q

Inhaled partial pressures (PI) must be ___ during initial phase of anesthetic

A

high

  • High initial partial pressures offset impact of uptake
  • Accelerates induction by increased rate of rise of PA (Alveolar partial pressures)
  • As uptake rate decreases, PI may be decreased
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14
Q

Concentration effect can be described as what?

A

The higher the PI (inhaled partial pressure), the more rapidly the PA (alveolar partial pressure) approaches PI.

IE - giving higher doses of inhaled anesthetic, the faster the equilibration.

PI offsets anesthetic uptake
PI also provides augmentation of tracheal gas flow - (which Lewis said was Phuey (sp?))

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15
Q

The second gas effect is what?

A

Reflects the ability of a high volume uptake of one gas (nitrous) to ACCELERATE the rate of increase of the PA of a concurrently administered second gas (volatile agent)

Increases tracheal gas flow
Concentration of volatile agent as uptake of nitrous occurs.

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16
Q

Alveolar ventilation is what?

A

Higher rates of alveolar ventilation promote the uptake of the anesthetic gas. (IE - the faster you breathe, the faster your PA gets to PI, so if you want your patient to get drugs faster, bag them.

  • Increased alveolar ventilation = increased rate of increase in the PA toward the PI
  • The increased alveolar ventilation to FRC ratio, the more rapid the rate of induction.
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17
Q

Neonate alveolar ventilation to FRC ratio is what?

A

5:1 (neonates induced quicker than adults)

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18
Q

Adult alveolar ventilation to FRC ratio is what?

A

1.5:1

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19
Q

Volatile agents are ventilatory ___?

A

depressants

Spontaneous ventilation provides a negative feedback protective mechanism here, in that when ventilation is reduced, the delivery of anesthesia is reduced. (IE - your patients RR drops, less volatile agent is delivered, which is why open drop ether was so safe.)

  • If patient is on controlled ventilation, this mechanism is lost.
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20
Q

The impact of alveolar ventilation changes on rate of increase in PA toward PI depends ___ of anesthetic in the blood.

A

solubility.

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21
Q

Changes in alveolar ventilation influence rate of increase of PA towards PI more with ___anesthetics than with ____ anesthetics

A

soluble

insoluble

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22
Q

Inhaled agent solubility in blood and tissues is quantified by what?

A

partition coefficients - is a ratio describing how inhaled anesthetics distribute themselves between 2 phases at equilibrium

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23
Q

Anesthesia machine’s characteristics influences the rate of increase of __ towards PI __.

A

PA
PI
-volume of breathing system, solubility of agent in circuit, fresh gas flow rates.

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24
Q

Have fresh gas flows equal to or greater than ___ to negate effects of volume of anesthetic breathing system.

A

5

higher flows on induction and emergence will speed both processes along

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25
Q

The rate of increase of PA towards PI is ___ proportional to solubility of anesthetic in the blood.

A

inversely

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26
Q

Blood is a pharmacologically __ __?

A

inactive reservoir.

The size of the blood reservoir depends on the solubility of anesthetic in blood.

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27
Q

High BGP (Blood Gas partition coefficient)

A
  • Large amount of anesthetic must dissolve in blood for Pa to equilibrate with PA.
    (body has a LARGE sponge)
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28
Q

Low BGP (Blood Gas partition coefficient)

A

Small amount of anesthetic must dissolve in blood for Pa to equilibrate with PA.
(body has a SMALL sponge)

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29
Q

BGP of Iso, Nitrous, Des, and Sevo

A

Iso - 1.46
Nitrous - 0.46
Des - 0.42
Sevo - 0.69

30
Q

Blood solubility of anesthetics during induction came be overcome with __?

A

Overpressuring

  • sustained delivery of high PI (Inhaled partial pressure)
  • Can result in anesthetic overdose with controlled ventilation!

Overpressuring comparable to concentration effect.

