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Flashcards in UNIT 4 Pharmacology I Deck (157):

define volume of distribution & recite the equation

Vd describes the relationship b/n a drug's plasma concentration following a specific dose. It is a theoretical measure of how a drug distributes throughout the body.
Vd assumes two things:
1. drug distributes instantaneously (full equilibration occurs at t=0)
2. drug isn't subjected to biotransformation or elimination before it fully distributes

Vd = amount of drug/desired plasma concentration


What are the implications when a drug's Vd exceeds TBW? What is Vd if less than TBW?

If Vd>TBW, the drug is assumed to be lipophilic:
- it distributes into TBW & fat
- it will require a higher dose to achieve a given plasma concentration
- ex: propofol, fentanyl

If Vd


How do you calculate the loading dose for an IV medication? For a PO medication?

loading = Vd*desired plasma concentration/bioavailability

for an IV drug, the bioavailability is always 1
for a PO drug, the bioavailability will be <1 d/t first pass metabolism


What is clearance? What factors increase/decrease it?

clearance is the volume of plasma that is cleared of drug per unit time

increased by:
- increased blood flow to clearing organ
- increased extraction ratio
- increased drug dose

decreased by
- increased half life
- increased drug concentration in central compartment


What is steady state?

occurs when the amount of the drug entering the body is equivalent to the amount of drug being eliminated from the body- there is a stable plasma concentration. Each of the compartments has equilibrated, although the total amount of drug may be different in different compartments

steady state is achieved after 5 half-times


compare and contrast the alpha and beta distribution phases on the plasma concentration curve

graphical depiction of the biphasic decrease of a drug's plasma concentration following a rapid IV bolus

alpha phase: describes drug distribution from the plasma to the tissues
beta phase: begins as plasma concentration falls below tissue concentration. Concentration gradient reverses, which causes the drug to re-enter the plasma. B phase describes drug elimination from the plasma by the clearing organs


You have administered 30mg of esmolol to a patient after a sudden (and profound) elevation in HR. After 3 half-lives, what percentage of your initial dose remains in the patient's bloodstream?



What is context sensitive half-time?

the time required for the plasma concentration to decline by 50% after discontinuing the drug infusion


Discuss the CS1/2t of fentanyl, alfentanil, sufentanil, adn remifentanil. Which has the longest? Which has the shortest? Why?

The CS1/2t for a fentanyl infusion increases as a function of how long it was infused (since it has more time to fill up the peripheral compartments). This is also true for alfentanil & sufentanil to lesser degrees.
Remifentanil is the exception. Although it's highly lipophilic, it is quickly metabolized by plasma esterases & has a similar CS1/2t regardless of time infused.


What is the difference b/n a strong and weak acid or base?

the difference is the degree of ionization:
- if you put a strong acid or base in water, it will ionize completely
- if you put a weak acid or base in water, a fraction of it will be ionized and the remaining fraction will be unionized


What is ionization? What 2 factors determine how much a molecule will ionize?

ionization describes the process where a molecule gains a positive or negative charge

the amount of ionization is dependent on two things:
- the pH of the solution
- the pKa of the drug


Finish this sentence: When pKa and pH are the same, _____

50% of the drug will be ionized and 50% will be unionized


How does ionization affect solubility, pharmacologic effect, hepatic biotransformation, renal elimination, and diffusion across lipid bilayers?

- water solubility
- not pharmacologically active
- less hepatic biotransformation
- more renal elimination
- no diffusion across lipid bilayers (BBB, GI, placenta)

- lipid solubility
- pharmacologically active
- more hepatic biotransformation
- less renal elimination
- diffusion across lipid bilayers (BBB, GI, placenta)


What happens when you put an acid in a basic solution? How about an acidic solution?

"like dissolves like"

acid in a basic solution:
- acidic drug will be highly ionized in a basic pH
- acidic drug wants to donate protons & basic solution wants to accept

acid in an acidic solution
- acidic drug will be highly unionized in an acidic pH
- acidic drug & acidic solution both want to donate protons


Can you tell if a drug is an acid or a base by looking at it's name? if so, how?

most drugs are weak acids or weak bases. They are usually prepared as a salt that dissociates in solution.

Weak acid is paired w/ a positive ion such as sodium, calcium, or magnesium (ex. sodium thiopental)

weak base is paired w/ a negative ion such as chloride or sulfate (ex. lidocaine hydrochloride, morphine sulfate)


Name the 3 key plasma proteins. Does each bind acidic drugs, basic drugs, or both?

albumin: binds primarily acidic drugs, but does bind to some neutral and basic drugs

a1-acid glycoprotein: binds basic drugs

B-globulin: binds to basic drugs


What conditions reduce albumin concentration

liver disease
renal disease
old age


What conditions affect alpha1 acid glycoprotein concentration?

- surgical stress
- MI
- chronic pain
- RA
- advanced age

- neonates
- pregnancy


How do changes in plasma protein binding affect plasma drug concentration?

decreased PB --> increased plasma concentration

increased PB --> decreased plasma concentration


How do you calculate changes in plasma protein binding?

[free drug] + [unbound PB sites] [bound drug]

if a drug is 98% PB and the bound fraction is reduced to 96%, the unbound or free fraction has increased by 100%!


