Pharmacology 1 Flashcards
(170 cards)
1
Q
Define volume of distribution, and recite the equation.
A
The volume of distribution (Vd) describes the relationship between a drug’s plasma concentration following a specific dose. It is a theoretical measure of how a drug distributes throughout the body.
Vd= Amount of drug/ desired plasma concentration
Vd assumes two things:
* the drug distributes instantaneously (full equilibration occurs at t=0)
* the drug is not subjected to biotransformation or elimination before it fully distributes
2
Q
What are the implications when a drug’s Vd exceeds TBW? What if Vd is less than TBW?
A
If Vd> TBW (>0.6 L/kg or >42L) the drug is assumed to be lipophilic.
* It distributes into TBW + Fat
* It will require a higher dose to achieve a given plasma concentration
* examples: propofol and fentanyl
If Vd< TBW (0.6 L/kg or <42L), the drug is assumed to be hydrophilic:
* it distributes into some or all of the body water, but it does not distribute into fat.
* it will require a lower dose to achieve a given plasma concentration
* examples: NMBs (ECF), albumin (Plasma)
3
Q
How do you calculate the loading dose for an IV medication? How about a PO medication?
A
Loading dose = (Vd x desired plasma concentration)/ bioavailability
For an IV drug, the bioavailability is always 1. This is because all of the drug enters the bloodstream.
A drug administration by any other route may not be absorbed completely and/or it may be subject to first-pass metabolism in the liver. These conditions reduce bioavailability and explain why the dose that achieves a given plasma concentration is dependent on the route of administration. Therefore, bioavailability will be less than 1.
4
Q
what is clearance? What factors increase/decrease it?
A
Clearance is the volume of plasma that is cleared of a drug per unit time.
CL is directly proportional to: blood flow to cleaning organ, extraction ratio, drug dose
CL is inversely proportional to : Half-life, drug concentration in the central compartment
5
Q
What is steady state?
A
Steady state occurs when the amount of drug entering the body is equivalent to the amount of drug 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
(SS) rate of administration = Rate of elimination
SS is achieved after 5 half-lives
6
Q
Compare and contrast the alpha- and beta distribution phases on the plasma concentration curve
A
the plasma concentration curve graphically depicts the biphasic decrease of a drug’s plasma concentration following rapid IV bolus.
Alpha distribution phase:
* describes drug distribution from the plasma to the tissues
Beta distribution phase:
* begins as plasma concentration falls bellow tissue concentration
*the concentration gradient reverses, which causes the drug to re-enter the plasma
* the beta phase describes drug elimination from the central compartment
7
Q
You have administered esmolol to a pt after a sudden (and profound) elevation in heart rate. After three half-lives, what percentage of you initial dose remains in the patients blood stream?
A
12.5% of the drug remains
Half-time amount eliminated amt remaining
0 0 100
1 50 50
2 75 25
3 87.5 12.5
4 93.75 6.25
5 96.875 3.125
8
Q
What is context sensitive half-time?
A
the problem with half-life is that they do NOT consider time.
the context-sensitive half-time solves this problem. It is the time required for the plasma concentration to decline by 50% after discontinuing the drug.
9
Q
Discuss the context sensitive half-times of fentanyl, afentanil, sufentanil, ad remifetanil. Which has the longest? which has the shortest? why?
A
The context-sensitive half-time for a fentanyl infusion increases as a function of how long it was infused. An extended infusion of fentanyl had more time to fill up the peripheral compartments; therefore, more fentanyl has to be eliminated, and it will have a longer elimination half-time. This is also true for alfentanil and sufentanil to lesser degrees.
Remifentanil is an exception. Even though hit is highly lipophilic, it is quickly metabolized by plasma esterases. It also has a similar context- sensitive half-time regardless of how long it is infused
10
Q
What is the difference between a strong and weak acid or base?
A
the difference is the degree of ionization:
*if you put a strong acid or a strong base in water, it will ionize completely.
* if you put a weak acid or a weak base in water, a fraction of it will be ionized, and the remaining fraction will be unionized
an acid is a substance that donates a proton
a base is a substance that accepts a proton
11
Q
what is ionization? What 2 factors determine how much a molecule will ionize?
A
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
12
Q
finish this sentence: when pKa and pH are the same..
A
50% of the drug is ionized, and 50% is non-ionized
13
Q
comparing ionized vs non-ionized
A
Ionized: hydrophillic/lipophobic, not active, renal elimination, does not cross BBB/GI tract/placenta
Non-ionized: lipophilic/hydrophobic, active, hepatic biotransformation, does cross BBB/GI tract/ placenta
14
Q
Can you tell if a drug is an acid or a base by looking at its name? how?
A
most drugs are weak acids or weak bases. They are usually prepared as a salt that dissociates in solution.
A weak acid is paired with a positive ion such as sodium, calcium, or magnesium.
* example: sodium thiopental
A weak base is paired with a negative ion such as chloride or sulfate.
Example: lidocaine hydrochloride, morphine sulfate
15
Q
Name the 3 key plasma proteins. Does each bind acidic drugs, basic drugs, or both?
A
Albumin: primarily binds to acidic drugs; however, it also binds to some neutral and basic drugs.
Alpha 1 acid glycoprotein: binds to basic drugs
Beta-globulin: binds to basic drugs
16
Q
What conditions reduce the serum albumin concentration?
A
liver disease
renal disease
old age
malnutrition
pregnancy
17
Q
What conditions affect alpha 1 acid glycoprotein concentration?
A
Increase alpha1- acid glycoprotein concentration:
* surgical stress
* myocardial infarction
* chronic pain
* rheumatoid arthritis
* advanced age
Decreased alpha 1 acid glycoprotein concentrations
* neonates
* pregnancy
18
Q
How do changes in plasma protein binding affect plasma drug concentration?
A
Decreased PP binding -> increased Cp
Increased PP binding-> decreased Cp
19
Q
alcohol is cleared from the body via zero-order kinetics. How will this drug’s rate of elimination change as plasma drug concentration changes?
A
Zero order kinetics describes the situation where there is more drug than enzyme.
Under zero- order kinetics, a constant amount of drug is eliminated per unit time. Said another way, the rate of elimination is independent of plasma drug concentration.
Examples: aspirin, phenytoin, warfarin, heparin, and theophylline
20
Q
What is the function of a phase 1 reaction? list 3 examples.
A
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 of the molecule that will allow phase 2 reaction to take place. Most phase 1 biotransformation are carried out by the P450 system.
There are three phase 1 reactions that you should understand:
Oxidation- removes electrons from a compound
Reduction- Adds electrons to a compound
Hydrolysis: adds water to a compound to split it apart (usually an ester)
21
Q
what is the function of a phase 2 reaction? list 5 common substrates.
A
The phase 2 reaction conjugates (adds on) an endogenous, highly polar, water soluble substrate to the molecule. This results in a water-soluble, biologically inactive molecule ready for excretion.
Typical substrates for conjugation reactions include:
*glucuronic acid
* Glycine
* Acetic acid
* sulfuric acid
* methyl group
Some drugs do not require preparation by phase 1 reactions and many proceed directly to phase 2 reactions
22
Q
Discuss enterohepatic circulation, and list 3 drug examples
A
Enterohepatic circulation- some conjugated compounds are excreted in the bile, reactivated in the intestine, and then reabsorbed into the systemic circulation
Examples: diazepam and warfarin
23
Q
Regarding hepatic clearance, What is perfusion-dependent elimination?
A
For a drug with high hepatic extraction ratio (>0.7), clearance is dependent on liver blood flow.
Hepatic blood flow greatly exceeds enzymatic activity, so alteration in hepatic enzyme activity has little effect.
