Millers pharm Flashcards
What is pharmacokinetics?
Pharmacokinetics is the process by which the body “disposes” of drugs via
absorption, distribution, metabolism, and elimination. It can be thought of as “what
the body does to the drug”
What is pharmacodynamics?
Pharmacodynamics is the process by which drugs interact with specific receptors in
the body to produce pharmacologic effects. It can be thought of as “what the drug
does to the body”
What factors govern drug absorption?
Drug absorption is governed by route of delivery, bioavailability of the drug, and possibly first-pass metabolism
How is absorption via buccal mucosa significantly different from drug absorption via the stomach?
Drug absorption via buccal mucosa differs from absorption from lower in the gastrointestinal tract because presence of food does not hinder delivery of drug to the mucosa. Also, venous outflow from the buccal mucosa returns directly to the systemic circulation, thereby avoiding the potential for the first-pass hepatic effect that is present for drugs absorbed in the stomach, which first enter the portal venous system
What aspects of absorption make transdermal drug delivery distinct from other modes of drug delivery? Name some examples of drugs for which a transdermal application is clinically important.
Transdermal drug delivery is distinct in that skin is designed to be a significant barrier to absorption. This means that drugs delivered transdermally will have a markedly delayed onset of action following administration. Also, the skin serves as
a depot of the drug, resulting in prolonged drug effect following removal of the skin application. Examples of drugs delivered transdermally include clonidine, scopolamine, nitroglycerin, and fentanyl
What is the mechanism for the offset of local anesthetic effects following nerve block?
Local anesthetics applied in nerve blocks have their pharmacologic effects ended by movement of the drug away from the site of action. The process by which the body absorbs this locally applied bolus of drug, thus ending its local
effects, is the same by which the body absorbs drugs injected into tissues for the purpose of eliciting systemic drug effects that follow absorption
What is “first order” transfer? How does doubling the dose of a drug affect the shape of a plot of drug absorbed versus time?
“First order” transfer is when the rate of drug absorption is proportional to the concentration gradient. Doubling the dose of a drug does not affect the shape of the curve (absorption over time) when a “first order” transfer is occurring. Concentrations will be exactly twice as high at all times, but peak absorption will
occur at the same time and the shape of the curve will be identical
How does absorption rate from its delivery site affect peak plasma concentration of a drug? What does absorption rate mean regarding the relative safety of intercostal nerve blocks?
The absorption rate from drug delivery sites significantly affects peak plasma concentrations. The higher the absorption rate, the higher the peak plasma concentration that will result. Nerve blocks at sites with rapid absorption result in higher peak plasma concentrations of the local anesthetic injected, providing a risk of toxicity relatively greater than nerve blocks at sites with slower absorption. Intercostal blocks are performed in areas of relatively high absorption
Define distribution. Define volume of distribution.
Distribution is the process by which an injected drug mixes with blood and body tissues after its administration. Measuring plasma concentration of a drug allows calculation of a mixing volume, or volume of distribution. Volume of distribution is thus a calculated number (dose of drug administered intravenously
divided by plasma concentration) that reflects the apparent volume of body tissues that the drug is distributed across, assuming all the tissues it is distributed across are in equilibrium with plasma concentration. Higher levels of drug remaining in the plasma after drug administration lead to a smaller
calculated volume of distribution
Distinguish central volume of distribution from peripheral volume of distribution.
Central volume of distribution is the apparent volume immediately (within a minute) following intravenous drug injection. It anatomically consists of the heart,
the great vessels, and the lungs. Peripheral volumes of distribution are those volumes of distribution that are calculated after the injected drug has had time to distribute to tissues to which distribution of drug is slower. These peripheral
tissues include muscle, fat, and bone. While there is an anatomic correlation to central and peripheral volumes of distribution, volume of distribution is a calculated number that does not necessarily equate to an actual physical volume
What factors increase a peripheral volume of distribution for a drug?
The solubility of the drug in the tissue relative to the solubility in the blood
or plasma determines the peripheral volume of distribution. If the drug is
highly soluble in the tissue, then less of it will stay in the plasma. Sampling the
plasma concentration of the drug will result in calculation of a higher volume
of distribution than if plasma levels remained higher. Drug properties that lower free
plasma levels include low levels of binding to plasma proteins, a lower degree of
ionization, and higher lipid solubility
What are two empiric models of peripheral volumes of distribution that are
clinically useful?