31
Q

PA PI rate of increase

A

With insoluble anesthetics:
- Minimal amounts of agent are dissolved before PA=PI
- Minimal time required before onset of anesthesia
(the more insoluble an anesthetic, the more rapid the onset)

Metabolism:
- too small to affect rate of increase of PA

32
Q

BGPs (Blood gas Partitions) are influenced by what?

A

Anemia
- Decreased solubility due to decreased RBC binding sites.
Age
- Decreased solubility with neonates and elderly for more soluble volatile agents. (not true with sevo or des)

33
Q

OGP is what?

A

Oil Gas Partition Coefficient

34
Q

OGPs parallel what?

A

Anesthetic potency

35
Q

OGPs info…

A

MAC can be estimated by dividing 150 by the oil: gas partition coefficient

  • 150 is the average value of the product of oil:gas solubility & MAC for several volatile agents
  • Theoretical MAC with an OGP coefficient of 300 would be 0.5%, with 75 would be 2%
36
Q

BGP of Nitrous and Nitrogen

A

Nitrous - 0.46
Nitrogen 0.014

Nitrous is 34x more soluble than nitrogen, it diffuses faster than nitrogen can leave, and can enter air filled cavities and increase volume/pressure of closed gas spaces. (IE watch out for procedures/patients with pneumothorax risk)

37
Q

What are some compliant wall spaces that expand with nitrous?

A

GI
Pneumothorax (75% nitrous doubles pneumothorax volume in 10 minutes)
Airbubbles
Blebs (masses or airbubbles r/t lung disease - contain air but don’t participate in gas exchange)

38
Q

What are some NON-compliant wall spaces?

A

Middle ear
Cerebral Ventricles
Supratentorial (space in the brain that contains the cerebrum) spaces

-these spaces will have increases in intracavitary pressure.

39
Q

Regarding N20 and Closed gas spaces….

A

Amount of volume/pressure increase dependent on:

  • Nitrous %
  • Air filled cavity perfusion
  • Duration of nitrous administration
  • Increase in bowel gas volume produced by nitrous is of minimal consequence (the only exception - bowel obstruction) Just the same, don’t get caught using this in a bowel case. :)

Middle ear is an air filled cavity

  • Nitrous may rupture tympanic membranes
  • Negative middle ear pressures may occur after nitrous discontinuation (increased nausea/vomiting).
40
Q

Cardiac Output influences pulmonary ____ ____.

A

Blood flow

  • Increased CO = more rapid anesthetic uptake
  • Increased CO acts like increased blood solubility (increased CO allows increased blood storage capacity of inhaled agent)
  • Sick people go to sleep faster. (less uptake of agent means less opposition to input, PA rises quicker.
41
Q

Cardiac Output acts as a ___ feedback response with volatile agent administration.

A

positive
(decreased CO due to volatile agent overdose further increases anesthetic depth & CO depression.)
-contrasts with negative feedback response of ventilatory depression and anesthetic depth.

42
Q

CO alterations impact rate of increase of PA most with more ____ inhalation agents.

A

soluble

-Doubling CO increases rate of uptake of volatile anesthetic, thus slowing rate of increase of PA.

43
Q

Increases in CO are not necessarily accompanied with proportional _____ in perfusion to all tissues.

A

Increases

  • preferential increases in VRG (vessel rich group) perfusion results in more rapid increase in PA of anesthetic.
  • infants with proportionally increased VRG perfusion show faster rate of increase of PA of anesthetic.
44
Q

In the absence of shunt, PA and Pa are what?

A

Equal

R>L shunt (if there is a hole in the heart, less pulmonary blood flow)

R>L shunt slows induction of anesthesia.
Slows rate of Pa increase more with insoluble anesthetics.

45
Q

Shunted blood does what to partial pressure of anesthetic in blood coming from alveoli?

A

Dilutes it.

46
Q

Overall effect on a R > L shunt on speed of induction is what??

A

minimal

47
Q

Concerning L > R shunts…

A

Has a minimal effect on anesthetic induction.