- increased liver blood flow= Increased clearance
- decreased= decreased
24
Q
regarding hepatic clearance, what is capacity-dependent elimination?
A
For a drug with a low hepatic extraction (<0.3), clearance is dependent on the ability of the liver to extract the drug from the blood. Changes in hepatic enzyme activity or protein binding have a profound impact on the clearance of these drugs.
Since only a small amount of drug is removed per unit time, alteration in liver blood flow minimally affect clearance.
The amount of enzyme present influences changes in the liver’s intrinsic ability to remove the drug from the blood.
Enzyme induction -> increased clearance and vice versa
25
Whats the difference between a hepatic enzyme inducer and enzyme inhibitor? List examples of each.
the P450 system is the most important mechanism of drug biotransformation i the body. In the liver, these enzymes reside in the smooth endoplasmic reticulum.
A unique feature of the P450 system is that exogenous chemicals can influence the expression of these enzymes. This can be significant source of drug interactions.
Enzyme inducer: inducers increase clearance, decrease drug plasma level, dose increase my be required
* examples: tobacco smoke, barbiturates, ethanol, phenytoin (anticonvulsant), rifampin, carbamazepine (anticonvulsant)
Enzyme inhibitors: inhibitors decrease clearance, increase drug plasma level, Dose decrease may be required.
* ex: grapefruit juice, cimetidine, omeprazole, isoniazid, SSRI (citalopram, dapoxetine, sertraline), erythromycin, ketoconazole
26
Whats the difference between a hepatic enzyme inducer and enzyme inhibitor? List examples of each.
the P450 system is the most important mechanism of drug biotransformation i the body. In the liver, these enzymes reside in the smooth endoplasmic reticulum.
A unique feature of the P450 system is that exogenous chemicals can influence the expression of these enzymes. This can be significant source of drug interactions.
Enzyme inducer: inducers increase clearance, decrease drug plasma level, dose increase my be required
* examples: tobacco smoke, barbiturates, ethanol, phenytoin (anticonvulsant), rifampin, carbamazepine (anticonvulsant)
Enzyme inhibitors: inhibitors decrease clearance, increase drug plasma level, Dose decrease may be required.
* ex: grapefruit juice, cimetidine, omeprazole, isoniazid, SSRI (citalopram, dapoxetine, sertraline), erythromycin, ketoconazole
27
List 2 drug classes and 6 drugs that are metabolized by pseudocholinesterase.
Some neuromuscular blockers:
* succinylcholine (depolarizer)
* Mivacurium (nondepolarizer)
Ester-type local anesthetics:
* chloroprocaine
* Tetracaine
* benzocaine
* Cocaine (also metabolized by the liver)
28
List 6 drugs that are metabolized by non-specific plasma esterases.
1. Esmolol
2. Remifentanil
3. Remimazolam
4. clevidipine
5. Atracurium (and hofmann elimination)
6. Etomidate (and hepatic)
29
List 1 drug that is biotransformed by alkaline phosphatase hydrolysis.
Fospropofol (a propfol prodrug under the trade name lusedra)
30
Define Pharmacokinetics, pharmacobiophysics, pharmacodynamics. How do they relate to each other?
Pharmacokinetics: can be thought of as "what the body does to the drug." It explains the relationship between the dose that you administer and the drug's plasma concentration over time. This relationship is affected by absorption, Distribution, metabolism, and elimination.
Pharmacobiophysics: considers the drug's concentration in the plasma and the effect site (biophase)
Pharmacodynamics: can be thought of as "what the drug does to the body." it explains the relationship between the effect site concentration and the clinical effect
31
What is potency and how is it measured?
potency is the dose required to achieve a given clinical effect (x-axis of the dose-response curve)
The ED50 and ED90 are measures of potency. They represent the dose required to achieve effect in 50% and 90% of the population, respectively.
32
How is potency measure on the dose- response curve
Farther left = more potent and lower dose required, higher affinity for receptor
33
What is efficacy, an how it is 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 represent efficacy
high plateau= high efficacy and vice versa
Once the plateau phase is reached, any additional drug does NOT produce an additional effect. Increase dosing will only increase the risk of toxicity.
34
What does the slope of the dose-response curve tell you?
The slope tells us 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
35
what are the differences between a full agonist, partial agonist, antagonist, and inverse agonist?
Full agonist: binds to a receptor and turns on a specific cellular response ( Heroin, oxycodone, methadone, morphine, hydrocodone, opium)
Partial agonist: binds to a receptor, but it is only capable of partially turning on a cellular response. It is less effective that a full agonist. (buprenorphine, butorphanol, and tramadol)
Antagonist: occupies the receptor and prevents an agonist from binding to it. It does not tell the cell to do anything, By definition, it does not have efficacy. (naltrexone and naloxone)
Inverse agonist: binds the the receptor and causes an opposite effect to that of a full agonist. It has negative efficacy.(nalmefene, benzodiazepine, digoxin, propranolol, all antihistamines)
36
What is competitive antagonism? Give an example
Competitive antagonism
* competitive antagonism is reversible
* increasing the concentration of the agonist can overcome competitive antagonism
* examples: atropine, vecuronium, rocuronium
37
What is noncompetitive antagonism? give an example
Noncompetitive antagonism
* noncompetitive antagonism is NOT reversible. The drug binds to a receptor (usually through covalent bonds) and its effect cannot be overcome by increasing the concentration of an agonist.
* only be creating new receptors can the effect of a noncompetitive agonist be reversed. This explains why these drugs have long durations of action.
Examples: aspirin and phenoxybenzamine (antihypertensive for pheochromocytoma)
38
Define therapeutic index
therapeutic index helps us determine the safety margin of a desired clinical effect.
Therapeutic index: Toxic dose 50/effective dose 50
A drug with a narrow TI has a narrow margin of safety and vice versa
39
what is chirality?
Chirality is a division of stereochemistry. It deals with molecules that have a center of three-dimensional asymmetry. in biological systems, this type of asymmetry generally stems from the tetrahedral bonding of carbon- carbon binds to 4 different atoms.
A molecule with 1 chiral carbon will exist as 2 enantiomers. The more chiral carbons in a molecule, the more enantiomers created.
40
What is an enantiomer? What is the clinical relevance?
Enantiomers are chiral molecules that are non-superimposable mirror images of one another.
Different enantiomers can produce other clinical effects. For example: the side effect profile of one enantiomer of a drug can be different from another enantiomer of the same drug
41
What is a racemic mixture? List some commonly used examples.
A racemic mixture contains 2 enantiomers in equal amounts
About one-third of the drugs we administer are enantiomers, and just about all of these medications are racemic mixtures. Common examples include Bupivacaine, ketamine, isoflurane, and desflurane (not sevo)
42
MOA of propofol
Direct GABA- A agonist-> increased Cl- conductance-> neuronal hyperpolarization (prevent action potential)
43
What is the dose, onset, duration, and clearance mechanism of propofol?
Dose:
* induction: 1.5-2.5 mg/kg IV
* infusion: 25-200mcg/kg/min
Onset: 30-60seconds
duration: 5-10 min
Clearance: liver (P450 enzymes)+ extrahepatic metabolism (lungs)
44
What are the cardiovascular and respiratory effects of propofol?
Cardiovascular effects:
* decreased BP (due to decreased SNS tone and vasodilation
* decreased SVR
* decreased Venous tone-> decreased peload
* decreased myocardial contractility
Respiratory effects:
* shifts CO2 curve down and to the right (less sensitive to CO2)-> respiratory depression and/or apnea
* Inhibits hypoxic ventilatory drive
45
what are the CNS effects of propofol?