A new anesthetic drug is cleared from the body at a rate proportional to its plasma concentration. What kinetic model best describes the elimination of this drug?

first order kinetics (a constant fraction of drug is eliminated per unit time)

most drugs follow this model


alcohol is cleared from the body via zero order kinetics. How ill this drug's rate of elimination change as plasma drug concentration changes?

it won't

a constant amount of drug is eliminated per unit time. Said another way, the rate of elimination is independent of plasma drug concentration.

Other examples:
- aspirin
- phenytoin
- warfarin
- heparin
- theophylline


What is the function of a phase 1 reaction? List 3 examples.

Phase 1 reactions result in small molecular changes that increase the polarity (water solubility) of a molecule to prepare it for a phase 2 reaction - it creates a location on the molecule that will allow the phase 2 reaction to take place. Most phase 1 biotransformations are carried out by the P450 system.

oxidation: adds oxygen to a compound
reduction: adds electrons to a compound
hydrolysis: adds water to a compound to split it apart (usually an ester)


What is the function of a phase 2 reaction? List 5 common substrates.

conjugates (adds on) an endogenous, highly polar, water soluble substrate to the molecule. This results in a water soluble, biologically inactive molecule ready excretion

common substrates:
- glucuronic acid
- glycine
- acetic acid
- sulfuric acid
- methyl group

some drugs do not require preparation by phase I reactions & may proceed directly to phase II reactions


Discuss enterohepatic circulation & list 1 drug example.

some conjugated compounds are excreted in the bile, reactivated in the intestine, and then reabsorbed into the systemic circulation

example: diazepam


What is the extraction ratio?

a measure of how much drug is delivered to a clearing organ vs. how much drug is removed by that organ.

ER of 1.0 means that 100% of the drug delivered to the clearing organ is removed
ER of 0.5 means that 50% of the drug delivered to the clearing organ is removed.

Extraction ratio = (arterial concentration-venous concentration)/arterial concentration


Regarding hepatic clearance, what is flow limited elimination?

flow limited elimination (ER >0.7)
- for a drug w/ high hepatic extraction ratio (>0.7), clearance is dependent on liver blood flow
- HPF greatly exceeds enzymatic activity, so alterations in hepatic enzymes has little effect
- increase in HBF = increased clearance, decrease in HBF = decreased clearance


Regarding hepatic clearance, what is capacity limited elimination?

capacity limited elimination ( ER<0.3)
- for a drug w/ a low hepatic extraction ratio(<0.3), clearance is dependent on the ability of the liver to extract drug from the blood. Changes in hepatic enzyme activity or PB have a profound impact on clearance of these drugs
- changes in the liver's intrinsic ability to remove drug is influenced by the amount of enzyme present.
- enzyme induction --> increased clearance and vice versa


Theophylline has a low hepatic extraction ratio. Which will have a greater effect on it's metabolism: prolonged hypotension or CYP inhibition?

CYP inhibition. Given it's low hepatic ratio, prolonged hypotension will not impact its rate of metabolism to the same degree that CYP inhibition will.


List drugs w/ low, intermediate, and high hepatic extraction ratios.

- roc
- diazepam, lorazepam
- methadone
- theophylline, phenytoin

- midazolam
- vec
- alfentanil
- methohexital

- fentanyl, sufentanil, morphine, meperidine
- naloxone
- ketamine, propofol
- lidocaine, bupivacaine
- metoprolol, propranolol, alprenolol
- nifedipine
- diltiazem, verapamil


Whats the difference b/n a hepatic enzyme inducer & enzyme inhibitor? List examples of each.

inducers: increase clearance, decrease plasma drug level --> dose increases may be required
- tobacco smoke
- barbiturates
- ethanol
- phenytoin
- rifampin
- carbamazepime

inhibitors: decrease clearance, decrease plasma drug levels --> dose decreases may be required
- grapefruit juice
- cimetidine
- omeprazole
- erythromycin
- ketoconazole
- isoniazid


List 2 drug classes & 7 drugs that are metabolized by pseudocholinesterase.

some NMB:
- succinylcholine
- mivacurium

ester LA
- chloroprocaine
- tetracaine
- procaine
- benzocaine
- cocaine


list 6 drugs that are metabolized by non-specific plasma esterases.

atracurium (+ Hoffman)
etomidate (+ hepatic)


list 1 drug that is biotransformed by alkaline phosphatase hydrolysis.

fospropofol (propofol prodrug under the trade name Lusedra)


define pharmacokinetics, pharmacobiophysics, and pharmacodynamics. How do they relate to each other?

pharmacokinetics: "what the body does to the drug." It explains the relationship b/n the dose that you administer and the drug's plasma concentration over time. Affected by absorption, distribution, metabolism, and elimination.

pharmacobiophysics: considers the drug's concentration in the plasma & the effect site (biophase)

pharmacodynamics: "what the drug does to the body." It explains the relationship b/n the effect site concentration and the clinical effect.


What is potency, and how is it measured?

potency = dose required to achieve a given clinical effect
the ED50 & ED90 are measures of potency. They represent the dose required to achieve a given effect in 50% & 90% of the population respectively.


