Pharmacology I: Lecture 2 - Inhaled Anesthetics Flashcards

Question

How does the blood/gas partition coefficient affect anesthetic uptake?

Answer 1

A higher B:G coefficient means slower onset due to greater uptake into blood and tissue.

Answer 2

Fresh gas leaving the anesthesia machine mixes with volatile anesthetic in a vaporizer A series of partial pressure gradients serve to propel the inhaled anesthetic across various barriers Breathing circuit to FI to FA to Fa to FBr FI = fraction of inspired anesthetic FA = fraction of anesthetic in alveoli Fa = fraction of anesthetic in blood FBr = fraction of anesthetic in brain

Answer 3

The partial pressure of a agent determines the rate and direction of transfer between media The link between partial pressure and the actual concentration is solubility The solubility coefficient: Ratio of the concentration in blood to the concentration in gas, when the partial pressure in both compartments is at equilibrium It has the symbol λ When this liquid is blood it is called the blood/gas solubility coefficient or λBG

Answer 4

It is equivalent to partial pressure or gas tension In a gas mixture of 100 mL of N2O and 100 mL of O2 = 50% concentration by volume For example: If 1 mL of anesthetic vapor is dissolved into 100 mL of blood the concentration is 1% by volume

Answer 5

The principal objective of inhalation anesthesia is to achieve a constant and optimal brain partial pressure of the inhaled anesthetic – ‘wash-in’ period The alveolar partial pressure governs the partial pressure of the anesthetic in all the tissues PA = Pa = PBr at equilibrium The alveoli are “the windows to the brain” Uptake of an anesthetic through the alveoli into the bloodstream depends on many factors During the first breath a partial pressure gradient is established be FA and Fa Gases move along concentration gradients The more gas being taken up the slower the rate of rise of FA

Answer 6

* Fresh gas flow (FGF) * Administered dose (i.e. vaporizer %, higher concentration) * Breathing circuit * Lung exchange * Cardiac output (CO) * Blood:gas partition coefficient * Ventilation * Functional residual capacity (FRC)

Answer 7

A high FI is required during the initial phases of anesthesia to offset uptake and accelerating induction This is best accomplished by a high FGF, increased ventilation and a high concentration of VA Uptake is primarily by the breathing circuit and the anesthetic machine and in most cases can be negligible

Answer 8

B:G coefficients CO or alveolar Blood Flow (higher Blood Flow = slower onset, more dramatic effect on those with a higher Blood:Gas coefficient) Alv/v partial pressure difference Shunts R to L Cardiac: blood is bypassing the lungs because goes from R side to L side of heart, so increases onset, never had time to interact with agent Verses L to R (WHAT IS THIS EFFECT LOOK UP)

Answer 9

Inflow of anesthetic gas to alveoli (FA): Ventilation Increased ventilation = faster induction Concentration Increased concentration of anesthetic Concentration effect Second gas effect

Answer 10

A set concentration of gas is administered, and increasing the amount offsets the amount taken up by blood, speeding induction. If we increase the amount administered Increase PI This will offset the amount taken up by the blood and speed our induction Only gas that can be administered at high enough concentrations used today is N2O

Answer 11

The uptake of the first gas increases the partial pressure of the second gas, aiding in its onset. This is when a large volume of uptake of the 1st gas results in an increase in the rate of rise of the partial pressure of the 2nd gas The large uptake of the 1st gas reduces the total gas volume and thus increasing the concentration of the 2nd gas, thus aiding in onset (concentrates remaining gas) It also reduces expired volume Less VA expired Rise in CO2 will stimulate a SV patient to breath These factors will accelerate the increase in FA

Answer 12

Blood distributes the anesthetic around the body according to regional perfusion Anesthetic is transferred to tissues by the partial-pressure gradient between blood and tissue This transfer reduces the concentration gradient in the blood so on its return to the lungs more agent can be taken up

Answer 13

The CO is not distributed evenly in the body The more vascular organs receive more perfusion Greater perfusion = more rapid partial pressure equilibration of agent These better perfused tissues are called the vessel-rich group Brain, Heart, Kidney, Liver and Endocrine glands VRG receives 75% of CO but is only 10% of total body weight Highly perfused tissue equilibrate with Pa in about 5-15 minutes Adipose tissue takes a while to be saturated, and then becomes a reservoir and takes a long time for it to release the agent

Answer 14

Worried about the expiratory pressure/concentration because it is a representation of the concentration in the body

Answer 15

Elimination occurs exclusively through the lungs. Only halothane undergoes metabolism It is simply the reverse of uptake Fa blood now has a lower partial pressure of anesthetic then Fbr and other tissues Anesthetic diffuses out and back to the lungs Elimination is a slower process Emergence requires more finesse ***Really only turning the dial off is the way to reverse the patient***

Answer 16

Rate of ‘wash-out’ from brain is rapid due to low Br:Bl partition coefficients and high blood flow The concentration of inhaled anesthetic in tissues depends on solubility and the duration of administration

Answer 17

VA undergo varying degrees of metabolism, primarily by cytochrome P450 enzyme 2E1 in the liver, kidney, and lung. Metabolites from degradation are the major reason for liver and renal toxicity

Answer 18

Isoflurane has a B:G coefficient of 1.4, indicating it will have a higher concentration in blood compared to gas.