CNS effects:
* decreased cerebral oxygen consumption (CRMO2)
* decreased cerebral blood flow
* decreased intracranial pressure
*decreased intraocular pressure
* no analgesia
* anticonvulsant properties
46
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
Despite concerns that propofol might precipitate anaphylaxis in pts allergic to egg, soy, and/or peanuts, there is a gross lack of evidence to justify these fears
Most people with egg allergy are allergic to the albumin in egg whites. Egg lecithin is derived from the yolk. There is no good evidence to support cross-sensitivity in egg- allergic patients, and propfol is probably safe to administer to patients with egg allergies
There is no cross-sensitivity between propofol and soy or peanuts.
47
what is propofol infusion syndrome
Propofol contains long chain triglycerides, and an increased LCT load impairs oxidative phosphorylation and fatty acid metabolism. This starves the cells of oxygen, particularly in cardia and skeletal muscle. Propofol infusion syndrome is associated with high mortality rate.
48
what are the risk factors for propofol infusion syndrome
Risk factors:
* propofol dose >4 mg/kg/hr (67mcg/kg/min)
* propofol infusion duration >48 hrs
* adults >children (used to be the other way around)
* inadequate oxygen delivery
* sepsis
* significant cerebral injury
49
What is the clinical presentation of propofol infusion syndrome?
Clinical presentation include acute refractory bradycardia -> asystole + at least one of the following
* metabolic acidosis (base deficit >10mmol/L)
* rhabdomyolysis
* enlarged or fatty liver
* renal failure
* hyperlipidemia
*lipemia (cloudy plasma or blood) may be an early sign
50
what preservatives are used in brand and generic propfol? What patient populations are at risk?
Diprivan (branded propofol) contains EDTA (disodium ethylenediamine tetraacetic acid) as a preservative. Its not a problem for any specific patient population
Generic propofol formulations contain different preservatives, and these can cause unique problems of their own.
* Metabisulfite can precipitate bronchospasm in asthmatic patients.
* Avoid benzyl alcohol in infants. There are a few reports of toxicity and death attributed to the benzyl alcohol preservative when used in other medications
51
How can propofol injection pain be minimized?
Propofol injection pain can be minimized or eliminated by:
* injecting inot a larger and more proximal vein
* lidocaine (before propofol injection or mixed with propofol)
* giving an opioid before the propofol
52
What dose of propofol can be used to treat PONV?
Propofol (10-20 mg IV) can be used to treat PONV
An infusion of 10 mcg/kg/min can also be used
53
how is fospropofol converted to its active form?
Forspropofol is a prodrug, and propofol is the active metabolite. Alkaline phosphatase converts fospropofol to propofol.
This mechanism of action explains why it has a slower onset (5-13 min) and longer duration (15-45 min)
Fospropofol -> converted by alkaline phophatase to propofol + formaldehyde + phosphate
54
What is the primary MOA for anesthesia produced by ketamine?
Ketamine is an NMDA receptor antagonist ( antagonizes glutamate)
* secondary receptor targets include opioid, MAO, serotonin, NE, muscarinic, and Na+ channels
* ketamine dissociates the the thalamus (sensory) from the limbic system (awareness)
55
what are the potential routes of administration for ketamine? Include the doses for each.
IV
* Induction- 1-2 mg/kg
* analgesia =0.1-0.5 mg/kg
IM- 4-8 mg/kg
PO- 10mg/kg
56
What is the onset, duration, and clearance mechanism for ketamine?
Onset:
IV- 30-60 seconds
IM- 2-4 min
PO- variable
Duration- 10-20 min (may vary 60-90 min to return to full orientation)
Clearance: liver (P450 system)
* it produces an active metabolite- norketamine (1/3-1/5 the potency of ketamine)
* chronic ketamine use induces liver enzymes (ex burn pts)
57
What are the cardiovascular effects of ketamine?
Cardiovascular effects:
* Increase SNS tone (useful if the pt is hemodynamically unstable, but harmful if severe CAD)
* increased cardiac output
* increased heart rate
*increased SVR
* increased PVR (caution with RV failure)
* Subhypnotic doses (<0.5 mg/kg) usually don't activate the SNS
Its important to understand that ketamine is actually a myocardial depressant. The cardiovascular effects discussed above require and intact SNS. The myocardial depressant effects are unmasked in patients with depleted catecholamine stores (sepsis) or sympathectomy.
58
What are the respiratory effects of ketamine?
* bronchodilation (a great choice if the patient is actively wheezing)
* upper airway muscle tone and airway reflexes remain intact
* maintains respiratory drive, although a brief period of apnea may occur following induction
* does not significantly shift the CO2 response curve
* increased oral and pulmonary secretions -> increased risk of laryngospasm (glycopyrrolate helps reduce secretions)
59
What are the CNS effects of ketamine
* increased Cerebral Oxygen consumption (CRMO2)
* increased cerebral blood flow
* increased intracranial pressure
* Increased EEG activity (caution if hx of seizure)
* Nystagmus ( caution during ocular surgery that requires a still eye)
* emergence delirium
60
Discuss ketamine emergence delirium (presentation, tx, and risk factors)
Emergence delirium:
* presents as nightmares and hallucinations (risk persists for up to 24 hrs)
* benzodiazepines are the most effective way to prevent emergence delirium (midazolam is better than diazepam)
* risk factors: age >15 yrs, female gender, ketamine dose >3 mg/kg, hx of personality disorder
61
Discuss the analgesic properties of ketamine.
* Provides good analgesia and opioid-sparing effects (the only induction agent that does this)
* relieves somatic pain >visceral pain
* blocks central sensitization and wind-up in the dorsal horn of the spinal cord
* prevents opioid induced hyperalgesia (after remifentanil infusion)
* is excellent for burn pts (frequent dressing changes) and those with preexisting chronic pain syndrome
62
what is the dose, onset, duration, and clearance mechanism for etomidate?
Dose: 0.2 - 0.4mg/kg
Onset: 30-60 seconds
Duration: 5-15min
Clearance: hepatic P450 enzymes +plasma esterases
63
Cardiovascular and respiratory effects of etomidate?
Cardiovascular:
* etomidate's key benefit is hemodynamic stability (minimal change in HR, SV, or CO)
* SVR is decreased, which accounts for a small reduction in BP
* it does not block the SNS response to laryngoscopy. An opioid or esmolol will help.
Respiratory effects:
* mild respiratory depression ( less than propofol and barbiturates)
64
what are the CNS effects of etomidate?
* Decreased cerebral oxygen consumption
* decreased cerebral blood flow (cerebral vasoconstriction)
* Decreased intracranial pressure
* cerebral perfusion pressure remains stable
* no analgesia
65
what is the relationship between etomidate and myoclonus?
myoclonus is involuntary skeletal muscle contractions, dystonia, or tremor
Although the exact mechanism of myoclonus is unclear, it is likely due to an imbalance between excitatory and inhibitory pathways in the thalamocortical tract. It is NOT a seizure.
66
What is the relationship between etomidate and seizure activity?
if the pt does not have a history of seizures, then etomidate does not increase the risk of seizures.
If the pt has a history of seizures, then etomidate can increase epileptiform (seizure-like) activity and possibly increase the risk of seizures. This property can make it useful for mapping seizure foci
67
what is the relationship between adrenocortical suppression and etomidate?
Cortisol and aldosterone synthesis are dependent on the enzyme 11-beta-hydroxylase (located in the adrenal medulla). Some texts also add 17-alpha-hydroxylase.