How is potency measured on the dose response curve?

dose response curve:
x axis = log [dose]
y axis = intensity of effect

R shift = more potent


what is efficacy, and how is it measured on the dose response curve?

efficacy is a measure of the intrinsic ability of a drug to produce a clinical effect.

the height of the plateau on the Y axis represents efficacy (higher plateau = greater efficacy)

once the plateau phase is reached, additional drug doesn't produce additional effect, it will only increase the risk of toxicity.


what does the slope of the dose response curve tell you?

how many of the receptors must be occupied to elicit a clinical effect.

steeper slope = small increase in dose can have profound clinical effect
flatter slope = higher doses are required to increase the clinical effect.


what are the differences b/n a full agonist, partial agonist, antagonist, and inverse agonist?

full agonist: binds a receptor & turns on a specific cellular response

partial agonist: binds a receptor, but is only capable of partially turning on a cellular response (less efficacious)

antagonist: occupies the receptor and prevents agonist binding to it. Doesn't tell the cell to do anything (does not have efficacy)

inverse agonist: binds the receptor & causes an opposite effect to that of an agonist (it has negative efficacy)


What is competitive antagonism? Give an example.

increasing the [agonist] can overcome competitive antagonism

ex: atropine, vecuronium, rocuronium


what is noncompetitive antagonism? give an example.

not reversible (usually covalent binding)
increasing [agonist] cannot overcome noncompetitive antagonism, it can only be overcome by producing new receptors

ex: aspirin & phenoxybenzamine


define ED50

effective dose 50 = dose that produces the expected clinical response in 50% of the population. It is a measure of potency


define LD50

lethal dose 50 = dose that will produce death in 50% of the population


define therapeutic index

helps us determine the safety margin for a desired clinical effect.

TI = LD50/ED50

drug w narrow TI = narrow margin of safety


What is chirality?

division of sterochemistry. Deals w/ molecules that have a center of 3D asymmetry. In biologic systems this type of asymmetric stems from the tetrahedral bonding of C (when C binds to 4 different groups)

molecule w/ 1 chiral C will exist as two enantiomers. The more chiral C in a molecule = more enantiomers created


What is an enantiomer? What is the clinical relevance?

chiral molecules that are non-superimposable mirror images of one another.
different enantiomers can produce different clinical effects. For example, the side effect profile of one enantiomer of a drug can be different from another enantiomer of the same drug


What is a racemic mixture? List some commonly used examples.

A racemic mixture contains 2 enantiomers in equal amounts.
About 1/3 of the drugs we administer are enantiomers, and just about all of these are prepared as racemic mixtures. Common examples: bupivacaine, ketamine, isoflurane, and desflurane (not sevo)


What is the mechanism of action of propofol?

direct GABA-a agonist --> increased Cl- conductance --> neuronal hyperpolarization


What is the dose, onset, duration, and clearance mechanism for propofol?

induction = 1.5-2.5mg/kg
gtt = 25-200mcg/kg/min

onset 30-60sec
duration 5-10min
clearance P450 (liver) + extrahepatic (lungs)


What are the CV & respiratory effects of propofol?

- decreased BP d/t decreased SNS tone & vasodilation
- decreased SVR
- decreased venous tone --> decreased preload
- decreased contractility

- CO2 response curve shift = less sensitive to CO2 --> respiratory depression or apnea
- inhibition of hypoxic ventilatory drive


What are the CNS effects of propofol?

decreased CMRO2
decreased CBF
decreased ICP
decreased IOP
no analgesia
anticonvulsant properties


What is the formulation of propofol? Is there a patient population where this is a problem?

Propofol is prepared as a 1% solution in an emulsion of egg lecithin, soybean oil, and glycerol

probably safe to administer to those allergic to egg, soy, and/or peanuts.


What is propofol infusion syndrome?

contains long chain TGs & an increased long chain TG load impairs oxidative phosphorylation & fatty acid metabolism. This starves cells of oxygen, particularly in cardiac and skeletal muscle. Associated w/ a high mortality rate.


What are the risk factors for propofol infusion syndrome?

dose >4mg/kg/hr (67mcg/kg/min)
duration >48hrs
children >adults
inadequate O2 delivery
significant cerebral injury


What is the clinical presentation of propofol infusion syndrome?

acute refractory bradycardia --> asystole + at least one of:
- metabolic acidosis (bse deficit >10)
- rhabdomyolysis
- enlarged or fatty liver
- renal failure


When must a propofol syringe be discarded? How about an infusion?

syringe = 6hrs
infusion = 12hrs

propofol supports bacterial & fungal growth; use strict aspectic technique


What preservatives are used in brand & generic propofol? What patient populations are at risk?

Diprivan (branded propofol), contains EDTA (disodium ethylenediamine tetraacetic acid) as a preservative. It's not a problem for any specific patient population

generic formulations contain different preservatives:
- metabisulfate can precipitate bronchospasm in asthmatics
- benzyl alcohol should be avoided in infants (few case reports of toxicity & death)


How can propofol injection pain be minimized?

injecting into larger & more proximal vein
giving an opioid prior to propofol


Discuss the antipruritic effects of propofol.

10mg IV can reduce itching by spinal opioids & cholestasis


Discuss the antipruritic & antiemetic effects of propofol.

