Key Principles in Clinical Pharmacology

Key Principles in Clinical Pharmacology

• Pharmacokinetics relates drug administration to drug concentration at the action site
• Pharmacodynamics relates drug concentration to pharmacological effect
• Patient demographics influence anesthetic behavior

Pharmacokinetics

• Describes the relationship between drug dose and drug concentration in plasma or at the effect site over time
• Absorption, distribution, and elimination (metabolism and excretion) govern this relationship
• ADME = Absorption, Distribution, Metabolism, Excretion
• Absorption is not relevant to intravenously administered drugs, but it is relevant to other routes of drug delivery
• Intravenously administered drugs’ time course depends on distribution volume and clearance
• Pharmacokinetic parameters derive from mathematical formulas fit to measured blood or plasma concentrations over time after a known drug dose

Volume of Distribution (Vd)

• Vd shows the apparent size of the "tank" needed to explain a measured drug concentration once the drug has thoroughly mixed

• Distribution volume is estimated using the relationship between dose (mg) and measured concentration (mg/L)

• Human bodies aren't water tanks

• A drug begins to clear from the body as soon as it's injected

• Volume of distribution = Amount of dose (t) / Concentration (t)

• t = time

• The distribution volume calculated by the equation will be constant if elimination occurs as a first-order process

• When administered intravenously, a drug will stay in the vascular volume but most distributes to peripheral tissues

• Distribution is often represented as additional volumes, “tanks,” attached to a central tank (blood or plasma volume)

• Peripheral distribution volumes increase total distribution volume

• More soluble drugs in peripheral tissue have larger peripheral distribution volumes relative to blood or plasma

• Drugs distribute to the peripheral tank, which increases the volume of distribution and binds to tissue (protein) in the tank

• Total distribution volumes may be larger than the sum of tanks and the volume distribution no longer remains constant over time

• Some anesthetics have distribution volumes larger than vascular (0.07 L/kg) or extracellular volume (0.2 L/kg)

• With additional distribution volumes, the overall volume changes over time as a function of how the drug is administered

• Bolus dose volume increase is from the drug distributing to peripheral tissue and a decrease in plasma concentration

• When using a constant infusion plasma concentration increases to steady state over several hours

• Steady-state is when the plasma concentration of a drug is in equilibrium with all other body tissues

• Lipid-soluble drugs have a greater Vd than water-soluble drugs

• Propofol has a very large Vd

• Skeletal muscle relaxants have a small Vd

Clearance

• Describes the rate of drug removal from the plasma/blood

• Two processes contribute to drug clearance:

  • Systemic (out of the tank)
  • Intercompartmental (between the tanks) clearance

• Systemic clearance permanently removes drug from the body by:

  • Eliminating the parent molecule
  • Transforming it into metabolites

• Intercompartmental clearance moves drugs between plasma and peripheral tissue

• Defined in units of flow, such as the volume completely cleared of drug per unit of time (liters/minute)

• Clearance = Q X E (Q = blood flow; E = extraction ratio)

• Should not be confused with elimination rate (e.g., mg/minute)

• A better descriptor because it is independent of drug concentration

• With long infusions, drug concentrations reach a condition where drug elimination is in equilibrium with the rate of administration, about 4-5 half-times

• Directly proportional to the dose administered

• Inversely related to the half-life of the drug or decreases the volume that is cleared per unit of time as the half-life increases

• The kidneys rely on the liver to convert lipophilic drugs to water-soluble metabolites via phase I and phase II because they are unable to excrete them

Physiologic Model for Clearance

• Drug extraction occurs by metabolic organs

• Mass balance: the drug flow rate of metabolic organs is the rate at which drug flows into them less the metabolic rate

• Extraction ratio (ER): the fraction of inflowing drug extracted by the organ

• Clearance is estimated as organ blood flow multiplied by the ER

  • Clearance = Q X E (Q = blood flow; E = extraction ratio)

• ER of 1.0 = 100% of drug to clearing organ is removed

• ER of 0.5 = 50%

• Total clearance is the sum of clearance by metabolic organs including the liver, kidneys, and other tissues

• The rate-limiting step in metabolism involves drug flow to the liver, referred to as "flow limited"

• Clearance also contains the capacity of the liver to take up and metabolize drug - "capacity limited.”