*etomidate is a known inhibitor of 11-beta-hydroxylase and 17-alpha-hydroxylase
* a single dose of etomidate suppresses adrenocortical function for 5-8 hrs (some books say 24hrs)
* for this reason, avoid etomidate in pts reliant on the intrinsic stress response (sepsis or acute adrenal failure), These pts need all of the cortisol they can muster.
* Mortality may be increased by etomidate, particularly in pts with sepsis.
68
which induction agent is most likely to cause PONV?
etomidate, as high as 30-40%
69
what are the 2 sub-classes of barbiturates? list examples of each
barbiturates are derived from barbituric acid. Substitutions on the ring can modify the PK/PD profile for each drug
Thiobarbiturates:
* there is a sulfur molecule in the second position (increases lipid solubility and potency)
* Examples: Thiopental, Thiamylal (notice the T's)
Oxybarbiturates:
* there is an oxygen molecule in the second position
( Example: methohexital, pentobarbital
70
MOA of thiopental?
GABA-A agonist-> depresses the reticular activating system in the brainstem
* low/normal dose: increases the affinity of GABA for its binding site
* high dose: directly stimulates the GABA-A receptor
71
what is the dose, onset, duration, and clearance mechanism for thiopental?
Dose:
*adult= 2.5-5 mg/kg
* children= 5-6mg/kg
onset= 30-60seconds
duration- 5-10 min
clearance-Liver P450 enzymes
* redistribution (not metabolism) determines awakening
* repeated doses -> tissue accumulation -> prolonged wake up time + hangover effect
72
What are the cardiovascular and respiratory effects of thiopental?
Cardiovascular effects:
* Hypotension is primarily the result of venodilation and decreased preload; myocardial depression is a secondary cause
* thiopental causes non=immunogenic histamine release. This can also contribute to HoTN: however, this effect is short-lived
* the baroreceptor reflex is preserved, so a reflex tachycardia helps restore cardiac output
* compare to propofol, thiopental produces less HoTN
Respiratory effects:
*Respiratory depression (shifts the CO2 response curve to the right)
* histamine release can cause bronchoconstriction (caution with asthma)
73
What are the CNS effects of thiopental?
CNS effects:
* decreased Cerebral oxygen consumption
* Decreased cerebral blood flow (cerebral vasoconstriction)
* Decreased intracranial pressure (used in the treatment of intracranial HTN)
* Decreased EEG activity (can cause burst suppression and/or isoelectric EEG -> neuroprotection)
* no analgesia (low dose may increase the perception of pain)
74
In what circumstances can thiopental be used for neuroprotection?
Focal ischemia: yes (eg. carotid endarterectomy, temporary occlusion of cerebral arteries)
Global ischemia : No (eg. Cardiac arrest)
75
Discuss the pathophysiology of acute intermittent porphyria
Heme is a key component of hemoglobin, myoglobin, and the cytochrome P450 enzymes. Porphyria is caused by a defect in heme synthesis that promotes the accumulation of heme precursors (ALA induction).
Succinyl-coA + glycine-> ALA synthase -> precursors-> heme
The porphyria's can be classified as acute or cutaneous. Acute intermittent porphyria is the most common (and dangerous) type.
76
What drugs should be avoided in the pt with acute intermittent porphyria? why?
Any drug or condition that induces ALA Synthase will accelerate the production of heme precursors and must be avoided in the pt with acute intermittent porphyria
Drugs to avoid:
Barbiturates
Etomidate
Ketamine
Ketorolac
amiodarone
calcium channel blockers (many but not all)
birth control pills
Conditions to avoid: emotional stress, prolonged NPO status
Mnemonic: KEPT MAD (ketamine/ketorolac, Etomidate, pentazocine, thiopental, methohexital, amiodarone, nifeDipine)
77
what is the tx for acute intermittent porphyria?
Liberal hydration
glucose supplementation (reduces ALA synthase activity)
Heme arginate (reduces ALA synthase activity)
Prevention of hypothermia
78
what is the risk of intra-arterial injection of thiopental? what is the tx?
Intra-arterial injection-> intense vasoconstriction + crystal formation (occludes blood flow) + inflammation -> tissue necrosis
tx:
* injection of vasodilator: phentolamine or phenoxybenzamine
* sympathectomy: stellate ganglion block or brachial plexus block
79
what induction agent is the gold standard for electroconvulsive therapy? why?
Methohexital (Brevital) is the gold-standard for ECT. it decreases the seizure threshold and produces a better quality seizure
Induction dose= 1-1.15 mg/kg
80
what is the MOA for dexmedetomidine?
* alpha 2 agonist -> decrease cAMP -> inhibits the locus coeruleus in the pons (sedation)
* analgesia is produced by alpha 2 stimulation in the dorsal horn of the spinal cord ( decreased substance P and decreased glutamate release)
81
what is the dose, onset, duration, and clearance mechanism of precedex?
Dose:
* loading = 1mcg/kg over 10 min
* maintenance = 0.4-0.7 mcg/kg/hr
onset: 10-20 min
Duration: 10-30 min (after infusion stopped)
clearance: liver (P450)
82
what are the cardiovascular effects of dexmedetomidine?
the most common side effects are bradycardia and HoTN.
As an aside, rapid administration of precedex can cause HTN (alpha 2 stimulation in the vasculature-> temporary vasoconstriction-> HTN). This effect is usually short lived
83
why is precedex attractive for procedural sedation?
it does not cause respiratory depression, and this makes it attractive for difficult airway management.
* no change in oxygenation
* no change in blood pH
* no change in the slope of CO2 response curve (there's some evidence to contradict this, but this is answer to use on exam)
84
what are the CNS effects of precedex?
unique because it produces sedation the resembles natural sleep.
* sedation is the result of reduced SNS tone and decreased level of arousal
* pts arouse easily
* it does not provide reliable amnesia
Other CNS effects:
* decreased CBF
* No change in CMRO2
* No change in ICP
85
How does precedex produce analgesia?
analgesia is produced by alpha-2 stimulation in the dorsal horn of the spinal cord (decreased substance P and decreased glutamate release)
86
what other routes can precedex be administered and doses?
the nasal and buccal routes have a high degree of bioavailability. This makes it useful for preoperative sedation in children (3-4mcg.kg 1 hr before surgery)
87
midazolam contains an imidazole ring. How does this affect its solubility?
The imidazole ring can assume an open or closed position depending on the environmental pH
* Acidic pH -> imidaxole ring opens -> increased water solubility
* physiologic pH-> imidazole ring closes -> increased lipid solubility
because Midazolam is water soluble inside the vial, it does not require a solvent such as propylene glycol (diazepam and lorazepam require it)
88
What is the mechanism of action of midazolam?
GABA A agonist -> increase frequency of channel opening -> neuronal hyperpolarization
* most GABA-A agonists increase channel open-time, but benzos increase open FREQUENCY
89
what are the IV and PO doses of midazolam? why are they different?
IV sedation: 0.01-0.1 mg/kg
IV induction: 0.1 - 0.4 mg/kg
PO sedation in children 0.5-1mg/kg
* PO availability is 50% due to significant first pass metabolism
90
Which induction agents produce an active metabolite?
Always think about active metabolites when a pt has kidney or liver dysfunction or with prolonged administration.
* midazolam produces 1-hydroxymidazolam (0.5x potency parent compound)
* ketamine produces norketamine (0.33- 0.5x potency of parent compound)
* Fospropofol produces propofol
* Propofol, etomidate, and dexmedetomidine do not produce active metabolites
91
what are the cardiovascular and respiratory effects of midaxolam?