10-20mg IV can be used to treat PONV. An infusion of 10mcg/kg/min can also be used


How is fospropofol converted to its active form?

alkaline phosphatase converts fospropofol to propofol
- explains why it has a slower onset (5-13min) & longer DOA (15-45min) than propofol
- another byproduct is formaldehyde & phosphate


What is the mechanism of action for ketamine?

NMDA receptor antagonist (antagonizes glutamate)
- secondary receptor targets: opioid, MAO, serotonin, NE, muscarinic, Na+ channels
- ketamine dissociates the thalamus (sensory) from the limbic (awareness)


What are the potential routes of administration for ketamine? Include the doses for each.

IV: 1-2mg/kg induction, 0.1-0.5mg/kg analgesia

IM: 4-8mg/kg

PO: 10mg/kg


What is the onset, duration, and clearance mechanism for ketamine?

- IV 30-60sec
- IM 2-4min
- PO variable

DOA 10-20mins

clearance (CYP450)
- produces active metabolite: norketamine w/ 1/3-1/5 potency
- chronic ketamine use induces liver enzymes


What are the CV effects of ketamine?

increased SNS tone
increased CO
increased HR
increased SVR & PVR
subhypnotic doses (<0.5mg/kg don't activate SNS)

ketamine is actually a myocardial depressant. The CV effects above require an intact SNS


What are the respiratory effects of ketamine?

upper airway m tone & airway reflexes remain intact
maintains respiratory drive
- although a brief period of apnea may occur post induction
doesn't significantly shift CO2 response curve
increased oral & pulmonary secretions
- increased risk of laryngospasm


What are the CNS effects of ketamine?

increased CMRO2
increased CBF
increased ICP, IOP
increased EEG activity (caution w/ sz)
emergence delirium


Discuss ketamine & emergence delirium (presentation, tx, risk factors)

presents as nightmares & hallucinations (persists for up to 24hrs)
benzos = most effective way to prevent (midaz>diaz)
- age >15yrs
- female gender
- ketamine dose >2mg/kg
- hx of personality disorder


Discuss the analgesic properties of ketamine.

good analgesia & opioid-sparing effect (the only induction agent that does this)
- relieves somatic pain > visceral pain
- blocks central sensitization & wind up in the dorsal horn of the SC
- prevents opioid-induced hyperalgesia (after remifentanil infusion)
- is good for burn pts & those w/ pre-existing chronic pain syndromes


What is the dose, onset, duration, and clearance mechanism for etomidate?

dose: 0.2-0.4mg/kg IV
onset: 30-60sec
DOA: 5-15min
clearance: CYP450 & plasma esterases


What are the CV & respiratory effects of etomidate?

- key benefit = CV stability (minimal change in HR, SV, CO)
- SVR is decreased = small BP decrease
- doesn't block SNS response to DL (use opioid or esmolol)

- mild resp depression (less than propofol & barbiturates)


What are the CNS effects of etomidate?

decreased CMRO2
decreased CBF (cerebral vasoconstriction)
decreased ICP
stable CPP
no anlagesia


What is the relationship b/n etomidate and myoclonus?

myoclonus = involuntary skeletal muscle contractions, dystonia, or tremor

exact mechanism is unclear, it is likely d/t an imbalance b/n excitatory & inhibitory pathways in the thalamocortical tract. It is NOT a seizure


What is the relationship b/n etomidate & sz activity?

if the pt doesn't have a hx of sz, then etomidate doesn't increase the risk

if pt has hx of sz, etomidate can increase epileptiform (sz-like) activity & possibly increase the risk of sz


What is the relationship b/n adrenocortical suppression & etomidate?

cortisol & aldosterone synthesis are dependent on the enzyme 11-beta-hydroxylase (in the adrenal medulla)
- etomidate inhibits 11-B-hydroxylase & 17-alpha-hydroxylase
- single dose suppresses adrenocortical function x5-8hrs, up to 24hrs
- avoid etomidate in those reliant on the intrinsic stress response
- etomidate may increase mortality, esp in those w/ sepsis


Which induction agent is most likely to cause PONV?

etomidate, up to 30-40%


What are the two subclasses of barbiturates? List examples of each.

Thiobarbiturates (those w/ a sulfur molecule in the 2nd position - increases lipid solubility & potency)
- thiamylal

Oxybarbiturates (those w/ an oxygen molecule in the 2nd position)
- methohexital
- pentobarbital


What is the mechanism of action for thiopental?

GABA-A agonist --> depresses the RAS in the brainstem

low/normal dose = increases affinity of GABA for its binding site
high dose = directly stimulates the GABA-A receptor


What is the dose, onset, duration, and clearance mechanism for thiopental?

adult = 2.5-5mg/kg
child = 5-6mg/kg

onset 30-60sec
DOA 5-10min
clearance CYP450
- awakening is determined by redistribution
- repeated doses = tissue accumulation = prolonged wake up & hangover effect


What are the CV & respiratory effects of TPL?

