Exam 1B

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Questions and Answers

What is the result of a receptor spending 80% of its time in the inactive state and 20% of its time in the active state?

The receptor is partially active (correct)

The receptor is always inactive

The receptor's activity cannot be changed

The receptor is always active

What is the primary difference between competitive and non-competitive antagonism?

The potency of the antagonist

The location of the antagonist binding

The reversibility of the antagonist's binding to the receptor (correct)

The type of bond formed between the antagonist and the receptor

What is the effect of an inverse agonist on the receptor?

It turns off the constituent activity of the receptor (correct)

It increases the receptor's activity

It decreases the receptor's activity

It has no effect on the receptor

What is the primary function of an agonist in relation to a receptor?

To bind to the receptor and activate it Signup and view all the answers

What is the primary mechanism of non-competitive antagonism?

Permanent binding to the receptor Signup and view all the answers

What is the term for a partial agonist that also has antagonist activity?

Agonist-antagonist Signup and view all the answers

What is the term for the process by which the body reduces the effect of a drug over time, requiring larger doses to achieve the same effect?

Tolerance Signup and view all the answers

Where is the primary location of hepatic microsomal enzyme activity responsible for drug clearance?

Liver smooth ER Signup and view all the answers

What is the term for the movement of drugs in the body, including absorption, metabolism, distribution, and elimination?

Pharmacokinetics Signup and view all the answers

What is the primary function of phase II reactions in drug metabolism?

Conjugate drugs to make them water soluble Signup and view all the answers

What do acidic drugs tend to bind to?

Albumin Signup and view all the answers

What is the term for the fraction of inflowing drug extracted by the liver?

Extraction ratio Signup and view all the answers

What is the term for the decrease in receptor sensitivity to a ligand or a decrease in receptor density as a result of repeated or continuous stimulation?

Cellular tolerance Signup and view all the answers

What is the term for the rate of metabolism of a drug, which is proportional to the drug concentration?

Clearance Signup and view all the answers

What is the primary mechanism by which the renal system clears drugs from the bloodstream?

Glomerular filtration Signup and view all the answers

What is the term for the amount of drug that is required to produce a desired effect?

Potency Signup and view all the answers

What is the term for the ability of a drug to produce a desired effect?

Efficacy Signup and view all the answers

What is the term for the time necessary for the plasma drug concentration to decrease by 50% during the elimination phase?

Elimination half-time Signup and view all the answers

What is the term for the process by which the liver eliminates a fixed amount of drug per unit time?

Zero-order kinetics Signup and view all the answers

What is the term for the initial volume of distribution of a drug?

Vdi Signup and view all the answers

What is the term for the process by which the liver eliminates 50% of drug per unit time?

First-order kinetics Signup and view all the answers

What is the term for the amount of drug that remains in the body after a single dose?

Volume of distribution Signup and view all the answers

What is the primary difference between an agonist and an antagonist?

Agonists activate the receptor, while antagonists do not Signup and view all the answers

What is the primary mechanism by which covalent bonding affects receptor activity?

Forming a permanent bond with the receptor Signup and view all the answers

What is the primary implication of a drug having high lipid solubility?

It will have a large volume of distribution Signup and view all the answers

Which type of drugs tend to bind to alpha1 acid glycoprotein?

Basic drugs Signup and view all the answers

What is the primary consequence of protein binding on drug availability?

It decreases the availability of the drug for hepatic extraction and glomerular filtration Signup and view all the answers

What is the primary characteristic of a partial agonist?

It activates the receptor less completely than a full agonist Signup and view all the answers

What is the primary consequence of increasing the concentration of a competitive antagonist?

Receptor activation is inhibited Signup and view all the answers

What is the primary outcome of metabolism on lipid soluble drugs?

It converts them to more water soluble drugs Signup and view all the answers

Which of the following is a characteristic of highly protein bound drugs?

They are highly sensitive to changes in plasma protein concentration Signup and view all the answers

What is the primary function of Phase I Reactions in drug metabolism?

To increase the polarity of a drug Signup and view all the answers

What is the purpose of conjugation in Phase II Reactions?

To tie the agent to a polar compound, increasing its water solubility Signup and view all the answers

What is the formula used to quantify the process of drug metabolism?

R = Q(Cin-Cout) Signup and view all the answers

What is the definition of Clearance in the context of drug metabolism?