• Capacity can be changed (liver disease or enzymatic induction)

Extrahepatic Metabolism

• A few anesthesia medications are not cleared by hepatic metabolism
• Remifentanil, succinylcholine, and esmolol are cleared by ester hydrolysis in the plasma and tissues
  • Three of the four plasma pathways are enzymatic
  • Hofmann elimination is based on pH and temp.
• Pancuronium clears via the kidneys

Enterohepatic Circulation

• The process where the liver excretes a substance into the bile, then that substance is reabsorbed from the small intestine to the liver
• Drugs that undergo enterohepatic circulation, like diazepam and warfarin, tend to have a long effect duration

Hepatic Biotransformation

• Most anesthetic drugs are cleared by hepatic biotransformation (oxidation, reduction, hydrolysis, or conjugation)
• Oxidation and reduction occur in the cytochrome P450 system
• Conjugation and hydrolysis often occur outside the P450 system
• Conjugation results in the transformation of hydrophobic molecules into water-soluble molecules through the addition of polar groups that allow the metabolites to be excreted via the kidneys
• Metabolites are generally inactive, but some drugs like morphine and midazolam have active and potent metabolites
• Genetic polymorphism can occur in these pathways and account for the variability in clearance in the population

Phase I, II, and III Reactions

• The primary role of metabolism converts a drug to a more water soluble, inactive byproduct
• Increases ionization and decreases Vd
• Phase I involves modification to increase water solubility, carried out by the P450 system through oxidation, reduction, and hydrolysis
• Phase II involves conjugation for synthetic reactions through the addition of a water-soluble substrate
  • Enzyme induction or enzyme inhibition through calcium channel blockers and some antibiotics
• Phase III Involves ATP dependent carrier proteins transporting drugs across cell membranes in the liver, GI tract, and kidneys

Renal Elimination

• Eliminates metabolic waste into urine
• A drug’s fate depends on polarity, and the pH of the glomerular fluid
• Lipophilic drugs must undergo biotransformation before kidney excretion
• Drugs get to the urine by glomerular filtration and organic ion transporters
• Urine pH affects whether drug will be excreted or reabsorbed
• Ammonium chloride or cranberry juice will acidify urine to eliminate basic drugs
• Sodium bicarbonate or acetazolamide will alkalize urine for acid drugs

Pharmacokinetic Models

• Models provide estimates of drug concentrations over time in response to dosing regimens
• Physiologic models consider organ and tissue physiologic and anatomic data
• Organ drug concentration, blood flow, and distribution volume are needed
• Compartment pharmacokinetic models are empirical, and equations are based on measured plasma concentrations following a known dose
• Central clearance accounts for metabolism and excretion
• Clearances are between the central and peripheral compartments

Zero- and First-Order Kinetics

• Metabolism depends on drug concentration at the metabolism site and the intrinsic rate of the metabolic process
• Kinetic models consider finite enzyme activity

Zero Order

• Constant amount per time is eliminated
• Biotransformation process is saturated
• Example is EtOH, aspirin

First Order

• A constant fraction per time is eliminated
• Proportional to amount of drug present at time
• Half of the drug is reduced regardless of concentration
• 4-5 half-lives = fully eliminated
• Directly proportional to Vd
• Inversely proportional to rate of clearance
• When enzymes are saturated, the kinetics transition to Zero Order

One-Compartment Model

• For a one-compartment model with first-order kinetic elimination, the amount of drug at a given time is described where the initial drug amount undergoes a first-order kinetic elimination at a constant rate

Multicompartmental Model

• Plasma concentrations over time after an intravenous bolus become a curve
• The concentrations continuously decrease over time
• The rate of decline is initially steep but continuously becomes less steep
• The curve follows a log-linear path
• Plasma concentration < tissue concentrations

Three Distinct Distribution Phases

• Rapid-distribution phase begins immediately after injection of a bolus that rapidly moves from plasma to equilibrating tissues

• Slow distribution is characterized by drug movement into more slowly equilibrating tissues and drug return from plasma and most rapidly equilibrating tissues

• The terminal phase is when decreasing drug concentration and elimination occur

• The drug returns from the rapid- and slow-distribution volumes to plasma and is permanently removed by metabolism or excretion during the terminal phase

Plasma Protein Binding

• Intravascular drug storage compartment
• Drugs bond weakly to a protein which prevents drug receptor binding
• Albumin is most plentiful and favors acidic drugs in a 3 week half-life
• Only the unbound fraction is active
• Vd is inversely related to degree of protein binding
• Protein binding and drug lipid solubility are proportional
• Affects plasma and tissue proteins

Front-End Kinetics

• Front-end kinetics describes intravenous drug behavior after administration
• The speed with which a drug moves from the blood to peripheral tissues affects the peak plasma drug concentration
• An injected drug requires 30-40 seconds to get to the arterial circulation
• It’s important to be patient on the front lines

Back-End Kinetics

• Back-end kinetics describes the behavior of intravenous agents when administered as continuous infusions
• Decrement time predicts how long it takes to reach a certain plasma concentration after an infusion stops
• 50% decrement time is known as context-sensitive half-time
• The term context-sensitivity refers infusion duration

Hysteresis

• Hysteresis accounts for the time required for a drug to diffuse from the plasma to the site of action to illicit a drug effect
• Two different plasma concentrations can correspond to one drug effect or one plasma concentration may correspond to 2 drug effects
• The principle here is, changes in drug effect will lag behind changes in plasma drug concentration when drug concentrations are in flux
• Half-life has limited meaning to anesthetic practice