  • Is best noticible if R > L shunt also present
  • L > R shunts seen in:
    • AV fistulas
    • Atrial septal defect
    • Ventricular septal defect
    • Patent ductus arteriosis
48
Q

A-vD

A

Alveolar to venous partial pressure difference

  • reflects tissue uptake of inhaled anesthetic
  • VRG (vessel rich group)
    • fastest to equilibrate returning venous blood to PA
    • 10% of body mass but 75% of CO

Continued uptake of anesthetic after VRG equilibration

  • Reflects skeletal & fat uptake
  • Skeletal muscle and fat (75% of mass, 25% of CO)
  • For this reason A-vD difference is maintained for several hours after induction
  • Infants equilibrate A-vD quicker due to decreased muscle mass
49
Q

Recovery from Anesthesia is shown by the rate of decrease in the ____ ____, which we measure by __.

A

Brain
Pbr
PA

  • Anesthetic washout from the brain is rapid.
  • Brain receives large portion of CO.
  • Anesthetics are minimally soluble in the brain.

End tidal = brain concentration

50
Q

The rate of recovery is only _____ to rate of induction.

A

similar

  • no concentration effect - can’t give decreased % of agent.
  • rate of decrease of PA more rapid than rate of increase of PA during induction.
  • Even during long anesthetics, vessel poor tissue like bone and connective tissue have no equilibrated with PA.
  • When PI changes to zero, only VRG tissue has sufficient concentration gradients to return anesthetic blood.
  • Continued passage of anesthetic to VPG hastens rate of decrease of VA.
51
Q

Rate of Recovery…

A

TIME to recovery is proportional to length of anesthetic.

  • more noticeable with soluble anesthetics.
  • less pronounced with des & sevo.

TIME to recovery does not correlate with BGP.

  • drug metabolism hastens recovery.
  • tissue solubility other than blood affects time to recovery.
52
Q

Context sensitive 1/2 times

A

For volatile agents:
- time needed for a 50% reduction in anesthetic concentration
- For a six hour anesthetic, the time needed for 90% reduction of anesthetic concentration for
1. Des - 14 minutes
2. Sevo - 65 minutes
3. Isoflurane - 86 minutes
(sevo has comperable total tissue coefficient with ISO than Des)

MAC awak is 0.5 MAC and involves only 1 context sensitive half time.
- Little difference in recovery time to MAC awake with skilled practitioners.

53
Q

MAC

A

Minimum Alveolar concentration of anesthetic require to prevent SKELETAL muscle movement in response to a supramaximal painful stimulus in 50% of patients.
-ED50

Immobility is mediated by the spinal cord -
- REMEMBER: movement does NOT correlate well with awareness. (IE alot of people move during sleep, they are completely unaware!)

  • Decerebation (removal of cerebral response) does not alter MAC.
54
Q

MAC values vary ___ to ___% among individuals.

A

10-15 (this is unique in pharmacology)
MAC is altered by numerous physiologic & pharmacological factors.
MAC values for inhaled anesthetics are ADDITIVE. (0.5 MAC nitrous + 0.5 MAC sevoflurane = 1 MAC anesthetic)

55
Q

Red Hair = ?

A

BEWARE!
MAC is increased in women with natural red hair
- Reflects mutations of melanocortin-1 receptor gene.
- Reflects increased pheomelanin concentrations.

56
Q

MAC values for Iso, Des, Sevo, and Nitrous. (test Q)

A

Iso - 1.17
Des - 6.6
Sevo - 1.8
Nitrous - 104% (yes, 104%)

57
Q

What INCREASES mac?

A

Hypthermia, Red Hair, Durg increased CNS catecholamine levels, cyclosporine, hypernatremia.

58
Q

What DECREASES mac?

