Anesthesia Pharm Lecture 2

Absorption (Uptake): movement of the anesthetic from alveoli into the pulmonary capillary blood

• Distribution: transport of the anesthetic to the
• sites of action (CNS)

Metabolism: often limited for inhaled agents

Elimination: principally via the lungs

They go from the anesethesia machine, through the vaporizer, to the fresh gas flow, into the breathing circuit, to the fraction of inspired anesthetic, from there to lungs, FA (alveolar), and to the Fa (arterial).

• partial pressure gradient
• Pi ↔ PA↔Pa↔Pbr

because of the differences in solubility of each of the groups, particularly the fat group.

inversely related to solubility (of the agent in blood) the more soluble the agent is, the more of the Fi (inspired gas) that’s dissolved so that the FA doesn’t build up as quickly

Solubility of the agent in tissue

• Inhaled partial pressure
• Alveolar ventilation
• Spontaneous vs mechanical ventilation
• Cardiac output
• Alveolar-to-venous partial pressure differences
• Concentration effect
• Second gas effect
• Solubility

How quickly FA will approximate Fi.

• Increased inspired concentration helps to off-set uptake speeding the rise in Palveolar
• -want to offset uptake because if it gets taken up by blood it's not building partial pressure (which is what drives onset!)
• this is called “Overpressurization"-like giving a bolus to get FA to approximate Fi more quickly

• Increased alveolar ventilation promotes input to off-set uptake. (If certain amount of agent is being taken up, (uptake) by the blood, but more isn’t being brought in to offset that, then we’re not able to get the alveolar concentration to build up that quickly)
• This effect is less with an agent less soluble in blood.  (because if the agent isn’t that soluble then then uptake isn’t as big of an issue)

Because the inhaled anesthetics will depress respiration. So unless we increase alveolar ventilation artificially, there is in essence a negative feedback. The patient slows their breathing, less anesthetic is taken up.  So hypoventilation (a natural side effect of the inhaled agents) is we don’t do anything else, will slow the rate of raise of FA over Fi.

Hyperventilation, the  PCO2 goes down, decrease cerebral perfusion, so there could conceivably be less delivery of inhaled anesthetic to the brain. That could slow the clinical effect of the inhaled agent as well.

• ↑ CO causes more rapid uptake and a decrease in rate of rise of P alveolar & slows induction
• (equilibrium with vessel rich groups, like the brain, is slow)

Most prominent with a soluble anesthetic

Reflects tissue uptake of anesthetic

• The fraction of anesthetic removed from blood as it passes through the tissues depends on
•    a) Solubility of anesthetic in tissue
•    b) Blood flow
•    c) Partial pressure difference
• Vessel-rich groups equilibrate rapidly with arterial partial pressure
• After 3 times constants (5-15 minutes), uptake is decreased due to decreased inspired-to-alveolar partial pressure difference (saturation of vessel-rich groups)

Concentrating effect

Augmentation of tracheal inflow

Impact of inspired partial pressure on rate of rise of alveolar partial pressure

Explained by Fick’s Law

The higher the inspired partial pressure, the more rapidly the alveolar partial pressure approaches inspired.

• Concentration of the inhaled anesthetic in a smaller lung volume due to uptake of all gases from the lung.
• When you take up 50% (or any % of the gas) from the alveoli. If that was higher concentration of anesthetic, more is taken out, and less left of total volume in the alveolus, the anesthetic is concentrated in a smaller total volume. (the part that is left). Goes up  exponentially because of this.

• Because of the uptake of gases from the alveoli, the absorbed gas must be replaced by an equal volume of the gas mixture to prevent alveolar collapse
• This creates a negative pressure which pulls in more inspired gas
• (50% of anesthetic was taken up but now because of negative pressure situation need to replace the amount (in ml) that was taken up w/inspired gas volume (Which is a concentration mixture). We’re essentially adding mls of high concentration anesthetic

Concentration effect is more significant w/N2O than with the volatiles as N2O can be given in much higher concentrations

High nitrous concentration will augment its own uptake but also that of a concurrently administered volatile

The volatile is the second gas

*Second gas effect is weak & probably insignificant

70% not more because then we're taking away FiO2

Initially if we turn on N2O, and we give in such a high amount, it gets taken up, you concentrate the volatile more quickly. And get induction (FA/Fi) ratio equilibrium faster.

