Exam 1B

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

Pharmacology