Answer 19

* Methoxyflurane: nephrotoxicity * Enflurane: renal injury * Halothane: hepatitis * Sevoflurane: safe but results in high serum F- ions. Probably due to uniquely low B:G λ

Answer 20

Inhaled anesthetics interact with various receptors, including GABA and NMDA receptors, causing a decrease in neuronal excitability. Unknown N20 is believed to inhibit NMDA excitatory receptors in brain Some VA appear to interact with GABA Others block excitatory channels and activate inhibitory channels There does not seem to be a single site of action that is shared by all agents VA site of action is most likely GABAA They potentiate inhibitory Cl- currents though GABAA receptors by increaseing the efficacy of GABAA Produces a decrease in neuronal excitability Also, Glycine receptors when activated open a Cl- permeable channel that hyperpolarizes neurons Decrease nervous system excitability VA may also inhibit nAChRs, because their activation in the brain aids in function of learning, memory, and attention. Thus, inhibiting nAChR may contribute to cognitive components of anesthesia VA may inhibit NMDA receptors responsible for learning and memory VA have been shown to inhibit excitatory neurotransmitter release, reducing CNS excitability

Answer 21

Compared to IV anesthetics inhaled anesthetics are generally more promiscuous in the molecular targets, lacking the receptor-specific, and even subtype-specific, effects of certain IV anesthetics

Answer 22

False: Inhaled anesthetics are generally more promiscuous in their molecular targets compared to IV anesthetics.

Answer 23

Evidence exists that loss of consciousness and immobility are the result of two or more separate mechanisms rather than one Consciousness and Immobility are not the same thing

Answer 24

The concentration that prevents skeletal muscle movement in response to a painful noxious stimulus in 50% of patients Roughly additive when VA are used with N2O Considered the ED50 of an inhaled anesthetic Analogous to the EC50 for IV drugs MAC is not about unconsciousness, its about immobility ## Footnote Considered the ED50 of an inhaled anesthetic

Answer 25

0.75% ## Footnote This is among the lowest MAC values for inhaled anesthetics

Answer 26

1.15% ## Footnote Isoflurane is known for its stability and minimal metabolism

Answer 27

1.6% ## Footnote Enflurane is less commonly used compared to Isoflurane and Sevoflurane

Answer 28

2.1% ## Footnote Sevoflurane is often used for inhalational induction due to its favorable properties

Answer 29

6.0% ## Footnote Desflurane has the highest MAC among commonly used inhaled anesthetics

Answer 30

105% ## Footnote Indicates its low potency as an anesthetic agent

Answer 31

Alveolar concentration of anesthetic that inhibits appropriate responses in ½ of patients

Answer 32

Alveolar concentration of anesthetic that blunts autonomic response to noxious stimulus

Answer 33

Roughly additive when volatile anesthetics are administered concurrently with N2O Examples: 1% Isoflurane with 50:50 N2O and O2 1/1.15 = 0.87 + 0.5 = 1.37 MAC Patient undergoing GETA maintained with 50% O2, 50% N2O, and 1.5% Sevoflurane 50% N2O (MAC 105%) = ~ 1/2 MAC 1.5% Sevo (MAC 2.0%) = ~ 3/4 MAC Total MAC = 1/2 + 3/4 = ~ 1.25 MAC (ALWAYS A TEST QUESTION)

Answer 34

* Hyperthermia (>42° C) * Hypernatremia * Youth * Red hair (19% more Desflurane) * Chronic EtOH * Drug Abuse (Cocaine, Amphetamines) * Smoking (?)