• Blood Gas partition coefficient: 12
• Brain Blood partition coefficient: 2
• Muscle Blood partition coefficient: 1.3
• Fat Blood partition coefficient: 48.8
• Oil Gas partition coefficient: 970

**Very soluble**

• Blood Gas partition coefficient: 2.54
• Brain Blood partition coefficient: 1.9
• Muscle Blood partition coefficient: 3.4
• Fat Blood partition coefficient: 51.1
• Oil Gas partition coefficient: 224
• *Intermediately soluble*

• Blood Gas partition coefficient: 1.9
• Brain Blood partition coefficient: 1.5
• Muscle Blood partition coefficient: 1.7 
• Fat Blood partition coefficient: 36.2
• Oil Gas partition coefficient: 98
• *Intermediately soluble*

• Blood Gas partition coefficient: 1.46
• Brain Blood partition coefficient: 1.6
• Muscle Blood partition coefficient: 2.9
• Fat Blood partition coefficient: 44.9
• Oil Gas partition coefficient: 98
• *Intermediately soluble*

• Blood Gas partition coefficient: 0.46
• Brain Blood partition coefficient: 1.1
• Muscle Blood partition coefficient: 1.2
• Fat Blood partition coefficient: 2.3
• Oil Gas partition coefficient: 1.4
• *Poorly soluble*

• Blood Gas partition coefficient: 0.42
• Brain Blood partition coefficient: 1.3
• Muscle Blood partition coefficient: 2
• Fat Blood partition coefficient: 27.2
• Oil Gas partition coefficient: 18.7
• *Poorly soluble*

• Blood Gas partition coefficient: 0.69
• Brain Blood partition coefficient: 1.7
• Muscle Blood partition coefficient: 3.1
• Fat Blood partition coefficient: 47.5
• Oil Gas partition coefficient: 55
• *Poorly soluble*

You can give N20 in higher concentrations so it can equilibrate in higher concentrations.

Determines uptake of anesthetic into tissues & time for equilibration with those tissues

• Amount of inhaled anesthetic that can be
• dissolved in the tissue divided by tissue blood flow

• Capacity (ml)
•  Flow(ml/min)

Capacity means volume of tissue. Time constant is in minutes (the mls cancel out)

• LONGER!
• the longer it’s going to take for the anesthetic to equilibrate in that tissue. So again fat has a larger volume, of all the tissue group, and a lower flow. (why fat has a longer time constant!)

large and low

• 1 time constant   = 63% change 
• 2 time constants = 86% change 
• 3 time constants = 95% change 
• 4 time constants = 98% change

•  8L    =     2min
• 4L/min

• So that means  as we change the vaporizer setting from the vaporizer to the circle system, it takes 2minutes to get to that point. (@ 2 min see 60% change, it takes 3 -4 time constants, so 6-8 min) unless we increase the flow. To
• accelerate that we increase the flow. We can’t change the capacity but we can increase the flow to change the time constant.

• •Low blood solubility
• •Low Cardiac output
• •High alveolar ventilation

• •High blood solubility
• •High cardiac output
• •Low alveolar ventilation

• body mass % is 9
• L/70kg is 6
• % of CO is 75
• L/min is 4

• Body mass % is 50
• L/70kg is 33
• % of CO 18
• L/min is 1

• Body mass % is 19
• L/70kg is 14
• % of CO is 7
• L/min is 0.4

• body mass % is 22
• L/70kg is 12
• % of CO is 0
• L/min is 0

• Can’t “underpressurize” to speed emergence
• Can only turn off vaporizer and increase fresh gas flows

minimal

• Time to 50% ↓ in anesthetic concentration independent of duration.
• What takes longer, that 50% is less than 5min for the agents we use now, but if we’re looking to get lower than that (say 80%) so we want 0.4 inspired and expired 0.3. The 80% is going to take longer. The first 50% happens quickly,
• it’s the last 20% takes more time.