The volume of plasma cleared of a drug per unit of time Signup and view all the answers

What is the location of hepatic microsomal enzyme activity responsible for drug clearance?

Hepatic smooth ER Signup and view all the answers

What is the rate of metabolism for most anesthetic drugs proportional to?

Drug concentration Signup and view all the answers

What is the primary fate of highly fat-soluble drugs in the initial distribution phase?

They are taken up by the lung Signup and view all the answers

What is the primary term for the phenomenon where the body reduces the effect of a drug over time?

Tolerance Signup and view all the answers

What is the primary mechanism by which IV injection delivers drugs to the vessel-rich group?

Through the central compartment Signup and view all the answers

What is the primary term for the effect of a drug that is opposite to that of an agonist?

Antagonist Signup and view all the answers

What is the primary term for the phenomenon where the effect of a drug is greatly increased when combined with another drug?

Synergistic effect Signup and view all the answers

What is the primary factor that determines the distribution of a drug to tissues?

Blood flow Signup and view all the answers

What is the term for the concentration of a drug in the plasma at which the drug's effect is observed?

ED50 Signup and view all the answers

Which of the following drugs is characterized by a shorter effect-site equilibration?

Remifentanil Signup and view all the answers

What is the primary determinant of potency for drugs with very different time courses?

Time of measurement Signup and view all the answers

What is the term for the movement of a drug from the central compartment to other compartments?

Distribution Signup and view all the answers

What is the primary determinant of tissue storage capacity?

All of the above Signup and view all the answers

What is pharmacodynamics?

The study of the effects of drugs on the body Signup and view all the answers

What are some factors that influence pharmacokinetic variability in individuals?

All of the above Signup and view all the answers

What are some factors that influence pharmacodynamic variability in individuals?

Enzyme activity and gender differences Signup and view all the answers

What type of effect do anesthetic drugs tend to have?

Synergistic Signup and view all the answers

What is a racemic mixture?

A mixture of two enantiomers that are equal in amount Signup and view all the answers

Enantiomers often have different pharmacokinetic and pharmacodynamic properties.

True Signup and view all the answers

Administering drugs in high doses may mask interpatient variability

True Signup and view all the answers

Drugs excreted unchanged by the kidneys tend to have greater pharmacokinetic differences than metabolized drugs.

False Signup and view all the answers

In drugs with a high extraction ratio, a change in hepatic blood flow produces a proportional change in clearance

True Signup and view all the answers

Administration of inhalation agents alter hepatic, circulatory and renal function and may alter drug pharmacokinetics.

True Signup and view all the answers

What is the therapeutic index of a drug?

The ratio of the LD50 to the ED50 Signup and view all the answers

What is the LD50?

Lethal dose that kills 50% of a test population Signup and view all the answers

What is the ED50?

The dose of a drug that produces a desired response in 50% of test subjects. Signup and view all the answers

What factors influence potency of a drug?

All of the above Signup and view all the answers

Fentanyl is more efficacious than Tylenol because it produces better analgesia

True Signup and view all the answers

Sufentanyl is more potent than fentanyl because 1/5 of a dose of sufentanyl produces the same effect as 1 fentanyl

True Signup and view all the answers

What is the elimination half-time directly proportional to?

Volume of distribution Signup and view all the answers

What is the elimination half-time inversely proportional to?

The clearance Signup and view all the answers

What is the elimination half-life?

The time it takes to eliminate half the drug from the body after rapid IV injection. Signup and view all the answers

What is the context sensitive half-time?

The time it takes for the concentration of a substance to decrease by half i.e. half life where the context = duration of infusion Signup and view all the answers

What is the primary function of the CSHT?

To provide clinically useful guidance on the expected increase in the time required to eliminate the drug Signup and view all the answers

What is the primary benefit of using the CSHT in drug administration?

It helps clinicians to adjust the dosage and administration schedule to optimize the drug's effect Signup and view all the answers

What is the relationship between the duration of drug administration and the expected increase in elimination time according to the CSHT?

The elimination time increases as the duration of drug administration increases Signup and view all the answers

What is an advantage of using Propofol perioperatively?

context sensitive half time doesn't change Signup and view all the answers

Drugs that have the most rapid onset have the greatest effect site equilibration

True Signup and view all the answers

The plasma is almost never the effect site

True Signup and view all the answers

What is the effect site equilibration?