- hypotension d/t venodilation & decreased preload; myocardial depression is a secondary cause
- causes non-immunogenic histamine release that contributes to hypotension (short-lived)
- preserves baroreceptor reflex --> reflex tachycardia helps to maintain CO
- less hypotension c/w propofol

- resp depression (CO2 response curve shift)
- histamine release can cause bronchoconstriction


What are the CNS effects of TPL?

decreased CMRO2
decreased CBF
decreased ICP
decreased EEG activity (can cause burst suppression/isoelectric EEG; neuroprotective)
no analgesia (low dose may increase the perception of pain)


In what circumstances can TPL be used for neuroprotection?

focal ischemia: yes (i.e. CEA, temporary occlusion of cerebral arteries)

global ischemia: no (i.e. cardiac arrest)


Discuss the pathophysiology of acute intermittent porphyria

heme is a key component of hemoglobin, myoglobin, and the CYP450 enzymes. Porphyria is caused by a defect in heme synthesis that promotes the accumulation of heme precursors (ALA induction)

succinylCoA+glycine --> ALA synthase --> precurors --> heme

the porphyrias can be classified as acute or cutaneous. Acute is the most common & dangerous type


What drugs should be avoided w/ acute intermittent porphyria and why?

any drug that induces ALA synthase will accelerate the production of heme precursors

drugs to avoid:
- barbiturates
- etomidate
- glucocorticoids
- hydralazine

conditions to avoid
- emotional stress
- prolonged NPO status


What is the treatment for acute intermittent porphyria?

liberal hydration
glucose supplementation (reduces ALA synthase activity)
heme arginate (reduces ALA synthase activity)
prevention of hypothermia


What is the risk of intra-arterial injection of TPL? What is the treatment?

--> intense vasoconstriction & crystal formation (occludes blood flow) & inflammation --> tissue necrosis

tx: injection of vasodilator (phentolamine or phenoxybenzamine)
sympathectomy: stellate ganglion or brachial plexus block


What induction agent is the gold standard for ECT? Why?

methohexital: it decreases the sz threshold and produces a better quality seizure

induction dose: 1-1.5mg/kg


What is the mechanism of action for dexmedetomidine?

alpha2 agonist --> decreased cAMP --> inhibits the locus coeruleus in the pons (sedation)


What is the dose, onset, duration, and clearance mechanism for dexmedetomidine?

loading = 1mcg/kg over 10mins
gtt = 0.4-0.7mcg/kg/hr

onset 10-20mins
DOA 10-30mins (after gtt stopped)
clearance CYP450


What are the CV effects of dexmedetomidine?

most common = bradycardia & hypotension

rapid administration can cause HTN (a2 stim in the vasculature --> temporary vasoconstriction --> HTN)
- this effect is usually short lived


Why is dexmedetomidine attractive for procedural sedation?

it doesn't cause respiratory depression
- no change in oxygenation
- no change in blood pH
- no change in the slope of the CO2 response curve


What are the CNS effects of dexmedetomidine?

produces sedation that resembles natural sleep
- sedation is the result of decreased SNS tone & decreased level of arousal
- patients are easily aroused
- doesn't provide reliable amnesia

other CNS effects:
- decreased CBF
- no change in CMRO2
- no change in ICP


How does dexmedetomidine produce analgesia?

via alpha2 stim in the dorsal horn of the SC (--> decreased substance P & glutamate release)


Aside from IV, what other routes can dexmedetomidine be administered? What is the dose?

nasal & buccal routes have a high degree of bioavailability (useful for pre-op sedation in children)

3-4mcg/kg 1hr pre-op


Midazolam contains an imidazole ring. How does this affect it's solubility?

the ring can assume the open or closed position depending on the environmental pH

acidic pH --> ring opens --> increased water solubility
physiologic pH --> ring closes --> increased lipid solubility

versed is water soluble in the vial, and thus doesn't require a solvent such as propylene glycol (like diazepam & lorazepam do)


What is the mechanism of action for midazolam?

GABA-A agonist --> increased frequency of channel opening --> neuronal hyperpolarization

note that most GABA-A agonists increase channel open time, but benzos increase the open frequency


What are the IV & PO doses for midazolam? Why are they different?

IV sedation: 0.01-0.1mg/kg
IV induction: 0.1-0.4mg/kg

PO sedation in children: 0.5-1mg/kg
PO bioavailablility = 50% d/t the significant first pass metabolism


Which induction agents produce an active metabolite?

always think about active metabolites when a patient has kidney or liver dysfunction or with prolonged administration

midazolam: 1-hydroxymidazolman (50% potency)
ketamine: norketamine (33-50% potency)
fospropofol: propofol

propofol, etomidate, and dexmedetomidine do not produce active metabolites


What are the CV & resp effects of midazolam?

sedation dose = minimal
induction dose = decreased BP & SVR

sedation dose = minimal
induction dose = resp depression
opioids potentiate the resp depressant effects
those w/ COPD are more sensitive to the resp depressant effects


What are the CNS effects of midazolam?

sedation dose: minimal effects on CMRO2 & CBF
induction dose: decreased CMRO2 & CBF
cannot produce isoelectric EEG (like propofol & TPL can)

anterograde amnesia (not retrograde)
spinally mediated skeletal m relaxation
no analgesia


What is the reversal agent for benzodiazepines? How does it work?

flumazenil is a competitive antagonist of the GABA-A recepotr.
- has high affinity, but short DOA (30-60mins)
- repeat dosing may be necessary to prevent resedation
- the initial dose 0.2mg IV , titrated in 0.1mg increments Q1min