Answer 35

* Hypothermia * Increasing age * Acute EtOH intoxication * Benzodiazepines * Opioids * Pregnancy * Hyponatremia * Lidocaine * Metabolic Acidosis

Answer 36

* Nitrous Oxide * Halothane * Enflurane * Isoflurane * Desflurane * Sevoflurane

Answer 37

'Laughing Gas' at the dentist

Answer 38

* Inorganic * Stable * Tasteless * Odorless * Non-Flammable * Low potency and low solubility (0.46 = Onset is fast, offset is fast) * Commonly administered with opioids or other VA due to the inability to achieve MAC alone * Analgesic effects * High incidence of N/V * Avoid in pregnancy

Answer 39

Due to nitrous oxide's solubility in blood, its rapid absorption from alveoli causes an abrupt rise in the FA of an accompanying volatile agent The concentration of the second gas rises faster than it would in the absence of Nitrous oxide Useful in mask inductions

Answer 40

N2O is ~ 30 times more soluble than N2 in blood It tends to diffuse into air-containing spaces more rapidly than N2 is absorbed by the blood This is because N2O is carried to the closed air spaces and diffuses down the concentration gradient (high to low) N2 in air will transfer from inside the space to outside but it is much slower because it is less soluble (N2 0.015 vs. N2O 0.46) These spaces will enlarge and increase size and pressure For Example: A 100 ml pneumothorax inhales 50% N2O, the gas content of the pneumothorax will tend to approach that of the blood Because N2O will diffuse into the cavity more rapidly than air (principally N2) diffuses out, the pneumothorax will expand until it contains 100 ml of air and 100 ml of N2O or a 50:50 concentration

Answer 41

Occurs when inhalation of nitrous is abruptly discontinued, leading to a dilution of PAO2, which can lower the PaO2

Answer 42

Potent bronchodilator Sweet smell Slowest onset and offset Due to high blood solubility Replaced by newer agents Highly metabolized Decreases blood pressure Blunts baroreceptor reflex Myocardial depressant MAC 0.75% B:G λ 2.5 Vapor pressure 243 mmHg Thymol preservative due to spontaneous degradation via UV light Red

Answer 43

Cardiac sensitization to catecholamines - arrhythmias Decomposition byproducts ‘Halothane hepatitis’ Myocardial depression

Answer 44

Highly stable High blood/gas solubility Slower uptake and elimination Maintains CO (BIG CLAIM TO FAME) Potent vasodilator Pungent odor and stimulates respiratory reflexes (not used for mask inductions) Coronary ‘steal’ phenomenon Cheap or ‘cost effective’ MAC 1.15% B:G λ 1.4 Vapor pressure 238 mmHg Minimal metabolism Purple

Answer 45

Coronary Steal Syndrome - dilates coronary arteries which can lead to redistribution of coronary blood flow away from diseased areas to areas with normal arteries Flow always follows the path of least resistance

Answer 46

Used in neurosurgery due to reduced CMRO2 and can suppress EEG which can provide cerebral protection

Answer 47

Pungent airway irritant Relatively expensive Decreased potency Tachycardia Specialized vaporizer Due to vapor pressure Low solubility Fastest on and off MAC 6% B:G λ 0.42 Vapor pressure 669 mmHg Minimal metabolism Favorable solubility Blue

Answer 48

Terrible for the Environment Very rapid onset and recovery due to low blood solubility Differs from isoflurane by one atom – a F- Change decreased solubility at the expense of potency Extremely pungent – causes coughing, breath holding, and laryngospasm Irritation can cause tachycardia and HTN

Answer 49

6% ## Footnote Desflurane has the highest MAC among commonly used inhaled anesthetics

Answer 50

Can produce CO in an exothermic reaction when CO2 absorbents are dried up

Answer 51

Potent bronchodilator No pungency Sweet odor The agent for inhalational induction Low solubility Rapid onset and offset Most common agent used MAC 2.1% B:G λ 0.65 Vapor pressure 157 mmHg Slight metabolism Favorable solubility Yellow

Answer 52

Not terrible for the environment CO If CO2 absorbents are dried up, Sevo can produce CO in an exothermic reaction which has led to canister fires Compound A (vinyl halide) K and NaOH in CO2 absorbents react with sevoflurane and form nephrotoxic byproducts in rats, not proven in humans

Answer 53

Convert the liquid to a vapor Agent specific Variable bypass Splits FGF either into or bypassing the vaporizer

Answer 54

Exothermic Reaction from interaction of desiccated carbon dioxide absorbent and VA Conventional absorbents containing sodium and potassium hydroxide Sevoflurane can lead to explosions Don’t see it now with modern absorbents

Answer 55

* Do not cause retrograde amnesia or intellectual impairment * Cause anterograde amnesia * ↑ CSF production * ↑ CBF * ↑ ICP * ↓ CMRO2 & EEG