The process of achieving equilibrium between the concentration of a drug in the blood and at the site of action Signup and view all the answers

What intervals should be adjusted to reflect effect-site equilibration?

Dosing intervals Signup and view all the answers

In what drugs would effect-site equilibration be short?

All of the above Signup and view all the answers

In what drugs would effect-site equilibration be longer?

All of the above Signup and view all the answers

What is PKA?

constant that represents the pH in which a drug is 50% ionized Signup and view all the answers

Where does the drug have to return first in order to be eliminated?

Plasma of central compartment Signup and view all the answers

What enzyme aids in the metabolism of lipid soluble molecules?

Cytochrome P450 Signup and view all the answers

What are the phase I reactions?

all of the above Signup and view all the answers

What is the purpose of phase I reactions?

to increase drug polarity Signup and view all the answers

Oxidation and reduction involve CP450

True Signup and view all the answers

In phase II reactions, what is the role of conjugation?

Tying agent to a polar compound to increase its water solubility and its ability to be excreted Signup and view all the answers

When drugs are first administered, they are rapidly absorbed by the vessel rich group

True Signup and view all the answers

Drugs tied to proteins and large molecules do not get filtered through the kidneys

True Signup and view all the answers

Bound fractions are available for hepatic extraction and glomerular filtration

False Signup and view all the answers

What is a free fraction in pharmacology?

The unbound fraction of a drug in plasma that is able to diffuse out of bloodstream and exert its effect Signup and view all the answers

Ionized drugs are inactive and excreted by the kidneys

True Signup and view all the answers

Non-ionized drugs undergo renal metabolism and are water-soluble

False Signup and view all the answers

What is the primary determinant of tissue uptake?

Blood flow Signup and view all the answers

Blood flow, concentration gradient, the blood brain barrier, and physicochemical properties of drugs (ionization, lipid solubility, protein binding) are important determinants of tissue uptake

True Signup and view all the answers

In the three compartment model, rapid equilibration first occurs between which two tissues?

Plasma and vascular rich Signup and view all the answers

Is it true that potent drugs produce a greater response at lower doses?

True Signup and view all the answers

What is a characteristic of drug efficacy?

The maximum response that can be produced by a drug Signup and view all the answers

What is the biophase in pharmacology?

The biological phase of a drug's distribution Signup and view all the answers

What type of transport is tubular reabsorption in the renal system?

Passive transport Signup and view all the answers

What type of transport is tubular secretion in the renal system?

Active transport Signup and view all the answers

What factors determine the amount of drug entering the renal lumen?

GFR, and protein binding Signup and view all the answers

Tubular reabsorption is most prominent in what type of drug?

Lipid soluble Signup and view all the answers

What is the relationship between blood flow and clearance in drugs with a high extraction ratio?

Clearance is directly proportional to blood flow Signup and view all the answers

For drugs with a low extraction ratio, clearance is nearly independent of which physiological factor?

Rate of liver blood flow (capacity limited) Signup and view all the answers

What is true about a drug with an extremely low intrinsic clearance?

Hepatic blood flow will have minimal influence on its metabolic rate Signup and view all the answers

If the intrinsic clearance for a drug is very high, what limits its metabolism by the liver?

Hepatic blood flow Signup and view all the answers

What is allosteric inhibition?

A type of enzyme inhibition that binds to a site other than the active site Signup and view all the answers

What is drug sensitivity?

The dose that causes a threshold response Signup and view all the answers

What is drug reactivity?

The rate of response to a drug Signup and view all the answers

What is the main difference between tachyphylaxis and anaphylaxis?

Tachyphylaxis is an acute desensitization to a drug, while anaphylaxis is a severe, life-threatening allergic reaction. Signup and view all the answers

What is the additive effect in pharmacology?

When two medicines have the same effect, increasing the overall response Signup and view all the answers

What does protein binding tend to parallel?

Lipid solubility Signup and view all the answers

Doubling the initial IV dose of a drug will

increase the duration of action by one half lfe Signup and view all the answers

What is the effect of doubling the initial IV dose of a drug on the duration of action?