Influences on Kinetics

• Female patients exhibit a 20-30% increase in sensitivity to vecuronium, rocuronium, and pancuronium

• Males show an increased sensitivity to propofol resulting in reduced dosing requirements

• Females emerge from general anesthesia quicker but are more likely to experience recall under anesthesia

• Temperature impacts tissue blood flow and metabolism

• Increased patient temperature increases propofol elimination

Bioavailability

• The degree which a drug reaches the action site after administration
• Influences drug absorption, administration, blood flow, pH, pKa, and the molecular weight
• Some drugs are metabolized to a great extent after entering the portal circulation
  • first pass metabolism ~67% is metabolized with first-pass

Enteral Medication Administration

• Drugs administered orally may undergo presystemic elimination
• Stomach acids may hydrolyze or deactivate the drug, or it can be metabolized by first-pass hepatic elimination
• Sublingual administration bypasses the first-pass hepatic elimination
• Distal rectum bypasses the first-pass hepatic metabolism
• Proximal rectum are absorbed into the superior hemorrhoidal veins and DO undergo first-pass hepatic metabolism

Parental Medication Administration

• Intravenous administration has a bioavailability of 100%
• Intravenously administered drugs reach the systemic circulation quickly unless the distribution into the alveolar endothelium is extensive in the case of Fentanyl
• Pulmonary endothelium also contains enzymes that metabolize intravenous drugs like propofol on the first pass for reduce bioavailability

Other Routes

• Intramuscular and subcutaneous injections depend upon the capillary blood flow to the injection area
• Transdermal medications need a thin epidermis and good cutaneous blood flow
• Hands are a poor choice because the epidermis is 20-30 times thicker, whereas the back or abdomen is better
• Because the skin sloughs every 7 days, the maximum duration for a transdermal application is 7 days

Clinical Pharmacology

• What the drug does to the body

Pharmacodynamic Principles

• Relates drug concentration to pharmacologic effect
• Includes concepts like the dose-response relationship, receptor binding/affinity, and efficacy and therapeutic effect
• Plasma drug levels and drug effects are measured simultaneously
• a dose-response curve shows the rate of increased effect and dose

Pharmacodynamic Principles: Hysteresis Loop

• Ascending represents rising drug
• While rising, the increase in drug effect lags behind
• descending loop represents a decrease in the drug
• Effect lags behind concentration
• Relationships can be described using the Hill equation
• The C50 represents the concentration associated with 50% probability of having an effect

Potency and Efficacy

• Potency describes the amount of drug required to elicit an effect
• A common parameter used to describe potency is C50
• The drug is considered more potent if the relationship is shifted to the left and is small C50
• When shifted to the right, means shifted versus effect means that the relationship is shifted to the right
• A measure of effectiveness at producing effect once it occupies a receptor is called efficacy
• Achieving maximum effects are known as full agonist

Effective vs Lethal Doses

• A single drug can have multiple effects
• The C50 concept is used to compare various drug effects
• The dynamic range is where concentration ranges occur for changes in drug effect
• Concentrations outside the dynamic yield little to no change in drug effect
• Ineffective levels occur below the range but outside the range provide no additional effect
• The dose at which is a 50% probability of effect is ED50 and the dose at which is a 50% probability of death is LD50

Therapeutic Index

• A low ED50 = Potent drug
• LD50/ED50 ratio is the therapeutic index
• Larger ratio = a safer drug
• Dose with 99% Probability of unresponsiveness means it is ED99
• LD1 is the dose with the likelihood 1% probability of death
• Used in the safety margin LD1-ED99/ED99 x 100

Anesthesia Drug

• Interaction is used in the practice of applied drug
• Likely depends on drug exerting an effect on different receptors
• Ceiling effect exists, some Isoflurane is necessary regardless of fentanyl concentration to maintain MAC

Isobole

• Characterizes drug concentration continuum across combined drug pairs
• An isolbole represents a line for a selected rate of effect
• 50% is common
• The percentage needed to ensure responsiveness is 95%

Addition and Synergy

• Combination of the inhalation agents provides strictly additives suggesting it is a common acting mechanism exception is nitrous side that provides and infra- additive interaction
• IV various interactions with inhalation Agents is synergistic exception is nitrous oxide and sedatives
• Interactions also primarily synergistically

Drug Displays

• Models show response for surface drugs
• The drug helps identify the appropriate response
• Unique is given
• MAC does not embody the agents

Special Populations

• Body Habitus and gender exposure to opioids and kidney or heart liver or disease play a role
• The drug are all dependent

Obesity

• Dosing recommendation are for each body weight type
• Scaled are usually smaller than those with OB -Lean Ideal Weight

Propofol

• Liver and kidney are dependent and Cardiac output is affected
• Recommends LBM, CBW, and TBW affected

Others

• Dependent and is determined on what body type

Opioids

• Non specific and are similar
• Effects all the 3 categories above

Anesthetics

• Increase and decrease with OB