That may or may not be significant. When the patient is awake enough to open eyes and follow commands in a second…

less

Nitrous will dilute out the oxygen. When nitrous is stopped abruptly there is a reversal of partial pressure gradient. Removal of CO2 which can remove stimulus to breathe, always given 100% oxygen after nitrous is discontinued

• the alveolar partial pressure of a gas at which 50% of animals will not respond to a noxious stimulus
• (clamp tails for rats, surgical incision for humans)

• Very reproducible
• End-tidal concentration is an index (allows us to follow where the pt is at, at level of the brain)

• Patient is either anesthetized or not
• MAC represents a whole population (or 50%) not response of a single patient
• Only applies to anesthetic gases
• Difficult to measure plasma brain concentration of IV anesthetics

Even though we use MAC and 50% of patients won’t move (that’s a good thing)  it also means 50% of patients will move (that’s a bad thing) so anesthesia usually requires a concentration that exceeds MAC by 10-30%. If we go up by 10-30% than we can pretty much guarantee immobility in nearly all patients.

decreases the MAC of other volatile agents. . It’s useful to know because volatiles cause hypotension and vasodilation, and by using N2O with the carrier gas, you reduce the amount of volatile needed, decreasing the  hpotensive & vasodilating effect. (while still getting the CNS depression)

Substituting a halogen of low atomic weight (F,atomic weight of 19) for one of higher atomic weight (Cl,atomic weight of 35) decreases potency

Isoflurane vs Desflurane (potency decreases and MAC increases)

Approximately 1/3 of MAC for Isoflurane (0.4%), Desflurane, Sevoflurane (0.67%)

Approximately ½ of MAC for Halothane

More than 60% of MAC for nitrous oxide

TRUE. N2O

0.1 or less

Prevents movement or coughing or bucking

Equal to or greater than MAC

• MAC- B(locks) A(utonomic) R(reflexes)
• ---Prevents response (↑ BP & HR)  to surgical stimulation
• ---Considerably in excess of MAC

• Turn up the volatile anesthetic for a few
• breaths and make sure the patient is well above MAC (at the end tidal reading) to verify it was at the brain (it was higher than MAC). You can say you want to be 10-30% above MAC until they make incision and then titrate it back down.

Hypothermia = ↓ MAC

Hyperthermia = ↓ MAC **unless >42°C then it ↑

Young ↑ MAC

Elderly ↓ MAC

“Excluding patients <1yr of age (where MAC can be lower) there is a linear model that describes a decrease in MAC of approx. 6% per decade of life.”--Barash 

MAC decreases by 6% per decade after the age of 40.

• Acute intoxication ↓
• Chronic abuse ↑

Hct <10% ↓

PaO2 <40 ↓

PaCO2 >95mmHg ↓ caused by <pH in CSF

Trick question. There is NO CHANGE! Hypothyroidism or Hyperthyroidism just change the CO not the actual MAC

MAP <40mmHg ↓

↓

Hyponatremia ↓

Hypernatremia ↑

*caused by altered CSF

↓ MAC decreases by 1/2 @ 8weeks gestation, normal by 72hrs postpartum

TRUE (except cocaine!)

• Opioids
• Ketamine
• Barbituates
• Benzos
• Verapamil
• Lithium

• DECREASE!
• (Methyldopa, Reserpine, Clonidine, & Dexmedetomidine)

Chronic ↓

• Acute ↑
•  
• *opposite of alcohol

INCREASE!!!

decrease

• Duration of anesthesia
• MAP greater than 50 mmHg
• Gender
• Size

0.75

1.63

1.17

1.8

6.6

104

150 divided by the oil:gas partition coefficient (not quite identical)

no effect

• ↓↓ BP
• ↓ HR
• None on SVR
• ↓ CO

no change!!

• Increases Blood flow
• Increases ICP

15-20%

50%

Normal = 50-55 ml/100 grams of brain tissue/minute = 750 ml/min = 15% resting C.O.

Closely related to tissue metabolism

• ↑ CBF 2°
•     ↑ PaCO2
•     ↑ [H+]
•     ↓ oxygen concentration (low PaO2)

TRUE!

• GREATEST increase with Halothane
• Least increase with Isoflurane and Desflurane
• The increase in CBF occurs within minutes of start of volatile and independent of blood pressure  changes.