Cardiovascular effects:
* sedation dose: minimal effects
* induction dose: decrease BP and SVR
Respiratory:
* sedation dose: minimal
*induction dose: resp depression
* opioids potentiate the respiratory depressant effects, even at doses used for sedation
* Patients with COPD are more sensitive to the respiratory depressant effects
92
What are the CNS effects of midazolam?
* Sedation dose: minimal effects on CMRO2 and CBF
* Induction dose: decreased CMRO2, and CBF
( cannot produce isoelectric EEG ( propofol and barbiturates can)
* Anterograde amnesia (not retrograde)
* Anticonvulsant
* Anxiolysis
* Spinally mediated skeletal muscle relaxation (antispasmodic- useful for the pt with cerebral palsy)
* no analgesia
93
what are the unique features of remimazolam?
* its an ultra short acting benzo
* the vial must be protected from light
* a single use vial must be discarded 8hrs after reconstitution
* its metabolized by plasma esterases
* its contraindicated in pts with a history of sever hypersensitivity reaction to dextran 40
94
What is the reversal agent for benzodiazepines? How does it work?
Flumazenil (Romazicon) is a competitive antagonist of the GABA A receptor
* it has a very high affinity, but it has a short duration of action (30-60min)
* for this reason, repeat dosing may be necessary to prevent resedation
* the initial dose is 0.2mg IV and titrated in 0.1mg increments q1min
95
what are the potential side effects of flumazenil?
Unlike postoperative opioid reversal with naloxone (which can cause a profound increase in SNS tone), postoperative benzodiazepine reversal with flumazenil does NOT increase SNS tone, anxiety, or neuroendocrine evidence of stress.
In benzodiazepine-dependent pts (chronic use), flumazenil reversal can precipitate signs of withdrawal, including seizures
96
How does fluorination affect the physiochemical characteristics of halogenated anesthetics?
As a general rule, adding fluoride ions tend to:
* decrease potency
* increase vapor pressure
* Increase resistance to biotransformation
Even though sevoflurane is heavily fluorinated, its about 3x potent as desflurane. This is most likely due to the bulky propyl side chain
97
What is vapor pressure, and how is it affected by the ambient temperature?
Vapor pressure it the pressure exerted by a vapor in equilibrium with its liquid or solid phase inside of a closed container.
* vapor pressure is directly proportional to temperature (increase temp= increase vapor pressure)
98
how is anesthetic delivery affected by altitude? when does this matter?
As atmospheric pressure decreases at higher elevations, the vol% of a gas remains the same; however, the partial pressure of the gas decreases. This risk is under dosing the anesthetic agent (PP determines the depth of anesthesia)
Not a problem with sevo and iso
Des at sea level PP is 45.6mmHg, 1mi above is 37.2mmHG, 18% reduction
99
what are the vapor pressures of Sevo, Des, Iso and N20?
Sevo= 157
Des=669
iso= 238
N20= 38,770
Notice the VPs of the halogenated agents are less than atmospheric pressure. This explains why they exist as liquids. Conversely, the VP of N2O exceeds atmospheric pressure, so it exists as a gas (unless it's compressed in a cylinder, of course)
100
which inhalation anesthetics are stable in soda lime? What byproducts can each agent produce in soda lime?
Sevo: Not stable/Compound A (happens in functional soda lime- worse if soda lime is desiccated)
Des: not stable/ Carbon monoxide (only a problem if soda lime is desiccated), produces the most CO
Iso: Not stable/ Carbon monoxide (only a problem if soda lime is desiccated)
N2O: stable/none
101
What is solubility?
the tendency of a solute to dissolve into a solvent. In the case of inhalation anesthetics, it's the anesthetic agents ability to dissolve into the blood and tissues
The blood:gas partition coefficient
Sevo : 0.65
Des: 0.42
Iso; 1.45
N2O: 0.46
102
what does FA/FI curve tell us? How does anesthetic solubility affect the FA/FI curve for each agent?
The FA/FI curve allows us to predict the speed of induction
* low solubility -> less uptake inot the blood -> increase rate of rise -> faster equilibration of FA/FI-> faster onset
* High solubility -> more uptake into the blood-> decrease rate of rise -> slower equilibration of FA/FI-> slower onset
103
what factors affect agent delivery to an removal from the alveoli?
determinants of delivery:
*Setting on the vaporizer
* time constant of the delivery system
* anatomic dead space
* alveolar ventilation
* FRC
Determinants of uptake:
* Solubility of anesthetic in the blood (blood:gas partition coefficient)
* cardiac output
* partial pressure gradient between the alveolar gas and the mixed venous blood
104
What conditions increase FA/FI? which conditions decrease it?
For FA/FI to increase, there must be greater wash in an/or reduced uptake = faster onset
* higher FGF, Low FRC, low time constant, low anatomic dead space
* reduced uptake: low solubility, low cardiac output, low Pa-Pv difference
For FA/FI to decrease, there must be a reduced wash in an/or an increased uptake = slower onset
Decreased wash in: low FGF, High FRC, High time constant, high Vd
Increased uptake: High solubility, high CO, high Pa-Pv difference
pt with lower CO with have faster induction due to slower uptake
105
How are inhalation anesthetics removed from the body? For each agent, What percent is attributed to hepatic metabolism?
The body elimination inhaled anesthetics in 3 ways:
* elimination from the alveoli (most important)
* hepatic biotransformation
* percutaneous loss (minimal)
Agent Hepatic biotransformation
N2O 0.004
Des 0.02
Iso 0.2
Sevo 2-5
Halothane 20
you should remember this as the rule of 2s (0.02, 0.2, 2, and 20) halogenated agents spell DISH
106
Discuss the minimum FGF requirements for Sevo. What is a MAC hour?
Compound A is a halogenated vinylic ether. While its associated with renal tubular necrosis in rats. there's no supporting evidence that this complication occurs in humans. Even so, the FDA recommends a minimum FGF of 1L/min for up to 2 MAC hours and 2L/min after 2 MAC hours
107
what is a MAC hour?
1 MAC hour equals:
* 1% sevoflurane x 2 hours
* 2% sevo x1 hr
*4% sevo x 30 min
108
What is the concentration effect?
the concentration effect describes an increased rate of alveolar uptake as the concentration of a gas is increase. This is a function of 2 mechanisms:
* Concentrat"ing" effect: when nitrous oxide introduced into the lung, the volume of nitrous oxide going from the alveolus to the pulmonary blood is much higher than the amount of nitrogen moving in the opposite direction. This causes the alveolus to shrink, and the reduction in alveolar volume causes a relative increase in FA
* Augmented gas inflow: on the subsequent breath, the concentrating effect causes an increased inflow of tracheal gas containing the anesthetic agent to replace the lost alveolar volume. This increases alveolar ventilation and augments FA. Alveolar volume restores quickly, so this is only a very temporary phenomenon
109
When compared to nitrous oxide, desflurane has a lower blood-gas partition coefficient. Why does the FA/FI ratio for N2O rise faster than desflurane?
the concentration effect explains this phenomenon.
Despite a slightly higher blood/gas partition coefficient, the alveolar partial pressure of N2O rises faster than desflurane. This is because we can safely deliver a much higher inspiratory concentration, which negates the small difference imposed by the slight higher blood/gas partition coefficient.
110
How does N2O affect the uptake of a halogenated anesthetic during induction? what is this called?
The use of nitrous during anesthetic induction will hasten the onset of a second gas. This is called the second gas effect.
111
Explain diffusional hypoxia
*N2O moves form the body towards the lungs-> dilutes alveolar O2 and CO2 -> decreased respiratory drive and hypoxia
* administering 100% O2 for 3-5 minutes after discontinuing N2O prevents diffusional hypoxia
112
Which inhalation anesthetics are most greatly affected by a right to left shunt?
the FA/FI of an agent with lower solubility (des) will be more affected than an agent of higher solubility (iso)
113
Which inhalation anesthetics are impacted by a left-to right shunt?
none
114
why does N2O accumulate in closed air spaces?