Increase the duration of action by 1 half-life Signup and view all the answers

Study Notes

Receptors

Receptors can be found on the membrane or cytoplasm of a cell
Receptors can increase (upregulate) or decrease (downregulate) in response to stimuli
Receptors have multiple states and can switch spontaneously between them
Agonists bind to and activate receptors, increasing the amount of time they are active
Partial agonists activate receptors less completely than full agonists, and may also have antagonist activity
Inverse agonists turn off the constitutive activity of receptors
Antagonists bind to receptors without activating them, and can be competitive or non-competitive

Receptor States

Receptors can fluctuate between active and inactive states
Ligands can alter the relative time spent in each state

Competitive Antagonism

Increasing the concentration of an antagonist progressively inhibits the response to an agonist
Occurs when a protein binds to a receptor and prevents it from being activated
If enough agonist is present, it may overcome the antagonist
Works by binding to the receptor (reversibly) and preventing a normal ligand from binding

Non-Competitive Antagonism

No amount of agonist can overcome the antagonist
Works by binding to the receptor (permanently) and preventing a normal ligand from binding
Involves covalent bonding
Allosteric inhibition is an example of non-competitive antagonism

Tolerance and Sensitivity

Tolerance: any process that diminishes a drug's effect
Tachyphylaxis: decreased response to the same dose, often rapid and short-lived
Cellular tolerance: results from decreased receptor sensitivity or density
Hyperreactive: strong response to stimuli
Hyporeactive: weak response to stimuli
Hypersensitive: increased response to stimuli

Pharmacokinetics

Absorption: the process of a drug entering the body
Metabolism: the conversion of a drug into a more water-soluble form
Distribution: the movement of a drug throughout the body
Elimination: the removal of a drug from the body
Clearance: the rate of metabolism of a drug
Volume of distribution: the amount of drug in the body divided by the plasma concentration

Pharmacodynamics

What the drug does to the body
Dynamics: the study of the effects of a drug on the body
Potency: the amount of drug required to produce a desired effect
Efficacy: the ability of a drug to produce a desired effect

Elimination Half-Life

The time necessary for the plasma drug concentration to decrease by 50% during the elimination phase
Directly proportional to the volume of distribution
Inversely proportional to clearance

First Order and Zero Order Kinetics

First order kinetics: the rate of elimination is proportional to the plasma concentration
Zero order kinetics: the rate of elimination is constant and independent of the plasma concentration

Receptor Theory

Traditional thinking characterized receptor states as binary: effect is produced by ligand binding, and effect is absent when not bound by the ligand
An agonist binds to and activates a receptor, while an antagonist binds to the receptor without activating it
Receptors probably fluctuate between active and inactive conformations, spending various proportions of time between the two states
Ligands may alter the relative time spent in each state
Competitive antagonism: increasing concentration of the antagonist progressively inhibits the response to the agonist
Noncompetitive antagonism: antagonist administration prevents receptor activation even when exposed to high concentrations of the agonist
Partial agonists/agonist-antagonists: activate the receptor less completely than full agonists, can reduce agonist effects
Inverse agonists “turn off” the constituent activity of the receptor

Receptor Basics

Receptors may increase (up-regulate) or decrease (down-regulate) in response to specific stimuli
May exist on the surface of a cell (membrane-bound) or within cytoplasm of a cell
May respond to ligand or alterations in polarity of adjacent cell membranes
May either allow something into or out of a cell
Cause a process to start, accelerate, decelerate, or stop a cellular activity (usually protein or enzyme-mediated)

Pharmacokinetics of Injected Drugs

Determines the concentration in the plasma or effect site: Absorption, Distribution, Metabolism, and Elimination
Important terms to learn:
- Hyperreactive
- Hyporeactive
- Hypersensitive
- Tolerance
- Tachyphylaxis
- Agonist
- Antagonist
- Additive effect
- Synergistic effect

Distribution

Initial distribution (within 1 minute) mixing within the central compartment
IV injection delivers drugs to the vessel-rich group
Highly fat-soluble drugs may be vigorously taken up by the lung
Non-polar molecules (lipid-soluble) will be preferentially taken up by fat
Drug concentrations in the various compartments will be reflected in the calculated volume of distribution (Vd)
Pharmacologic effects may or may not reflect the current or steady-state concentration in the various compartments

Protein Binding

Acidic drugs tend to bind to albumin
Basic drugs tend to bind to alpha1 acid glycoprotein
Protein binding parallels lipid solubility (hydrophobic drugs are more likely to bind to plasma proteins or fat)
Only free fractions can cross cell membranes
Bound fractions are not available for hepatic extraction nor glomerular filtration