All inhaled agents produce dose-dependent decreases in cerebral metabolic oxygen requirements (good thing)

• Greater with Isoflurane than Halothane
• The greater decrease with Isoflurane may explain why CBF isn’t predictably increased by Isoflurane at low concentrations
• ↓cerebral metabolism → ↓ carbon dioxide produced (TCA & oxidative phosphorylation)
• This creates opposition to vasodilation

• ↓ at 0.4 MAC 
• Amnesia also likely occurs at this dose

• Problematic in setting of space occupying lesions
• Hyperventilation to off-set

TRUE

1 MAC. Get burst suppression (straight line) at 2MAC

• Halothane decreases CO
• All the others decrease SVR

• INCREASE = ISO/DES/SEVO
• DECREASE = Halothane

Nitrous produces no change or slight increase in BP, so for pt that can’t tolerate a full MAC of volatile, we can add a little nitrous oxide (additive anesthesia) without the same amount of vasodilation

DECREASES. Use the vasodilation to our advantage and get IVs

• ↓ (Halothane)
• No change (others volatiles)
• Slight ↑ (nitrous oxide)

Halothane

N2O

• sensitizing myocardium to EPI, (endogenous or exogenous). More of an issue w/Halothane and less of an issue w/Isoflurane/Desflurane/Sevoflurane
• (exogenous limit for Iso/Des/Sevo is at 6mcg/kg of EPI)

Volatile agents (Isoflurane) can cause coronary vasodilation, dilating the small resistance  vessels. It’s called steal because it redirects blood from ischemic to non ischemic areas. The negative effect of Isoflurane in causing steal is offset by fact that it has negative inotropic effect as well, so it’s thought that only in patients w/steal prone anatomy are likely to be prone to coronary steal from Isoflurane.

• Steal prone anatomy
• Total occlusion of major coronary artery
• 90% stenosis by collateral distal to the occlusion
• ~12 % of patients (are at risk for Isoflurane) (risk but low incidence. The reason for that is as long as adequate HD are maintained, then Isoflurane doesn’t increase the risk of  myocardial ischemia, more of potential than real phenomenon. Isoflurane, Desflurane, and Sevoflurane in concentration up to 1.5 MAC don’t cause steal

Preconditioning: refers to patient that has brief periods of occlusion and ischemia from some sort of CAD, those areas of ischemia will begin cellular processes that are protective and it’s believed that the volatiles mimic this  preconditioning. There are a couple of things related to that we should know. The  sulfonylurea oral hypoglycemics and hyperglycemia, prevent this cardio protection. So if the patient were at high risk for ischemia, you may want to d/c the sulfonylurea oral hypoglycemics 24-48hrs pre-op cardiac surgery.

• ↑ respiratory rate
• ↓ tidal volume
• ↓ minute volume
• ↑ PaCO2

• YES, there is a decrease in responsiveness to CO2.
• Apnea at 1.5-2 MAC

**Ventilatory response to hypoxemia also decreases

relaxation of bronchial smooth muscle.

Desflurane. At 2MAC Desflurane is more of an irritant and at 1MAC they are all considered to be the same.

70% from portal vein, poorly oxygenated but nutrient rich (because it’s coming from GI tract)  30% is hepatic artery (Well oxygenated because it’s coming from the Aorta).

• 1. 20% of adults develop mild self-limited postop liver toxicity following halothane
•    -Lethargy, fever, nausea, minor ↑ liver enzymes
• 2. Halothane hepatitis
•    - Immune-mediated response
•    - 1 in 10,000 - 1 in 30, 000 adults following halothane
•    - Massive hepatic necrosis & death possible
•    - Children are less susceptible (why we still use it in pediatrics)

• female
• middle age
• obesity
• multiple exposures to halothane

the 4 Fs Female, Forty, Fat, & Frequent

Hydrate the patient :)

Due to extensive metabolism of  Methyoxyflurane (& Enflurane) to a fluoride ion. Metabolized in liver but the effect is on the kidney. Clinical toxicity occurs when plasma fluoride concentration is > than 80mmols/L (Clinical toxicity level). A threshold of 50mmol/L is indicator that renal toxicity could occur.

What seen is vasopressin resistant, high output renal failure.

• Polyuria, hypernatremia, hyperosmolarity
• Inability to concentrate urine so urine is hypo-osmolar (dilute)

• Methyoxyflurane (after 2-3hrs)
• Enflurane (after 10hr)

• Compound A formed when sevoflurane
• reacts with CO2 absorbents

Dose-dependent nephrotoxin The amount of compound A that is produced is far less than what’s been found to cause nephrotoxicity, but because of possibility, the company recommends a 2L/min of fresh gas flow (oxygen, nitrous, air or any combo) when using Sevoflurane

• Ether-derived volatiles produce twice the skeletal muscle relaxation of halothane
• Enhance neuromuscular blockers (DON’T REPLACE, just enhance)
• Nitrous doesn’t produce muscle relaxation

• Halothane
• Nitrous

N2O

• Colorless, odorless, non-explosive & non-flammable but will support combustion (careful around lasers)
• A gas at room temp & pressure but stored as a liquid under pressure

• Stimulates SNS
• Depresses myocardial contractility

These two kind of cancel each other out and BP, CO, HR unchanged or slightly increased

in hypovolemia or coronary artery disease, could become ischemic.