Nitrous oxide is 34x more soluble than nitrogen. This means it will enter a space 34 times faster than nitrogen can exit the space.
* N2O blood: gas partition coefficient =0.46
* Nitrogen blood:gas partition coefficient= 0.014
This can be problematic, because N2O can accumulate in closed air spaces (middle ear, bowel, pneumothorax, brain, air bubbles in the blood, gas bubble in the eye, pneumoperitoneum)
115
How does N2O affect a pt with an ocular gas bubble? When can N2O be used in these pts?
During retinal detachment surgery, a gas bubble is placed over the sit of retinal break. This functions as a "splint" to hold the retina in place while healing occurs. Because nitrous oxide can diffuse into the bubble faster than the other gases in the bubble can move out, nitrous can expand the SF6 bubble, compromise perfusion, and cause permanent blindness.
* discontinue N2O 15 min before placing the SF6 bubble
* avoid N2O for 7-10 days after the SF6 bubble was placed
Alternates to SF6 and when to avoid N2O
* air: 5 days
* perfluoropropane: 30 days
* silicone oil: no contraindications to N2O
116
What is the relationship between N2O and anesthesia equipment?
N2O can increase the volume and pressure in an:
* ETT cuff
* LMA cuff
* balloon-tipped PAC
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 inaccurate.
117
How do we quantify anesthetic potency? what is this value for each inhalation agent?
Minimum alveolar concentration (MAC) is a measure of potency. You can think of it as the same thing as ED 50
drug MAC for 40 yr old% relative potency
iso 1.2 ++++
Sevo 2 +++
Des 6.6 ++
N2O 104 +
118
What are MAC bar and MAC awake?
MAC bar- is the alveolar concentration required to block the autonomic response following a supramaximal painful stimulus. It is around 1.5 MAC
MAC awake: is the alveolar concentration at which a patient opens his or her eyes. This shows hysteresis in that MAC awake is around 0.4-0.5 during induction. But during recovery, MAC-awake is as low as 0.15 MAC
119
What factors increase MAC?
Drugs:
* chronic alcohol consumption
* acute amphetamine intoxication
* acute cocaine intoxication
* MAOIs (isocarboxazid, Phenelzine, Selegiline)
* ephedrine
* levadopa
Electrolytes: Hypernatremia
Age: Increased in infants 1-6 months, Sevo is the same for neonates and infants
Body temp: hyperthermia
Other: Red hair (data is questionable)
120
what factors decrease MAC?
Drugs: Acute alcohol intoxication
* IV anesthetics
* N2O
* Opioids (Iv and neuraxial)
* alpha 2 agonists (precedex, clonidine)
* Lithium
* lidocaine
*hydroxyzine
Electrolytes: hyponatremia
Age: older age ( decrease 6% per decade after 40)
* prematurity
Body temp: hypothermia
Other: Hypotension (MAP< 50mmHG)
* hypoxia
* Anemia (<4.3 mL O2/dL blood)
121
what factors do not affect mac
Hyper or hypokalemia
Hyper or hypomagnesemia
Other:
hyper or hypothyroidism ( changes in CO does)
gender
PaCO2 15-95
HTN
122
What is the Meyer-overton rule?
states that lipid solubility is directly proportional to the potency of an inhaled anesthetic. This theory implies the number of anesthetic molecules that are dissolved in the brain determines the depth of anesthesia
123
What is the unitary hypothesis?
states that all anesthetics share a similar MOA, although each may work at a different site
124
What is the most important site of halogenated anesthetic action in the brain?
the most essential site of action is the GABA A receptor
* the GABA A receptor is a ligand-gated chloride channel
* stimulation of the GABA-A receptor increases chloride influx and hyperpolarizes neurons. This impairs neurotransmission
* volatile anesthetics most likely increase the duration that the chloride channel remains open
125
How do halogenated anesthetics produce immobility?
volatile anesthetics produce immobility in the ventral horn of the spinal cord
126
Which cerebral receptors are stimulated by nitrous oxide?
nitrous oxide produces:
* NMDA antagonism
*Potassium 2P channel stimulation
Nitrous oxide does not stimulate the GABA A receptor
127
In which regions of the brain do halogenated anesthetics produce unconsciousness?
Cerebral cortex, thalamus, reticular activating system
128
in which regions of the brain do halogenated anesthetics produce amnesia?
Amygdala, hippocampus
129
In which regions of the brain do halogenated anesthetics produce autonomic modulation?
Pons, medulla
130
How do halogenated agents reduce blood pressure?
They decrease MAP in a dose dependent fashion. At equivalent doses, there is little difference between agents
* primary cause: decreased intracellular Ca2+ in vascular smooth muscle-> systemic vasodilation-> decrease SVR and Decrease venous return
Secondary cause: Decreased intracellular Ca 2+ in the myocyte -> myocardial depression -> decrease inotropy
131
How do halogenated anesthetics affect heart rate?
Halogenated anesthetics directly affect cardiac conduction in a dose dependent fashion. They do this in several ways:
* Decrease SA node automaticity
* decrease conduction velocity through the AV node, His-Purkinje system, and ventricular conduction pathways
* Increased duration of myocardial repolarization by impairing the outward K+ current (prolongs action potential duration and the QT interval)
* altered baroreceptor function
132
Why do desflurane and isoflurane sometimes increase heart rate?
Desflurane and isoflurane increase HR from baseline 5-10%. this is most likely due to SNS activation from respiratory irritation.
Rapid increases in Desflurane, and to a lesser degree, isoflurane cause tachycardia. Pulmonary irritation -> SNS activation-> Increase norepinephrine release -> beta 1 stimulation
* opioids, alpha 2 agonists, or beta 1 antagonists can minimize tachycardia
133
What is the relationship between isoflurane and coronary steal?
Iso is the most potent coronary artery dilator.
This gave rise the the fear that iso might contribute to coronary steal syndrome. The underlying principle is that atherosclerotic vessels can't dilate, while normal vessels can. This would preferentially divert blood away from areas of higher resistance, starving those regions of oxygen.
This is more of a textbook thing than a real-world problem
134
How does N2O ( by itself) affect hemodynamics?
activates the SNS. This increases MAP as a function of increased SVR. CVP and RAP may increase.
N2O is also a myocardial depressant, but the increased SNS stimulation outweighs the physiologic consequences of this
* N2O combined with an opioid will more likely depress the myocardium
135
How do halogenated anesthetics contribute to hypercarbia?
dose dependent depression of the central chemoreceptor and the respiratory muscles. This contributes to hypercarbia. Mechanisms include:
* altering the resp pattern ( decrease Vt and compensatory increase RR-> decrease Ve and increase Vd)
* impairing the response to CO2 (slope CO2 response curve shifts down and right)
* impairing motor neuron output and muscle tone to the upper airway and thoracic muscles
136
How do halogenated anesthetics affect cerebral metabolic rate?
CMRO2 is a function of
* electrical activity (60%)
* Cellular homeostasis (40%)
Volatile anesthetics reduce CMRO2, but only to the extent that they reduce electrical activity. Once the brain is isoelectric, volatile agents cannot reduce CMRO2 any further.
* isoelectricity on EEG occurs at 1.5-2 MAC
137
Compare and contrast the effects of halogenated anesthesia and N2O on CBF.
the brain matches its blood flow with its metabolic requirement.
