עקרונות בסיסיים של פרמקולוגיה

Basic Principles of Pharmacology

• Pharmacokinetics shows the link between drug dosage and drug concentration over time.
• Distribution and elimination affect this relationship for anesthetic drugs.
• Estimates of distribution volumes and clearances come from mathematical formulas. These are based on blood or plasma concentrations after giving a known drug dose over time.
• Front-end kinetics are heart alterations that affect drugs' effects (onset, duration).
• Context-sensitive decrement time marks how long it takes to reach a plasma concentration after stopping long infusions.
• Hysteresis refers to the time it takes for drug effects to show up after concentration changes.
• Hysteresis includes how long it takes for drug to move from plasma to action site and then to have an effect
• Pharmacodynamics studies what drugs do to the body.
• It links drug concentration to its effects.
• Effect-site concentration involves mathematically determining where an anaesthetic drug works.
• Cannot show mechanism of action like drug-receptor interaction
• A single anaesthetic drug can cause several different effects which occur at different effect-site concentrations:
  • Analgesia
  • Ventilatory depression
  • Loss of response to laryngoscopy
  • Changes in electroencephalogram
• Dynamic range is when drug effect changes with concentration.
• Outside this range, drugs aren't effective enough or don't provide additional effect.
• Anesthesia uses drug interactions.
• Anesthetics combine drugs for hypnosis, analgesia, and muscle relaxation.
• Drugs interact such that when administered together, they don't act as if they were given alone.
• Pharmacokinetic and pharmacodynamic principles highlight drug effect magnitude and timeline.
• They have limited clinical use because of complex calculations.
• Computer displays show how drugs act in real-time, which is a breakthrough.
• Special patients must have the correct dose via:
  • Age
  • Body habitus
  • Gender
  • Chronic exposure:
    • Opioids
    • Benzodiazepines
    • Alcohol
  • Presence of:
    • Heart disease
    • Lung disease
    • Kidney disease
    • Liver disease
  • Extent of:
    • Blood loss
    • Dehydration
• Anesthetic medicine changes due to obesity and age
• Anesthetic behavior is weakly linked to use of opioids and renal failure.

Intro To Pharmacology for Anesthesia

• This section is made up of three parts:
  • How drugs move around the body
  • The effects that drugs have
  • How patient traits affect choices
• Pharmacokinetics regards drug amount in body relating to concentration at action point
• Core Concepts:
  • Volumes of distribution
  • Drug clearance
  • Drug transfer
• Pharmacodynamics links amounts of drug to the drug effects
• Most anesthesia uses several drugs for:
  • Pain relief
  • Sedation
  • Muscle relaxation
• Patient biology is important to how they respond to drugs and it is determined by:
  • Age
  • Weight
  • Gender
  • Existing and historical exposure to:
    • Opioids
    • Benzodiazepines
    • Alcohol
  • Dysfunction of:
    • Heart
    • Lung
    • Kidney
    • Liver
  • How well they compensate for:
    • Blood loss
    • Dehydration
• Age and weight are important considerations

Pharmacokinetics Concepts

• It links drug concentration to its movement through out body
• Movement factors:
  • Absorption (not relevant to IV)
  • Distribution
  • Metabolism and Excretion
• The timespan of IV drugs relies on volume and clearance
• Models can predict levels of concentration after amount given

Volume of Distribution

• An over-simplified model is that a drug is diluted into a water tank.
• Distribution volume regards size of tank where known amount of drug spread evenly after a time.
• How distribution is estimated: An injected medicine (mg) dissolves in tank where volume is estimated by looking at concentration (mg/L)
• Vd = amount/concentration
• Body isn't tank but this helps calculate appropriate dose and figure out drug effect once levels stabilizes
• Because body clears drugs almost immediately, a faucet in these models represents body removing drug
• If the drug removal in the tank changes concentration, volume is estimated with the amount and concentration over time:
  • Vd=Amount(t)/Concentration(t)
• If drug is removed at a constant rate, its estimate can be constant
• However, IV introduced medicines don't stay and usually travel to tissues
• Peripheral distributes volume to a central one with blood
• Sizes in periphery show how blood soluble the drug is.
• High peripheral solubility means larger dispersion and lowers measurable concentration
• So, total amount of distribution bigger than starting dose.
• Anesthetics (fentanyl) can spread to 4L/kg but vascular is lower at 0.07 L/kg or 0.2 L/kg on extra.

