Apex Unit 4 Flashcards
Define volume of distribution, and recite the equation.
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 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.
What are the implications when a drug’s Vd exceeds TBW? What if Vd is 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.
Examples: propofol, fentanyl
If Vd < TBW, 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)
How do you calculate the loading dose for an IV medication?
How about a PO medication?
For an IV drug, the bioavailability is always 1. This is because all of the drug enters the bloodstream.
A drug administered by any other route may not be absorbed completely and/or it may be subjected to first pass metabolism in the liver. These conditions reduce bioavailability and explain why the dose that achieves a giv
What is clearance? What factors increase/decrease it?
Clearance is the volume of plasma that is cleared of drug per unit time.
What is steady state?
Steady state occurs when the amount of 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.
(SS) Rate of Administration = Rate of Elimination
Steady state is achieved after 5 half-times.
Compare and contrast the alpha- and beta distribution phases on the plasma concentration curve.
The plasma concentration curve graphically depicts the biphasic decrease of a drug’s plasma concentration following a rapid IV bolus.
Alpha distribution phase:
Describes drug distribution from the plasma to the tissues.
Beta distribution phase:
Begins as plasma concentration falls below tissue concentration.
The concentration gradient reverses, which causes the drug to re-enter the plasma.
The beta phase describes drug elimination from the plasma by the clearing organs.
You have administered 30 mg of esmolol to a patient after a sudden (and profound) elevation in heart rate. After three half-lives, what percentage of your initial dose remains in the patient’s bloodstream?
12.5% of the drug remains in the patient’s bloodstream.
The half-time is the amount of time required for the drug concentration to decrease by 50%. You must know this chart!
What is context sensitive half-time?
The problem with half-times 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.
Discuss the context sensitive half-times of fentanyl, alfentanil, sufentanil, and remifentanil. Which has the longest? Which has the shortest? Why?
The context-sensitive half-time for a fentanyl infusion increases as a function of how long it was infused. A longer infusion 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 it is highly lipophilic, it is quickly metabolized by plasma esterases and has a similar context-sensitive half-time regardless of how long it is infused.
What is the difference between a strong and weak acid or base?
what is the equation?
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.
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?
What happens when you put an acid in a basic solution?
How about an acidic solution?
Remember that “like dissolves like”
An Acid in a Basic Solution:
An acidic drug will be highly ionized in a basic pH.
The acidic drug wants to donate protons and the basic solution wants to accept protons.
The acidic drug happily donates its protons and will become ionized.
An Acid in an Acidic Solution:
An acidic drug will be highly unionized in an acidic pH.
The acidic drug wants to donate protons and the acidic solution wants to do the same.
Since there are no proton acceptors, the acidic drug retains its proton and will remain unionized.
Can you tell if a drug is an acid or a base by looking at its name? If yes, how?
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
Name the 3 key plasma proteins. Does each bind acidic drugs, basic drugs, or both?
Albumin primarily binds to acidic drugs, however it also binds to some neutral and basic drugs.
α1-acid glycoprotein binds to basic drugs.
Beta-globulin binds to basic drugs.
What conditions reduce albumin concentration?
Liver disease
Renal disease
Old age
Malnutrition
Pregnancy
What conditions affect α1-acid glycoprotein concentration?
Increased α1-acid glycoprotein concentration:
Surgical stress
Myocardial infarction
Chronic pain
Rheumatoid arthritis
Advanced age
Decreased α1-acid glycoprotein concentration:
Neonates
Pregnancy
How do changes in plasma protein binding affect plasma drug concentration?
Decreased PP binding → Increased Cp
Increased PP binding → Decreased Cp
How do you calculate changes in plasma protein binding?
[Free drug] + [Unbound protein binding sites] ↔ [Bound drug]
If a drug is 98% bound and the bound fraction is reduced to 96%, the unbound or free fraction has increased by 100%! Said another way, if the free fraction is 2% and it increases to 4%, then the free fraction has increased by 100%.
***You must calculate the percent change to complete this calculation***
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 will this drug’s rate of elimination change as plasma drug concentration changes?
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.
Other examples: aspirin, phenytoin, warfarin, heparin, and 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 I biotransformations are carried out by the P450 system.
There are 3 phase I reactions that you should understand:
Oxidation – adds an oxygen molecule 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.
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.
Common substrates for conjugation reactions include: glucuronic acid, glycine, acetic acid, sulfuric acid, or a methyl group.
Some drugs do not require preparation by phase I reactions and may proceed directly to phase II reactions.
Discuss enterohepatic circulation, and list 1 drug example.
Enterohepatic circulation - 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?
The extraction ratio is 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.
Regarding hepatic clearance, what is flow limited elimination?
Flow Limited Elimination (ER > 0.7)
For a drug with a high hepatic extraction ratio (> 0.7), clearance is dependent on liver blood flow.
Hepatic blood flow greatly exceeds enzymatic activity, so alterations in hepatic enzyme activity has little effect.