* when metabolic demand increases, the blood vessels dilate (cerebrovascular resistance decreases)
* when metabolic demand decreases, the blood vessels constrict ( cerebrovascular resistance increases)
Volatile anesthetics uncouple this relationship : CMRO2 decreases and CBF increases. This can increase ICP as well.
Nitrous is different. It increases the CMRO2 and CBF appropriately
138
How do halogenated anesthetics affect evoked potentials? how about N2O?
Des, iso and sevo produce a dose-dependent effect on evoked potentials. THey:
* decrease amplitude (signal is not as strong)
*increase latency (signal is slower to conduct)
The addition of N2O to a halogenated anesthetic agent can lead to a more profound amplitude reduction. Therefore, N2O should not be used during evoked potential monitoring.
139
Which type of evoked potential is most sensitive to the effects of volatile anesthetics? which is the most resistant?
Sensitivity ranking:
* visual evoke potentials are the most sensitive to volatile anesthetics
*brainstem evoked potential are the most resistant to volatile anesthetics
* SSEPs and MEPS are somewhere inbetween
140
What is the relationship between N2O and bone marrow depression?
Nitrous inhibits methionine synthase and folate metabolism. This can cause megaloblastic anemia.
141
Which route of administration is associated with the LOWEST bioavailability?
Intrathecal
this is because we are administering the drug directly to its effect-site (don't need the blood to take it anywhere)
142
percentage CO that each tissue group receives
Vessel rich: 75% (heart, lungs, kidney, liver, brain) only 10% of total body mass
Muscle: 19%
Fat: 6%
Drugs leave the central compartment in two phases: distribution into tissue and biotransformation/excretion
143
Acetazolamide favors:
Excretion of acidic drugs and reabsorption of basic drugs
"like dissolves like"
Acidic urine favors: reabsorption of acidic drugs and excretion of basic drugs
basic urine: reabsorption of basic drugs and excretion of acidic drugs
how to alter urine pH: Acidify the urine with ammonium chloride of cranberry juice and alkalize the urine with acetazolamide
144
Which agents are most likely to cause pain on injection?
Diazepam: +++
Etomidate: +++
Propofol:++
Lorazepam: +
Propylene glycol is used as a solvent for etomidate, diazepam, and lorazepam formulations. This stuff can be quite irritating, and it can result in venous irritation and phlebitis following injection. Additionally, this explains why we don't give diazepam or etomidate intramuscularly. Eliminating the propylene glycol carrier in favor of a non-irritating solvent eliminates the pain.
Propofol injection pain can be minimized or eliminated by using a larger, rather that smaller, vein. Administering lidocaine (before injection or mixed with propofol) or a potent opioid reduces the pain as well.
The following durgs do NOT cause pain on injection:
* Dexmedetomidine
* Ketamine
* Fospropfol
* Midazolam...well, at least is what Nagelhout says
145
What is the primary pathway of etomidate metabolism?
Hydrolysis
Biotransformation is the result of ester hydrolysis at the ethyl-ester side chain. Plasma esterases and hepatic microsomal enzymes drive the reaction.
Etomidate does not produce an active metabolite
146
Best treatments for a pt experiencing an episode of acute intermittent porphyria
Glucose and heme arginate
The porphyrias can be classified as acute (inducible) or chronic (non-inducible or cutaneous). The most common (and dangerous) type of inducible porphyria is acute intermittent prophyria.
Porphyria is a defect in heme synthesis leading to the accumulation of heme precursors. Heme is a key component of hemoglobbin, myoglobin, and the cytochrome P450 enzymes
Succinyl-CoA + Glycine-> ALA synthase -> precursors-> Heme
Triggering agents: Barbiturates, Etomidate, Ketamine, Ketorolac, Amiodarone, CCBs, Birth control pills
Anesthetic considerations: Liberal hydration, glucose supplementation, and prevention of hypothermia. This condition can be made worse by stimulation of ALA synthase, emotional stress, prolonged NPO status, and CYP450 induction
An acute exacerbation is treated with glucose and heme arginate. These agents reduce ALA synthase activity.
147
Which anesthetic agent is LEAST affected by alterations in plasma protein binding?
Ketamine
You can think of plasma proteins as an intravascular drug storage compartment. A drug bound to a protein cannot bind to a receptor, so any bound drug can be considered inert. Only the free fraction can exert a physiologic effect.
Alterations in plasma protein binding can theoretically affect a drug's therapeutic effect. Drugs that are highly protein-bound are most affect by changes in plasma protein binding.
IV anesthetic protein binding percent:
* Propofol= 98%
* Diazepam= 98%
* Midazolam = 94%
* Dexmedetomidine= 94%
* Lorazepam= 90%
* Etomidate= 75%
* Ketamine= 12%
note: propofol is at the top and etomidate and ketamine are at the bottom
148
Which anesthetic agent produce an active metabolite?
Ketamine and midazolam
Ketamine
* Primary metabolite= norketamine
* Potency= 0.2-0.33x ketamine
* Metabolic pathway= hepatic P450 enzymes
* Chronic ketamine use induces the enzymes that metabolize it. This manifests as a rapid escalation of tolerance (more drug is required to obtain the same effect)
Midazolam
* Primary metabolite= 1-hydroxymidazolam
* potency= 0.5x midazolam
* Metabolic pathway= hepatic and small intestine P450 enzymes
* The active metabolite is rapidly conjugated to an inactive compound
propofol- no active metabolite, depends on P450 enzymes
Etomidate- no active metabolites- depends on ester hydrolysis by plasma esterases and hepatic P450 enzymes
149
Which anesthetic agent is a methyl isopropyl ether?
Sevo
All of the potent inhaled anesthetics used today are halogenated, ether-based molecules (ether bond= C-O-C)
there are two classes you should know
Methyl isopropyl ether:
Ex: sevo
Methyl ethyl ether
ex: Des and iso
Halothane is a halogenated hydrocarbon-no ether bond
150
Make up of halogenated agents
Isoflurane
* 1-chloro 2,2,2-trifluoroethyl difluoromethyl ether
* Fluorine= 5
* Chlorine- 1
Desflurane
* difluromethyl 1,2,2,2-tetrafluoroethyl ether
* Fluorine=6
sevo
* Fluoromethyl 2,2,2,-trifluoro-1-(trifluoromethyl) ethyl ether
* Fluorine= 7
Halothane:
* 2-bromo-2-choro 1,1,1,-trifuoroethane
* Bromine=1
* This is the only agent with bromine
151
volatile agents agent and their oil:gas partition coefficient
Nitrous oxide: 1.4
Desflurane= 19
Sevoflurane=47
isoflurane=91
Volatile anesthetics do not form hydrogen bonds making them hydrophobic (lipophilic)
Instead, volatile agents tend to dissolve in non-polar substances, such as oils. The oil:gas partition coefficient is a measure of hydrophobicity.
The larger the number, the greater the tendency to dissolve in a non-polar solvent.
152
which anesthetic agent has the lowest boiling point?
Desflurane- boils at 24 Degrees C, which why it requires a special heated and pressurized vaporizer (TEC- 6 or Drager D-Vapor)
Nitrous exists as a gas in ambient temperature. This is because if boils at a very low temperature -88 degrees C
Sevo boils at 59C and Iso 49 C
153
Which factor influences anesthetic uptake the LEAST?
Fresh gas flow
FA is a function of 2 opposing actions:
* FI= the rate of delivery TO the alveoli (fills the alveoli)
* Uptake= the rate of removal AWAY from the alveoli (empties the alveoli)
Determinants of delivery to the alveoli (FI):
* Setting on the vaporizer
* Time constant of delivery system
* Anatomic dead space
* Alveolar ventilation
* FRC
Determinants of removal from the alveoli (uptake):
* Agent solubility (blood/gas partition coefficient)
* Cardiac output
* Partial pressure gradient between alveolar gas and mixed venous blood
154
What concept BEST describes how a gas distributes between two compartments at equilibrium?