Elimination Example

• A tank gets continuously drained at 50% of the total every 120 minutes. The level goes 10 to 5 to 2.5 mg/ml
• The estimates remain that Vd is at 1 L
• Volume distribution doesn't change as the drug gets eliminated
• In two tanks, distribution changes.
• Measuring concentrations is made difficult with tissue
• Schematic models plasma and tissue volumes
• Ellipses show drug tied up in tissue
• 10mg injected and reading of 2.5 uses 4L 
• Anesthetic doses need to take the changing Vd volume into consideration as with varying volume is an outcome with bolus/infusion

Clearance

• Clearance measures quickness of drug removal
• Systemic releases through excretion or change
• Tank release is systemic and is “intercompartmental”
• Intercompartmental transfers drug between tanks
• Clearance measures how much liquid is being clear of drugs at a certain measurement
• Clearance amount isn't elimination 
• With first order estimates, high concentration causes rates of removal is high 
• Clearance independent rate/time based so good to measure drug

Visualizing Clearance

• The quantity in tank and how it moves at 1L/min rate, as a way to evaluate its constant removal.
• Amount eliminated is related to its level as “first order”. The initial change as "Drug concentration" changes greater than what is observed later.
• Drug at Time-A is quicker while window changes in "Drug concentration B" from 3-4 minutes
• Elimination shows mg/ml over how it breaks down: A is from 28 down to 14. B is from 10.4 down to about 5. 
• Estimate as the ratio of how much drug scaled to concentration for amount of volume
• The "amount of drug in Tank= Concentration+Clearance in relationship to amount of drug in ml or microgram".

Equations of Clearance

• Amount that is to be eliminated is equal that the location is under graph.
• Clearance can then be is the dose or size of area in graph.
• Constant IV gives state where removed equalled rate.
• Then ratio of rates can be understood where Css is continuous stage.
• Volume of drug and it being cleansed equals level of what's around with flow to volume is 1L/min
• Continuous drugs are consistent as drugs get cleaned all the time because kinetics constant. 
• When first injected and volume equal to 4 L equals 64 mg then as the body reacts it eliminates and lowers it. 
• This all goes down as drug broken.

Mass Balance

• Amount of drug flows by organ equals rate it enters in balance to metabolism.
• Amount getting removed over C-in and C-out.
• Total clearance equals metabolic organ
• Hepatic is how it is then how ER relates.
• Low extraction the flow does not change effect
• All extracted then large metabolism rate is flow limited: hepatic goes reduces.
• Moderate affects may have little affect

Rates

• Volume has first rate and has constant and inverses it
• Extraction models need to be examined.

Models

• Pharmacology depends on time as is with bolus amounts. Can use physiologic or “curve models."
• Physiology depends on blood organ
• Curve are complex
• Simple depends to know is good and useable to figure out levels that are right.
• Modeling can be transformed with variables

Compartment Models

• They used when calculating curve levels
• They made off formula
• Kinetic changed as clearance changes
• Three stages with one central and two outward as all equals one final volume

Rate Example

• System clearance removes both the outward and central.
• Rate are drug change from compartment I to J
• 1-0 is is central to out
• Two is how it enters and leaves
• These are all from the models.
• Rates have zero in constant while first are amount relative.
• Amounts change the rates in first.
• One needs sat the rates change

One Compartment Model

• Formula is A(t) as amount equal A zero as constant and change over time
• Volume and time relate to "concentration", with an opposite reaction if it is too quick or slow
• Volume= the amount of concentration or a set.

Multi Example

• This requires constant change:
  • Rate of level drops
  • Initial is greater
• Fast rate early after shot
• Has medium and slow
• Long it is over will it move into the slow.

Visual aid

• It moves to two tanks and as it moves that way tanks change, the more they change or are slow the longer that part acts to decrease levels or has effect.
• Rate changes make some drugs slow to reduce or take time for the drug to finally leave.