↑ liver blood flow → ↑ clearance
↓ liver blood flow → ↓ clearance
Regarding hepatic clearance, what is capacity limited elimination?
Capacity Limited Elimination (ER < 0.3)
For a drug with 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 protein binding have a profound impact on clearance of these drugs.
Changes in the liver’s intrinsic ability to remove drug from the blood is influenced by the amount of enzyme present.
Enzyme induction → ↑ clearance
Enzyme inhibition → ↓ clearance
Theophylline has a low hepatic extraction ratio. Which will have a greater effect on its metabolism: prolonged hypotension or CYP inhibition?
CYP inhibition.
Because theophylline has a low hepatic ratio, prolonged hypotension will not impact its rate of metabolism to the same degree that CYP inhibition will.
What’s 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 in 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 a significant source of drug interactions.
List 2 drug classes and 7 drugs that are metabolized by pseudocholinesterase.
Some neuromuscular blockers:
Succinylcholine (depolarizer)
Mivacurium (nondepolarizer)
Ester-type local anesthetics:
Chloroprocaine
Tetracaine
Procaine
Benzocaine
Cocaine (also metabolized by the liver)
List 6 drugs that are metabolized by non-specific plasma esterases.
Esmolol
Remifentanil
Aspirin
Clevidipine
Atracurium (and Hofmann elimination)
Etomidate (and 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 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.
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 a given effect in 50% and 90% of the population respectively.
How is potency measured on the dose-response curve?
Drug A is more potent than Drug B.
Drug A: The curve shifts left with → increased affinity for receptor → higher potency → lower dose required
Drug B: The curve shifts right with → decreased affinity for receptor → lower potency → higher dose required
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
Lower plateau = lower efficacy
Once the plateau phase is reached, additional drug does NOT produce additional effect. Additional drug will only increase the risk of toxicity.
Go back to the last question, and notice that drug A and drug B share the same efficacy. This means that drug A and drug B can achieve the same clinical effect, however you’ll need to give a larger dose of drug B to accomplish this.
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 a profound clinical effect
Flatter slope = Higher doses are required to increase the clinical effect
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.
Partial agonist: Binds to a receptor, but it is only capable of partially turning on a cellular response. It is less efficacious than a full agonist.
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.
Inverse Agonist: Binds to the receptor and causes an opposite effect to that of a full agonist. It has negative efficacy.
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
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 agonist.
The effect of a noncompetitive agonist can only be reversed by producing new receptors. This explains why these drugs have long durations of action.
Examples: aspirin and phenoxybenzamine
Define ED50.
Effective dose 50 is the dose that produces the expected clinical response in 50% of the population. It is a measure of potency.
Define LD50.
Lethal dose 50 is the dose that will produce death in 50% of the population.
Define therapeutic index.
Therapeutic index helps us determine the safety margin for a desired clinical effect.
Therapeutic Index = Lethal Dose 50 / Effective Dose 50
A drug with a narrow TI has a narrow margin of safety.
A drug with a wide TI has a wide margin of safety.
What is chirality?
Chirality is a division of stereochemistry. It deals with molecules that have a center of three-dimensional asymmetry. In biologic 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 that are created.
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 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 one third of the drugs we administer are enantiomers, and just about all of these are prepared as racemic mixtures. Common examples include: bupivacaine, ketamine, isoflurane, and desflurane (not sevo).
What is the mechanism of action of propofol?
Direct GABA-A agonist → ↑ Cl- conductance → neuronal hyperpolarization
What is the dose, onset, duration, and clearance mechanism for propofol?
Dose:
Induction: 1.5 - 2.5 mg/kg IV
Infusion: 25 - 200 mcg/kg/min
Onset: 30 - 60 seconds
Duration: 5 - 10 minutes
Clearance: Liver (P450 enzymes) + extrahepatic metabolism (lungs)
What are the cardiovascular and respiratory effects of propofol?
Cardiovascular effects:
Decreased BP (due to ↓SNS tone and vasodilation)
Decreased SVR
Decreased venous tone → decreased preload
Decreased myocardial contractility
Respiratory effects:
Shifts CO2 response curve down and to the right (less sensitive to CO2) → respiratory depression and/or apnea
Inhibits hypoxic ventilatory drive
What are the CNS effects of propofol?
CNS effects:
↓ Cerebral oxygen consumption (CMRO2)
↓ Cerebral blood flow
↓ Intracranial pressure
↓ Intraocular pressure
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.
Despite concerns that propofol might precipitate anaphylaxis in patients 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 propofol is probably safe to administer to patients with egg allergies.
There is no cross sensitivity between propofol and soy or peanuts.
What is propofol infusion syndrome?
Propofol contains long chain triglycerides, and an increased LCT load impairs oxidative phosphorylation and fatty acid metabolism. This starves cells of oxygen, particularly in cardiac and skeletal muscle. Propofol infusion syndrome is associated with a high mortality rate.
What are the risk factors for propofol infusion syndrome?