What are the potential side effects of flumazenil?

unlike post-op opioid reversal w/ naloxone (which can cause a profound increase in SNS tone), post-op benzo reversal does NOT increase SNS tone, anxiety, or neuroendocrine evidence of stress

in benzo-dependent pts, flumazenil reversal can precipitate signs of withdrawal, including sz


How can you tell the difference b/n the chemical structures of the halogenated agents?

count the halogens

iso = 5 Fl & 1 Cl
des = 6 Fl
sevo = 7 Fl


How does fluorination affect the physiochemical characteristics of halogenated anesthetics?

adding fluoride ions tends to:
decrease potency
increase VP
increase resistance to biotransformation

even though sevo is heavily fluorinated, it's approx 3x as potent as des; most likely this is d/t the bulky propyl side chain


What is VP & how is it affected by the ambient temperature?

VP is the pressure exerted by a vapor in equilibrium w/ its liquid or solid phase inside of a closed container

VP is directly proportional to temperature (increased temp --> increased VP)


How is anesthetic delivery affected by altitude? When does this matter?

For this to make sense, you need to know that the depth of anesthesia is determined by the partial pressure of anesthetic agent in the brain: not the volumes percent

partial pressure = vol% x total gas pressure

as atmospheric pressure decreases at higher elevations, the vol% of gas remains the same, but partial pressure decreases --> there is a risk of underdosing the anesthetic agent

- not a problem for sevo/iso since the variable bypass vaporizer automatically compensates for elevation change
- des: tec6 doesn't compensate for elevation


What are the VP of sevo, des, iso, and N2O?

sevo 157mmHg
des 669mmHg
iso 237mmHg
N2O 38770mmHg


Which inhalation anesthetics are stable in soda lime? What byproducts can each agent produce in soda lime?

sevo: not stable --> compound A (more production in dessicated soda lime)

des: not stable --> CO (only if dessicated)

iso: not stable --> CO (only if dessicated)

N2O: stable


What is solubility, and how do we measure it?

solubility is the tendency of a solute to dissolve into a solvent. In the case of IA, it's the ability of the anesthetic agent to dissolve in blood & tissues.

blood: gas partition coefficent describes the relative solubility of an IA in the blood vs. in teh alveolar gas when the partial pressures b/n the 2 compartments are equal


What is the blood:gas solubility for sevo, des, iso, and N2O?

sevo = 0.65
des = 0.42
iso = 1.45
N2O = 0.46


How do we establish an anesthetic concentration inside the alveolus?

1. turning vaporizer on: produces concentration gradient b/n vaporizer & alveoli (Fi)
2. ventilation washes the anesthetic agent into the alveoli (FA)
3. buildup of anesthetic partial pressure inside the alveoli is opposed by continuous uptake of agent into the blood (uptake)
4. CO distributes the anesthetic agent throughout the body (distribution)


What does the FA/Fi curve tell us? How does anesthetic solubility affect the FA/Fi curve for each agent?

allows us to predict the speed of induction

low solubility = less uptake into the blood = increased rate of rise, faster equilibration of FA/Fi (faster onset)

high solubility = high uptake into the blood = decreased rate of rise, slower equilibration of FA/Fi (slower onset)


What factors affect agent delivery to and removal from the alveoli?

determinants of delivery:
- setting on the vaporizer
- time constant of the delivery system
- anatomic dead space
- alveolar ventilation
- functional residual capacity

determinants of uptake:
- solubility of anesthetic in the blood (blood:gas partition coefficient)
- CO
- partial pressure gradient b/n the alveolar gas & the mixed venous blood


What conditions increase FA/Fi? What conditions decrease it?

For FA/Fi to increase, there must be greater wash in and/or reduced uptake.
- high FGF
- high alveolar ventilation
- low FRC
- low time constant
- low anatomic dead space
- low solubility
- low CO
- low Pa-Pv difference

For FA/Fi to decrease, there must be a reduced wash in and/or increased uptake.
- low FGF
- low alveolar ventilation
- high FRC
- high time constant
- high anatomic dead space
- high solubility
- high CO
- high Pa-Pv difference


In which patient will the onset of sevo be the fastest? Pt A has HR 55 w/ SV 100. Pt B has HR 60 w/ SV 85.
Assume all other factors are equal.

Patient B.

Anesthetic uptake is proportional to CO. Additionally, a high CO removes more anesthetic agent from the alveoli, so it slows the rate of rise of FA/Fi (i.e. slows induction)

Pt A has CO 5.5 & Pt B has CO 5.1


What are the 4 tissue groups? How much CO does each receive?

1. vessel rich group (75% of CO, 10% body mass)
2. muscle & skin (20% of CO, 50% of body mass)
3. fat (5% of CO, 20% of body mass)
4. vessel poor group (<1% of CO, 20% of body mass)


How are IA removed from the body? For each agent, what percent is attributed to hepatic metabolism?

removed from the body in three ways:
- elimination from alveoli (most important)
- hepatic biotransformation
- percutaneous loss (minimal)

hepatic biotransformation:
N2O 0.004%
Des 0.02%
Iso 0.2%
Sevo 2-5%


Discuss the FDA recommendations for the minimum FGF for sevo. What is a MAC hour?

compound A is a halogenated vinylic ether associated w/ renal tubular necrosis in rates (no supporting evidence that this complication occurs in humans).
Even so, FDA recommends a minimum FGF of 1L/min for up to 2 MAC hrs & 2L/min after 2 MAC hurs


What is a MAC hour?