• Limited due to high MAC
• Adjunct to volatile, TIVA

PONV

• in bone marrow depression (megaloblastic
• anemia) & neurological deficiencies exhibited by:
•   - Peripheral neuropathies
•   - Pernicious anemia (vitamin B-12 deficiency)
•         *Inhibits enzymes that are vitamin B-12 dependent including … 
•        Methionine synthetase (necessary for myelin formation)
•        Thymidylate synthetase (necessary for DNA synthesis)

Nitrous

• Air embolism, pneumothorax, intestinal obstruction, etc
• Pulmonary hypertension (↑PVR)

• low cost and non-pungent.
• (helps w/pediatrics because no smell or airway irritation)
• Low BG partition coefficient, and unlikely MH trigger

low potency, MAC awake is close to MAC, need a lot for anesthesia.  Increases PONV.

Environmental: destroys the ozone layer.

• Halogenated alkane, alkyl halide
• Nonflammable, nonexplosive
• Thymol preservative & amber colored bottle retards spontaneous oxidative decomposition

• Hypotension from myocardial depression
• Bradycardia and/or junction rhythm from SA node slowing* *very common
• Sensitizes the myocardium to catecholamines (Doses above 1.5mcg/kg of Epi should be avoided)

• Depression
• Potent bronchodilator (best of all volatiles)

• ↑ CBF with blunted autoregulation
• Halothane is worst choice for pt w/brain tumor and space occupying lesion. Want to hyperventilate pt before you give halothane to avoid increase ICP.

• Hepatic dysfunction
• Epinephrine use
• Pheochromocytoma (increased sensitivity to catecholamines)
• Myocardial depression exacerbated by beta-blockers & calcium channel blockers
• Dysrhythmias with concurrent aminophylline use

• Halogenated methyl, ethyl ether
• Light sensitive, stabilized with butylated  hydroxytoluene
• Nonexplosive, nonflammable
• Most potent
• **has similar effects on other organ systems

• Extensive metabolism by cytochrome P-450 system
• Resultant fluoride ion levels of 50 micromoles/L occurs with 2.5-3 MAC hours causes vasopressin-resistant, high output renal failure (F inhibits tubular function)

• Halogenated ethyl, methyl ether
• Nonflammable, nonexplosive

• Deep enflurane anesthesia associated with high voltage, high frequency EEG changes & tonic-clonic seizures
• Exacerbated by high anesthetic concentrations & hypocapnia
• *Avoid in patient w/seizure disorder.

• Likelihood went up if PaCO2 was low  (hyperventialted) and Enflurane
• concentration was high.

10

• Halogenated ethyl, methyl ether
• Structural isomer of enflurane
• Nonflammable, nonexplosive

• Minimal cardiac depression because CO is maintained by ↑HR
• Mild beta stimulation
• Coronary steal 2° coronary artery dilation

TRUE

NOPE....one less thing to memorize :)

• Halogenated ethyl, methyl ether
• F substitution on isoflurane
• Physical properties

• Most similar to others
• Transient ↑ HR, BP with rapid increasing dose
• Respiratory irritant *esp at higher doses

• Minimal metabolism
• Is degraded by dessicated (dryed out) carbon dioxide absorbent into clinically significant carbon monoxide levels(need to turn off flows and machine so we don’t dry out the CO2 absorbent).

Because of BG solubility, quicker wake up and tighter anesthetic control than the others.

• Halogenated methyl isopropyl ether
• Nonflammable, nonexplosive

• Degrades by carbon dioxide absorbents to compound A
• Most likely with dry absorbent, low gas flows, high sevo concentration, prolonged exposure (long case)

**Recommend gas flow of at least 2 liters/minute

• because sweet smelling and provides a relatively nice mask induction.
• Used Halothane before but has drawbacks (solubility and hepatitis).

• Loss of anesthetic
• Toxicity 
• --Compound A (only Sevoflurane)
• ---Carbon Monoxide (more likely w/Desflurane)

Low gas flow rates