A

Hypothermia, Increasing Age, Drug decreased CNS catecholamine levels, Benzos, opioids, Hyponatremia, Alpha-2 agonists, ETOH intoxication, pregnancy, lithium, lidocaine, hypoexmia, hypotension, CPB, neuroaxial opiods

59
Q

NO change in MAC

A

Anesthetic metabolism, alcoholism, gender, duration of anesthetic, PaCO2 -15-95mmHG, Pa02 > 38 mmhg, BP > 40mmhg, hyperkalemia, hypokalemia, hyperthyroidism, hypothyroidism

60
Q

Mechanism of imobility

A

The spinal cord mediates, NOT the brain.

  • drug induced depression of excitation
  • drug induced enhancement of inhibition
  • No one action or group of receptors responsible
  • concurrent action on numerous receptor types also unlikely.
61
Q

Spinal cord activity correlates with EEG. True or False

A

False. (it does NOT correlate)

62
Q

Ionotropic Receptors

A

Neurotransmitters signal via 2 families of receptors
Ionotropic recepters:

  • A.K.A. ligand-gated ion channels
  • GABA as neurotransmitter (gaba binds to ion channel proteins causing opening of ion channels allowing CI- ion transmission.
  • composed of several subunits called pentameric (5) receptors (each pentameric receptor consists of 4 transmembrane segments.

Ionotropic receptors play an incompletely understood role in anesthesia.

63
Q

Ionotropic receptor examples

A
  1. Glycine receptors
    - Major mediator of inhibitory neurotransmission in spinal cord
    - Mediates part of immobility associated with anesthesia
  2. GABA receptors
    - mediator of immobility with injectable anesthetics but not inhaled anesthetics.
64
Q

Metabotropic Receptors

A

Metabotropic receptors are monomeric receptors

  • Seven transmembrane segments
  • Acetylcholine as neurotransmitter
  • Ach binding to monomeric receptor causes activation of G proteins
  • Activated G proteins are second messengers activating
    1. protein kinases
    2. K + channels
    3. Ca++ channels
65
Q

Metabotropic receptors

A 
Glutamate 
 - principle excitatory neurotransmitter
  Examples: 
    1.  G protein coupled receptors
    2.  Ligand gated receptors
        - NMDA - mediator of immobility with volatile anesthesia
        - AMPA - mediator of immobility with volatile anesthesia
        - Kainate - ? Function?

Na + channels may inhibit presynaptic release of glutamine.

66
Q

Anesthesia induced unconciousness invovles the same mechanism as mobility. True or False?

A

False (involves different mechanisms)
- Loss of consciousness and response to pain are not a single continuum of increasing anesthetic depth!!!!!!!!! (per Lewis)

GENERAL anesthesia =
- Volatile agent action on brain
- Volatile agent action on spinal cord
THESE 2 ACTIONS LIKELY OCCUR AT SEPARATE ANATOMICAL and MOLECULAR sites!

67
Q

In anesthesia induced unconciousness….

A

Multpiple recognized potential targets for anesthetic action/
Volatile Agents:
- Hyperpolarize cortical and spinal neurons
- Enhance inhibitory synaptic transmission
- Potentiate glycine activated currents
- May act on presynaptic Na+ channels & voltage-gated Ca++ channels to inhibit neurotransmission release.

At molecular levels:

  • Anesthetics may directly bind to membrane proteins.
  • These membrane protein sites may be stereoselective.
  • Volatile agents typically exist as isomers
    1. Isoflurane - levo isomer > potency
68
Q

All but what Volatile agent are racemic mixtures.

A

Sevo

69
Q

Meyer-Overton

A

Theoretical, not always reliable.

Lipid solubility correlates with anesthetic potency
Oil-gas partition coefficient equates to MAC
Historical view that meyer-overton reflected inhaled anesthetic actions on lipid portions of nerve endings.
-Found to be NOT true as effects on lipid bilayers are very small.

70
Q

Partial pressure of alveoli

A

Depth of anesthesia

ANPH 500 - Pharmacology - McCarver (11 decks)

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