Answer 56

VA are direct vasodilators that abolish the bodies ability to autoregulate ↑ CBF Hypercapnia will ↑ CBF ↑ ICP Can be blocked by ↑ RR or barbiturate coma ↓ CMRO2 & EEG Isoflurane has the largest depression of CMR w/o hemodynamic depression Organ protection Due to ↓ O2 demand the major organs are protected from ischemia

Answer 57

* ↓ MAP * ↓ SVR with maintained CO (CO = HRxSV) * Myocardial depression with halothane ↓ CO due to depression of contractility * Dysrhythmogenic effects of halothane * Tachycardia with Desflurane * SA node and His-Purkinje conduction are prolonged * N2O has no effect on CV system

Answer 58

* ↑ RR & ↓ TV = can lead to atelectasis (MV goes down??? LOOK UP) * ↓ ventilatory response to CO2 * ↓ ventilatory response to hypoxemia * Bronchodilator Direct airway relaxation via VA Bronchoconstriction seen with desflurane Adrenoceptor β2 promote bronchiolar muscle relaxation via increase in cAMP

Answer 59

Smokers Have impaired mucociliary function, when combined with mechanical ventilation it sets up a scenario for inadequate clearing of secretions, mucus plugs, atelectasis, and hypoxemia HPV Hypoxic pulmonary vasoconstriction Decrease blood flow to under ventilated areas of the lung Results in V/Q matching and improved oxygenation

Answer 60

↓ HBF & O2 Requirement Halothane causes hepatic artery vasoconstriction Inhibition of hepatic drug metabolizing enzymes Hepatotoxicity ‘Halothane hepatitis’ Repeat exposure – immune-mediated IgG antibodies Hepatocyte toxicity – dec HBF

Answer 61

↓RBF ↓GFR ↓UO Sevo – Cpd A F- ion build up can lead to nephrotoxicity

Answer 62

VA potentiates NMB of NDMR Trigger for MH ↓Uterine smooth muscle contractility and uterine blood flow

Answer 63

* Air embolism * Increase middle ear pressure * Pneumothorax * Intracranial air * Intra-ocular air bubbles * Tympanic membrane grafting * Open bowel cases * Bowel obstruction * Known lung 'blebs' * Patient history of PONV

Answer 64

Acute uncontrolled increase in skeletal muscle metabolism leading to increased O2 consumption, lactate formation, heat production, and rhabdomyolysis Clinical signs are increase Temp, arrhythmias, muscle rigidity & rise in EtCO2 Increase in temperature is actually one of the last signs to see Increased rise in EtCO2 is the first you will actually see

Answer 65

Inhaled anesthetics

Answer 66

Severe Hypovolemia (typically a penetrating Trauma) Due to vasodilation and decrease CO Malignant Hyperthermia Trigger crisis Intracranial Hypertension Due to increase in CBF

Answer 67

* VA potentiates NMB of NDMR * Decrease uterine smooth muscle contractility * Contraindications include severe hypovolemia and intracranial hypertension

Answer 68

Sevoflurane

Answer 69

Desflurane

Answer 70

What is best VA for this case? Pt is 3 y/o male with a hx of Asthma and OSA. Pt presents for T&A. No IV access. What is your plan? What is the best VA? Which VA would you want to avoid? Prone to airway issues with the Asthma = don't want to use an irritating agent, so not use DES or ISO... would want to use SEVO as not irritating

Answer 71

Anesthetics concentration at their effect sites ## Footnote This parallels the alveolar anesthetic concentration and not the total amount of absorbed anesthetic.

Answer 72

MAC, the minimum alveolar concentration of anesthetic required to prevent movement in 50% of subjects

Answer 73

Partial pressure of gas and its Blood:gas or tissue:gas partition ratio

Answer 74

The physical properties, in particular solubility

Answer 75

Rate of inhaled anesthetic uptake and elimination from the alveoli

Answer 76

Alveolar ventilation and cardiac output

Answer 77

Changes in alveolar concentration including minute ventilation, fresh gas flow and inspired concentration

Answer 78

Relative perfusion, the gradient between arterial and venous anesthetic concentration and intertissue distribution

Answer 79

Minimally, and this is by Cytochrome P450

Answer 80

Yes, amnesia, unconsciousness and immobility

Answer 81

A site in the spinal cord

Answer 82

Incompletely understood supraspinal mechanisms

Answer 83

Alterations in synaptic transmission

Answer 84

Hydrophobic and amphipathic

Answer 85

Can act at a number of sites at the clinically relevant sites concentrations

Answer 86

Potentiate them

Answer 87

Inhibitory effects

Answer 88

NMDA-type glutamate receptor blocking effects

Answer 89

Organ protection

Answer 90

Respiratory and cardiovascular depression

Answer 91

Yes, pharmacologic, pharmacokinetics, and side effects