1 MAC hour equals:
1% sevo x2hrs
2% sevo x1hr
4% sevo x30mins


Which IA are metabolized to trifluoroacetic acid? What is a potential consequence of this?

Up to 40% of halothane undergoes hepatic biotransformation, and a high concentration of TFA in the liver is the mechanism for halothane hepatitis.

Although des & iso undergo a much smaller degree of hepatic biotransformation, there remains a very minute possibility that TFA could precipitate an immune mediated hepatic dysfunction, especially in a patient w/ previous TFA exposure


What are the theoretical consequences of sevo metabolism?

not metabolized to TFA, but its biotransformation does result in the liberation of inorganic Fl-

theoretical concerns of Fl- induced high output renal failure (no solid human evidence for this.
s/s: polyuria, hypernatremia, hyperosm, increased plasma creatinine, inability to concentrate urine


What is the concentration effect?

describes an increased rate of alveolar uptake as the concentration of a gas is increased. This is a function of 2 mechanisms:
1. concentrating effect - N2O transfer from alveolus to pulmonary blood is much higher than the amount of N2 moving in the opposite direction, causing the alveolus to shrink = a relative increase in FA
2. augmented gas inflow - on the subsequent breath, the concentrating effect causes an increased inflow of tracheal gas containing anesthetic agent to replace the lost alveolar volume. THis increases alveolar ventilation & augments FA


When compared to N2O, des has a lower blood-gas partition coefficient. Why does the FA/Fi ratio for N2O rise faster than des?

the concentration effect explains this phenomenon

despite a slightly higher blood/gas partition coefficent, the alveolar partial pressure of N2O rises faster than des. This is because we can safely deliver a much higher inspiratory concentration, and this negates the small difference imposed by the slightly higher blood/gas partition coefficient.


Anesthetic overpressure results in a more profound effect for agents w/ a (higher or lower) blood solubility?

Higher blood solubility.

The concentration effect says that an anesthetic's onset of action is directly proportional to the concentration of inhalation anesthetic delivered to the alveolus. When applied to the halogenated anesthetics (not N2O), overpressure will have a more profound effect w/ agents of higher blood solubility. Said another way, we can offset the effects of a higher blood solubility by increasing the inspired concentration on the vaporizer. It helps us reach FA/Fi equilibration faster.


How does N2O affect the uptake of a halogenated anesthetic during induction? What's this called?

hastens the onset of the second gas

called the second gas effect


explain diffusion hypoxia.

risk during emergence

N2O moves from body toward lungs --> dilutes alveolar CO2 & O2 --> decreased respiratory drive & hypoxia

can be prevented by administering 100% O2 for 3-5mins after the N2O has been turned off.


Which inhalation anesthetics are most greatly affected by a right to left shunt?

In the presence of a right to left shunt, the FA/Fi of an agent w/ lower solubility (des) will be more affected than one with a higher solubility (iso)


Which inhalation anesthetics are most greatly affected by a left to right shunt?

doesn't have a meaningful effect on anesthetic uptake or induction time.


Why does N2O accumulate in closed air spaces?

N2O is 34x more soluble than N2, meaning it will enter a space 34x faster than N2 can leave


How does N2O affect a patient w/ an ocular gas bubble? When can N2O be used in these patients?

N2O can expand the SF6 bubble, compromise retinal perfusion, and cause permanent blindness
- d/c N2O 15mins before the bubble is placed
- avoid N2O x7-10 days after bubble is placed

alternatives to SF6 & when to avoid N2O
- air: 5 days
- perfluoropropane: 30 days
- silicone oil: no contraindications to N2O


What is the relationship b/n N2O & anesthesia equipment?

N2O can increase the volume & pressure in:
- ETT cuff
- LMA cuff
- balloon-tipped PA cath

the most reliable way to check the internal pressure of the ETT or LMA cuff is to attach a manometer to the pilot balloon. Palpation is grossly inaccurate.


How do we quantify anesthetic potency? What is the value for each IA?

MAC (same thing as ED50)

iso 1.2
sevo 2.0
des 6.6
N2O 104


What are MAC-bar and MAC-awake?

MAC-bar: alveolar concentration required to block the autonomic response after a supramaximal painful stimulus (approx 1.5MAC)

MAC-awake: alveolar concentration at which a patient opens his/her eyes. This shows hysteresis in that MAC awake is approx 0.4-0.5 during induction, but during recovery is as low as 0.15 MAC


What factors increase MAC?

- chronic EtOH
- acute amphetamine or cocaine intoxication
- ephedrine
- levodopa

- hypernatremia

- increased in infants 1-6mo
- sevo is the same for neonates & infants


other: red hair


What factors decrease MAC?