Risk factors:
Propofol dose > 4 mg/kg/hr (67 mcg/kg/min)
Propofol infusion duration > 48 hours
Children > adults
Inadequate oxygen delivery
Sepsis
Significant cerebral injury
What is the clinical presentation of propofol infusion syndrome?
Clinical presentation includes acute refractory bradycardia → asystole + at least one of the following:
Metabolic acidosis (base deficit > 10 mmol/L)
Rhabdomyolysis
Enlarged or fatty liver
Renal failure
Hyperlipidemia
Lipemia (cloudy plasma or blood) may be an early sign
When must a propofol syringe be discarded? How about an infusion?
Propofol supports bacterial and fungal growth, therefore strict attention to asepsis must be observed while withdrawing the drug from the vial. Additionally, the vial and rubber stopper must be cleansed with 70% isopropyl alcohol before removing the drug.
Syringe (drug removed from vial) = must be discarded within 6 hours
Infusion (drug remains in vial after rubber stopper is violated) = must be discarded within 12 hours (this includes the tubing)
What preservatives are used in brand and 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 propofol formulations contain different preservatives, and these can cause unique problems of their own.
Metabisulfite can precipitate bronchospasm in asthmatic patients.
Benzyl alcohol should be avoided in infants. There are a few case reports of toxicity and death attributed to the benzyl alcohol preservative when used in other medications.
How can propofol injection pain be minimized?
Propofol injection pain can be minimized or eliminated by:
Injecting into a larger and more proximal vein
Lidocaine (before propofol injection or mixed with propofol)
Giving an opioid prior to the propofol
Discuss the antipruritic effects of propofol.
Propofol (10 mg IV) can reduce itching caused by spinal opioids and cholestasis.
Discuss the antipruritic and antiemetic effects of propofol.
Propofol (10 - 20 mg IV) can be used to treat PONV. An infusion of 10 mcg/kg/min can also be used.
How is fospropofol converted to its active form?
Fospropofol 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).
What is the mechanism of action for ketamine?
Ketamine is an NMDA receptor antagonist (antagonizes glutamate)
Secondary receptor targets: opioid, MAO, serotonin, NE, muscarinic, Na+ channels
Ketamine dissociates the thalamus (sensory) from the limbic system (awareness)
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 (notice the O’s)
How can you tell the difference between the chemical structures of the halogenated agents?
All you have to do is count the halogens.
Isoflurane has 5 fluorine atoms + 1 chlorine atom
Desflurane has 6 fluorine atoms
Sevoflurane has 7 fluorine atoms (sevo = 7)
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 inhalation anesthetics, it’s the ability of the anesthetic agent to dissolve into the blood and tissues.
The blood : gas partition coefficient (λ) describes the relative solubility of an inhalation anesthetic in the blood vs. in the alveolar gas when the partial pressures between the 2 compartments are equal.
How do we establish an anesthetic concentration inside the alveolus?
- Turn the vaporizer on. This creates a concentration gradient that pushes anesthetic agent from the vaporizer towards the alveoli. This is FI.
- Ventilation washes the anesthetic agent into the alveoli. This is FA.
- The buildup of anesthetic partial pressure inside the alveoli is opposed by continuous uptake of agent into the blood. This is uptake.
- The cardiac output distributes the anesthetic agent throughout the body. This is distribution.
What does the FA/FI curve tell us? How does anesthetic solubility affect the FA/FI curve for each agent?
The FA/FI curve allows us predict the speed of induction.
Low solubility → less uptake into the blood → ↑ rate of rise → faster equilibration of FA/FI → faster onset
High solubility → more uptake into the blood → ↓ 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)
Cardiac output
Partial pressure gradient between the alveolar gas and the mixed venous blood
What conditions increase FA/FI? Which conditions decrease it?
For FA/FI to increase, there must be greater wash in and/or reduced uptake.
For FA/FI to decrease, there must be a reduced wash in and/or an increased uptake.
What are the 4 tissue groups? How much cardiac output does each receive?
We can divide the body into 4 tissue groups. Each group is defined by how much cardiac output it receives relative to its percentage of body weight.
How are inhalation anesthetics removed from the body? For each agent, what percent is attributed to hepatic metabolism?
Inhaled anesthetics are eliminated from the body in 3 ways:
Elimination from the alveoli (most important)
Hepatic biotransformation
Percutaneous loss (minimal)
You should remember this as “the rule of 2’s – (0.02, 0.2, and 2).” Additionally, you should notice that halogenated agents are in alphabetical order from least to greatest metabolism (D – I – S).
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, and this negates the small difference imposed by the slightly higher blood/gas partition coefficient.
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 with lower solubility (Des) will be more affected than an agent with higher solubility (Iso).
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 that 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).
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 ED50.
How do halogenated anesthetics affect evoked potentials? How about N2O?
Desflurane, isoflurane, and sevoflurane 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 nitrous oxide to a halogenated anesthetic agent can lead to a more profound amplitude reduction. Therefore, N2O should not be used during evoked potential monitoring.