Metabolism of Drugs

Generally, metabolism converts active lipid-soluble drugs to water-soluble pharmacodynamically inactive drugs
Phase I reactions are mediated by CP450, and non-CP450 enzymes and mono-oxygenase enzymes
Phase II Reactions: Conjugation ties the agent to a polar compound, increasing its water solubility ability to be excreted

Hepatic Clearance

The rate of metabolism for most anesthetic drugs is proportional to drug concentration
Hepatic microsomal enzyme activity is located in the hepatic smooth ER

Clearance

The rate of clearance is proportional to drug concentration
Clearance is the volume of plasma cleared of a drug per unit of time
If the liver could completely extract the drug from afferent flow, clearance would equal liver blood flow

Zero-Order Kinetics

The rate of metabolism is independent of concentration

Three-Compartment Model

Initially, drug flows from the central compartment to the two other compartments
After rapid equilibration, the concentration in the central compartment falls below that of the rapid equilibration compartment, and the flow of drug is reversed
When the concentration in the central compartment falls below the concentration of the other two compartments, decreases in plasma concentration are dependent on elimination

Distribution and Tissue Uptake

Determinants of tissue uptake:
- Blood flow
- Concentration gradient
- Solubility
- Tissue mass
- Binding to macromolecules
- pH

Effect-Site Equilibration

The plasma is almost never the effect site (biophase)
Effect-site equilibration may be short (e.g., remifentanil, alfentanil, thiopental, propofol) or long (e.g., fentanyl, sufentanil, midazolam)
Dosing intervals should be adjusted to reflect effect-site equilibration

Context-Sensitive Half-Time

The time required for the concentration to decrease by 50%

Potency and Efficacy

Determinants of potency:
- Absorption
- Distribution
- Metabolism
- Excretion
- Receptor affinity
Efficacy is a measure of the intrinsic ability to produce a given physiologic or clinical effect

Dose Response Curve

The ED50 is the dose required to produce the desired effect in 50% of patients.

Pharmacokinetics

Clearance: the amount of blood completely cleared of drug per unit time
CSHT: provides clinically useful guidance on the expected increase in the time required to eliminate the drug as a function of the duration of drug administration
Infusion rate: to maintain a given steady-state arterial drug concentration, we must infuse drug at the same rate that it is being metabolized (Infusion rate = metabolic rate = Clearance × Cinflow)
Renal clearance: involves glomerular filtration, active tubular secretion, and passive tubular reabsorption
Volume of Distribution (Vd): the dose of drug administered / plasma concentration prior to elimination beginning; larger Vd means slower elimination of drug

Pharmacodynamics

Receptors: may be found on the membrane or cytoplasm of a cell; may increase (upregulate) or decrease (downregulate) in response to stimuli
Agonist: binds to and activates a receptor, increasing the amount of time it is active
Partial agonist: activates a receptor less completely than a full agonist, may also have antagonist activity
Inverse agonist: binds to a receptor and turns off its constituent activity
Antagonist: binds to a receptor without activating it, blocking the effect of an agonist

Pharmacokinetic Models

Simple pharmacokinetic model: 1-1/2 time, lose half of the drug; 2-1/2 time, lose half of the remaining half
Elimination half-time: the time necessary for the plasma drug concentration to decrease by 50% during the elimination phase
Three-compartment model: initially, the drug flows from the central compartment to the two other compartments; after rapid equilibration, the concentration in the central compartment falls below that of the rapid equilibration compartment, and the flow of drug is reversed

Pharmacological Effects

Potency: the amount of drug required to produce a desired effect
Efficacy: the ability of a drug to produce a desired effect
Additive effect: the combined effect of two or more drugs
Synergistic effect: the combined effect of two or more drugs that is greater than the sum of their individual effects
Tolerance: any process that diminishes a drug's effect
Tachyphylaxis: a rapid decrease in response to repeated doses over a short period of time

Pharmacokinetics and Pharmacodynamics

Kinetics: the movement of drugs in the body; what the body does to the drug
Dynamics: what the drug does to the body; the effects of the drug on the body
Distribution: the movement of drug from the site of administration to the site of action
Metabolism: the conversion of active lipid-soluble drugs to water-soluble pharmacodynamically inactive drugs
Clearance: the rate of metabolism for most anesthetic drugs is proportional to drug concentration

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