Partition coefficient
A partition coefficent is a measure of how a gas distributes between compartments (or phases) at equilibrium
the blood:gas partition coefficient is critical to your understanding of anesthetic uptake
It is the partial pressure of anesthetic agent in the brain that determines the depth of anesthesia, and that a concentration gradient exists from the vaporizer -> breathing circuit-> patient airway-> alveoli-> blood -> brain/tissue
* More soluble agents= increased uptake and partial pressure rises slower
* Less soluble agents= decreased uptake and partial pressure rises faster
155
Increased Cardiac output increases or decreases inhalation induction time
prolongs induction time
uptake of the agent is increased so more is dissolved in the blood
156
Hepatic biotransformation of desflurane produces?
Inorganic fluoride ions
Trifluoracetic acid
iso produces the same
Causes an immune-mediated hepatitis
Compound A (fluoromethyl-2,2-difluoro-1-[trifluromethyl]vinyl ether) is produced when sevo is exposed to soda lime (hydrated or desiccated)
Sevo is also broken down to inorganic fluoride ions but not TFA
157
How does the addition of a chlorine atom affect isoflurane's PK/PD profile?
Increase potency
increased Blood:gas solubility
158
How does full fluorination affect desflurane's PK/PD profile?
Decrease potency
increase vapor pressure
increase resistance to biotransformation
159
Factors that increase FA/FI
= faster onset
Increased wash in:
Higher FGF
Higher alveolar ventilation
Low FRC
Low time constant
Low anatomic dead space
Decreased uptake:
Low solubility
Low CO
Low Pa-Pv difference
160
Decreased Fa/Fi factors
= slower onset
Decreased wash in
Low FGF
Low alveolar ventilation
High time constant
High anatomic dead space
Increased uptake
High solubility
High cardiac output
High Pa-Pv difference
161
What are the 4 tissue groups and how much Cardiac output do they receive and what % do they make up?
Vessel rich group- 10% body mass, 75% CO, include Brain, heart, kidney, liver, endocrine glands
Muscle- 50% body mass, 20% CO, skeletal muscle and skin
Fat- 20% body mass, 5% CO
Vessel poor group: 20% body mass, <1% CO, bone, tendon, and cartilage
After the VRG becomes saturate with anesthetic, the muscle group is responsible for the majority of continued tissue uptake. The muscle group is slower to saturate, because it receives disproportionately lower amount of CO and has a much larger capacity
Fat group is a high capacity sink capable of storing large amounts of agent
Vessel poor group doesn't receive enough blood flow to contribute to anesthetic uptake meaningfully
162
What complication is a theoretical concern from sevoflurane metabolism?
Sevo has a high degree of metabolism so there is concern of fluroide-induced high output renal failure. This type of renal failure is characteristically unresponsive to vasopressin. Signs of high output renal failure include polyuria, hypernatremia, hyperosmolarity, increased plasma creatinine, and inability to concentrate the urine. To date, these concerns seem unjustified in humans.
163
FGF to sevo MAC hour
To prevent compound A buildup inside the breathing circuit, the FDA set guidlines about the minimum FGF you should use with sevo. They recommend FGF of 1 L/min for up to 2 MAC hrs and 2L/min after 2 MAC hours. FGF <1L/min are not recommended at any time.
A 40 yr old receives 2% sevo (1MAC) for 1 hr= 1 MAC hr
A 40 yr old receives 1% sevo (0.5 MAC) for 2 hours = 1 MAC hr
in the context of 1 l?min for up to 2 MAC hours
A 40 yr old receives 2% sevo (1 MAC) for 2 hrs= 2 MAC hours
A 40 yr old receives 1% sevo (0.5 MAC) for 4 hours = 2 MAC hrs
164
Which P450 enzyme is chiefly responsible for halogenated anesthetic metabolism in the liver?
CYP2E1
165
Which concept BEST explains why the rate of FA/FI is faster for nitrous oxide than desflurane
Concentrating effect
Even though Des has a lower blood:gas partition coefficient than nitrous, the concentrating effect explains why the rate of rise of FA/FI is faster for nitrous oxide than des
166
Concentration effect
says that the higher the concentration of inhalation anesthetic delivered to the alveolus (FA), the faster its onset of action (this is also called overpressuring). This effect is probably only clinically relevant for nitrous oxide.
there are two components:
1. Concentrat"ing" effect
* When the pt is breathing room air, nitrogen is the primary gas in the alveolus
* Nitrous oxide is 34x more soluble in the blood than nitrogen
* When nitrous oxide is introduced to the lung, the volume of nitrous oxide going from the alveolus to the pulmonary blood is much higher than the amount of nitrogen moving in the opposite direction. This causes the alveolus to shrink, and the reduction in alveolar volume causes a relative increase in FA
* The concentrating effect explains why nitrous oxide (not des) achieves the fastest rate of rise of FA/FI, even through des in less soluble in the blood. The sheer volume compensates for the small difference in blood solubility.
2. Augmented Gas inflow effect
* The concentrating effect temporarily reduces alveolar volume
* On the subsequent breath, the concentrating effect causes an increased inflow of tracheal gas containing the anesthetic agent to replace the lost alveolar volume. This increases alveolar ventilation and augments FA. Alveolar volume is restored quickly, so this is only a very temporary phenomenon
167
Ventilation effect
The ventilation effect describes how changes in alveolar ventilation can affect the rate of rise of FA/FI
* The greater the alveolar ventilation, the greater the rate of rise of FA/FI
* In the spontaneously ventilating patient, as the anesthetic is deepened, alveolar ventilation decreases, and this reduces anesthetic input in the alveolus. This can be thought of as a protective effect that minimizes the risk of anesthetic overdose
168
Second gas effect
Adding N2O significantly increases Iso concentration more than Sevo and Des (less soluble agents)
The reduction in alveolar volume from the shrinking due to N2O augments tracheal inflow causing a relative increase in concentration of the second gas (iso)
the partial pressure of alveolar oxygen also increases when the alveolus shrinks. This is also a transient effect .
The end result is that the alveolar concentration of the other gases is higher than if they were administered alone
169
Diffusion hypoxia
The gas-containing areas of the body can absorb up to 30 L of N2O within the first two hours of administration. When you shut off nitrous, the nitrous that has accumulated in the body transfers to the alveoli for elimination in the first 1 - 5 minutes. This can temporarily dilute the alveolar oxygen and CO2 concentrations, leading to diffusion hypoxia and hypocarbia (decreased stimulus to breathe). Additionally, this reduced stimulus to breathe can reduce PaO2 further.
Classic teaching is too administer 100% Oxygen for 3-5 minutes after N2O has been discontinued and will mitigate that dilution of alveolar oxygen. Newer evidence suggests a lower FiO2 during emergence as a way of reducing absorption atelectasis and improving post-operative gas exchange. so O2 doesn't have to be 100%
170
Which anesthetic is most affected by a right to left shunt?
Des due to being less soluble, iso is affected less
there would be a faster IV induction, blood bypasses the lungs and travels to the brain faster
5 examples of Right to left shunt
* Tetralogy of Fallot
* Foramen ovale
* Eisenmenger's syndrome
* Tricuspid atresia (no valve between right atrium and ventricle)
* Ebstein's anomaly- abnormal tricuspid valve
left to right shunt slows IV inductions
no effect on anesthetic uptake or induction time