- acute alcohol intoxication
- IV anesthetics, opioids
- N2O
- alpha2 agonists
- lithium
- lidocaine
- hydroxyzine

- hyponatremia

- older age (decrease 6% per decade after 40)
- prematurity


- hypotension (MAP <50)
- hypoxia
- anemia (<4.3mL O2/dL)
- metabolic acidosis
- hypoosmolariy
- pregnancy --> postpartum
- PaCO2 >95


What factors do not affect MAC?

electrolyes: K+ or Mg++ alterations

- hyper or hypothyroidism
- gender
- PaCO2 15-95mmHg


How do hyper & hypothyroidism affect MAC? Why?

do not directly affect MAC, however, changes in CO associated w/ these conditions may affect anesthetic uptake & subsequent onset of action.

For example, profoundly hypothyroid pts have a reduced CO --> decreased uptake into the blood --> faster rate of rise of FA/Fi. Bc of these, they are more susceptible to anesthetic overdose.


What is the Meyer-Overton rule?

that lipid solubility is directly proportional to the potency of an inhaled anesthetic. This theory implies that depth of anesthesia is determined by the number of anesthetic molecules that are dissolved in the brain.


What is the unitary hypothesis?

that all anesthetics share a similar mechanism of action, although each may work at a different site.


What is the most important site of halogenated anesthetic action in the brain?

GABA-A receptor (ligand-gated Cl- channel)

Stimulation of this receptor increases Cl- influx & hyperpolarizes neurons. This impairs neurotransmission.

IA most likely increase the duration that the Cl- channel remains open.


How do halogenated anesthetics produce immobilty?

in the SC, IA produce immobility in the ventral horn.


Which cerebral receptors are stimulated by N2O?

NMDA (antagonism)
K+ 2P-channel (agonism)

doesn't stimulate the GABA-A receptor


In which regions of the brain do halogenated anesthetics produce unconsciousness?

cerebral cortex
reticular activating system


In which regions of the brain do halogenated anesthetics produce amnesia?



In which regions of the brain do halogenated anesthetics produce autonomic modulation?



How do halogenated agents reduce blood pressure?

decrease MAP in a dose dependent fashion. At equivalent doses, there is little different b/n agents.

primary cause = decrease intracellular Ca++ in vascular smooth m --> systemic vasodilation --> decreased SVR & venous return

secondary cause = decrease intracellular Ca++ in myocyte --> myocardial depression --> decreased inotropy


How do halogenated anesthetics affect HR?

directly affect cardiac conduction in a dose dependent fashion (in several ways):
- decrease SA node automaticity
- decreased conduction velocity via AV node, His-Purkinje system, & ventriculare pathways.
- increased duration of myocardial repolarization by impairing the outward K+ current
- altered baroreceptor function


Why do des & iso sometimes increase HR?

most likely d/t SNS activation & respiratory irritation

rapid increases in des & to a lesser degree, iso, cause tachycardia. pulmonary irritation --> SNS activation --> increased norepi release --> beta1 stim

tachycardia can be minimized w/ opioids, alpha2 agonists, or b1 agonists


What is the relationship b/n iso & coronary steal?

iso is the most potent coronary artery dilator.

This gave rise to the fear that iso may cause coronary steal syndrome. The underlying principle is that atherosclerotic vessels cannot dilate, while normal vessels can --> preferentially diverts blood away from areas of higher resistance.

This is more of a textbook thing than a real world problem.


How does N2O (by itself) affect hemodynamics?

activates SNS --> increase in MAP as a function of increased SVR. CVP & RAP may increase.

N2O is also a myocardial depressant, but the increased SNS stimulation outweights the physiologic consequences of this.
- myocardial depression is more likely when N2O is used w/ an opioid.


How do halogenated anesthetics contribute to hypercarbia?

dose dependent depression of the central chemoreceptor & the respiratory muscles. This contributes to hypercarbia.
Mechanisms include:
- altering the respiratory pattern (decreased Vt & increased rr --> increased dead space)
- impairing the response to CO2
- impaired motor neuron output & muscle tone to upper airway & thoracic muscles


How do halogenated anesthetics affect cerebral metabolic rate?

CMRO2 is a function of:
- electrical activity (60%)
- cellular homeostasis (40%)

IA reduce CMRO2, but only to the extent that they reduce electrical acitivity. Once the brain is isoelectric, IA cannot reduce CMRO2 any further.
- isoelectricity on EEG occurs at 1.5-2MAC


Compare & contrast the effects of IA & N2O on CBF.

the brain matches BF w/ it's metabolic requirement.
- when metabolic demand increases, blood vessels dilate (decreased cerebrovascular resistance)
- when metabolic demand decreases, blood vessels constrict (increased cerebrovascular resistance)

IA uncouple this relationship. CMRO2 decreases & CBF increases --> increased ICP

N2O is different. It increases CMRO2 & CBF appropriately


How do halogenated anesthetics affect evoked potentials? How about N2O?

des, iso, & sevo produce a dose dependent effect on evoked potentials. They:
- decresae amplitude
- increase latency

The addition of N2O to a halogenated anesthetic agent can lead to a more profound amplitude reduction; therefore it shouldn't be used during evoked potential monitoring.


Which type of evoked potential is most sensitive to the effects of IA? Which is the most resistant?

sensitivity ranking:
- visual = most sensitive
- brainstem = most resistance
- SSEP & MEP are somewhere in between


What is the relationship b/n N2O & bone marrow suppression?

N2O inhibits methionine synthase & folate metabolism --> can cause megaloblastic anemia