One clinically useful model to describe peripheral volumes of distribution divides
the body into tissue beds: “vessel rich group” (brain, most organs), muscle group,
fat group, and “vessel poor group” (skin, cartilage, ligaments). Another is
to identify the number of compartments in the body needed to explain the
pharmacokinetics of the drug in question. The pharmacokinetics of most anesthetic
drugs can be explained by a three compartment model (one central volume of
distribution, and two peripheral volumes of distribution). In spite of names given
to different compartments in different models, such compartments are empiric,
and do not necessarily correlate directly to underlying anatomic structures
or physiologic processes
Generally speaking, what is clearance of a drug? What is the difference between
systemic clearance and “intercompartmental” clearance?
Clearance is the removal of drug from tissue. Systemic clearance is when the drug
is permanently removed from the body. “Intercompartmental” clearance is when
the drug leaves the body tissue in question but moves into a different body
tissue
How are most anesthetic drugs removed from the body?
Most anesthetic drugs are removed from the body by hepatic metabolism
What processes are used in the liver to metabolize drugs?
In the liver, drugs are metabolized through the processes of oxidation, reduction,
conjugation, and hydrolysis. Oxidation and reduction occurs via the cytochrome
P-450 system
What drugs are metabolized by cytochrome CYP 3A4?
Drugs important to anesthesia that are metabolized by CYP 3A4 include
acetaminophen, alfentanil, dexamethasone, fentanyl, lidocaine, methadone,
midazolam, and sufentanil. Also, propofol is partly oxidized by CYP 3A4
What drugs or substances induce CYP 3A4? What drugs or substances inhibit
CYP 3A4?
Rifampin, rifabutin, tamoxifen, glucocorticoids, carbamazepine, barbiturates, and
St. John’s wort induce CYP 3A4, increasing the metabolism of substrates of CYP 3A4
(hastening clearance). Inhibitors of CYP 3A4 include midazolam, propofol,
grapefruit juice, antifungal drugs, protease inhibitors, “mycin” antibiotics, and selective serotonin reuptake inhibitors (SSRIs). In the case of midazolam, this has
been shown to prolong the effects of other drugs metabolized by CYP 3A4, such as
alfentanil and fentanyl
What function important to anesthesia does CYP 2D6 have? What drugs inhibit CYP
2D6, and what clinical implication does this have?
CYP 2D6 is the cytochrome in the liver responsible for the conversion of codeine
to morphine (the active metabolite of codeine). CYP 2D6 is inhibited by
quinidine and SSRIs. The clinical implication of this is that codeine, oxycodone, and
hydrocodone, which all rely on activity of CYP 2D6 for production of the active
metabolite from which their clinically relevant pharmacologic effects are derived,
are poor analgesic choices for patients receiving SSRIs
Why do remifentanil, succinylcholine, and esmolol generally vanish from the
plasma so quickly after intravenous administration?
Remifentanil, succinylcholine, and esmolol are cleared in the plasma and tissue by
ester hydrolysis. This occurs very quickly because these esterases are so abundant
Why is the pharmacokinetics of succinylcholine less predictable than other drugs
cleared by ester hydrolysis?
The pharmacokinetics of succinylcholine are less reliable than that of other drugs
cleared by plasma and tissue esterases because it is metabolized specifically by
butylcholinesterase (formerly known as “pseudocholinesterase”). Defects in the
gene for butylcholinesterase lead to a potentially significant slowing in the
metabolism of succinylcholine
Define “linear” pharmacokinetics.
“Linear” pharmacokinetics are said to exist for a drug when the rate of the drug’s
metabolism is directly proportional to its concentration. This is a general
characteristic of anesthetic drugs
Describe the formula for rate of drug metabolism in terms of liver blood flow.
Rate of metabolism equals liver blood flow times the difference in drug
concentration between blood flowing into the liver and blood flowing out
What is an extraction ratio? What is the formula for clearance in terms of hepatic
blood flow? What are the units for clearance?
The extraction ratio of a drug is the fraction of the drug that is removed from
the plasma during passage through the liver. Clearance by the liver is equal to
hepatic blood flow multiplied by the extraction ratio. (Therefore, units of clearance
are liters per minute.) Hepatic extraction ratios are unchanging properties of
specific drugs. More of a drug is metabolized by the liver when the drug is being
delivered to the liver in increasing concentrations. This must be true for the
extraction ratio to remain constant
In the case of a drug exhibiting “linear” pharmacokinetics, what is significant about
the constant relationship between metabolic rate and drug concentration?
For most anesthetic drugs, metabolic rate is proportional to drug concentration
(“linear” pharmacokinetics). The proportionality constant that relates the drug
concentration to the metabolic rate is another definition of clearance.
Rate of metabolism grams ð Þ =minute ¼
proportionality constant liters ð Þ =minute
inflow concentration grams ð Þ =liter
Extraction ratio and proportionality constant (clearance) are only constant
if drugs exhibit “linear” pharmacokinetics, but this is generally true of anesthetic
drugs
