Pharmacology in Anesthesia Part 1

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Pharmacology in AnesthesiaPart 1

• Juan E. Gonzalez, CRNA, MS
• Assistant Clinical Professor

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Pharmacokinetics

• Pharmacokinetics (PK) describes relationship b/w
  dose of drug given its observed plasma and/or
  tissue.
• PK what the BODY does to the drug
• Clinical PK describes Absorption (A),
  Distribution (D), Metabolism (M), Elimination (E)
  of drugs. (ADME)
• Information about PK parameters (e.g. Vdss,
  CLtot) allows the prediction of plasma
  following different dosing regimens (dose
  individualization)

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Pharmacodynamics

• Pharmacodynamics (PD) describes relationship b/w
  drug and the response (pharmacological effect)
• PD what the DRUG does to the body
• PD effects responsible for desired (therapeutic
  efficacy) and undesired (toxicity) clinical
  outcomes
• Examples of PD measurements changes in BP during
  HTN Tx, decreases in HR during Beta-blocker Tx,
  changes in PT and INR during coumadin Tx
• drug receptor drug-receptor
  complex response

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PK PD

• Both PK PD are sources of variability in
  drug responses among pts (inter-patient
  variability e.g., age, concurrent illness,
  concomitant medications)

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PK PD

• Dosing regimen
• PK
• drug in the body (exposure)
• PD
• PD response
• Therapeutics
• Clinical outcome

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PK concepts

• When a drug is given extravascularly it must be
  absorbed across biological membranes to reach
  systemic circulation
• PO from GI tract into capillaries
  longer
• Transdermal from skin into capillaries
• Transfer of drug across membranes based on
• drug properties molecular size, degree of
  ionization, lipid solubility, protein binding
• other factors amount of blood flow to target
  tissue, gradient of drug across the membranes
• Vasculature transport of drug molecule to site
  of activity

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Transport
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Ionization

• Most drugs are salts of weak acids or weak bases
• For both weak acids and weak bases the total
  concentration of a drug is greater on the side of
  the membrane on which the drug is more ionized
• Degree of ionization of a drug (whether acidic or
  basic drug) at a particular site is determined by
  the dissociation constant (pKa) of the drug and
  the pH of the environment the drug is in

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pH, pKa, ionization

• Weak base
• If pHgtpKa unionized form predominates
• If pHpKa unionizedionized
• If pHltpKa ionized form predominates
• eg Basic Drug (diazepam)
• pKa 3.3
• In stomach pH1.3
• In plasma pH7.4
• Greater diazepam in GI compartment than in
  plasma

• Weak acid
• If pHgtpKa ionized form predominates
• If pHpKa unionizedionized
• If pHltpKa unionized form predominates

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PK concepts

• Once intravascular (IV)
• Drug can leave vasculature (penetrate tissues) or
  
• Drug can remain in blood
• Drug may bind to endogenous proteins (e.g.
  albumin)
• Binding is usually reversible (equilibrium b/w
  protein-bound drug and unbound drug)
• Unbound drug in blood is driving force of
  distribution of agent into body tissues

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PK concepts

• If unbound drug leaves the bloodstream and
  distributes to tissue
• drug may become tissue-bound
• drug may bind to receptor (pharmacologic or toxic
  response)
• drug may bind to a nonspecific site (no effect)
• drug may remain unbound in tissue
• drug may be rendered inactive and/or eliminated
  from the body (if tissue can metabolize or
  eliminate the drug)

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PK concepts

• Organs (e.g. liver, GI tract wall, lung) have
  enzymes that metabolize drugs. Resulting
  metabolites may be active (biological effect) or
  inactive (no effect)
• Blood has esterases enzymes that cleave ester
  bonds in drug molecules ? inactive

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Metabolism

• Metabolism (usually in the liver) via one or both
  types of reactions
• Phase I reactions
• make the drug more polar and water soluble ? more
  prone to elimination by the kidney (e.g.
  oxidation, hydrolysis, reduction)
• Phase II reactions
• Inactivate the pharmacologic activity of the drug
  and may make it more prone to elimination by the
  kidney (e.g., conjugation to form glucuronides,
  acetates, sulfates)

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Linear PK

• Most drugs follow linear pharmacokinetics
• drug in serum change proportionally with daily
  dosing (e.g., If X drug were doubled from
  400mg/d to 800mg/d, the patients serum drug
  would double
• If drug is given via continuous IV infusion,
  serum drug will increase until equilibrium b/w
  drug dosage rate and the rate of drug elimination
• e.g., if pt receiving theophylline at a rate of
  40mg/hr (dose), the serum theophylline will
  increase until the pts body was eliminating
  theophylline at 40mg/hr. When serum reaches a
  constant value ? STEADY STATE

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Compartmental PK

• Describes the body as a system of hypothetical
  compartments linked by transfer rate processes
  (assumed to be first-order proportional to the
  concentrations in their initial compartments)
• Linear or dose-proportional PK (e.g. drug is
  proportional to the dose given)
• These PK compartments group together several
  physiological compartments (tissues) that have
  similar kinetic properties
• Each compartment is characterized by its size
  (volume). Each compartment has homogeneous
  concentrations.

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One-compartment model
Only one Compartment
Drug given
Drug Eliminated
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Two-compartment model
Peripheral Compartment (vessel-poor group) 90
body mass 25 cardiac output
Central Compartment (vessel-rich group) 10 body
mass 75 cardiac output
Drug given
Drug Eliminated
-Central Compartment Can be sampled through the
blood. Made up of intravascular fluid and
organs/tissues highly perfused with blood, e.g
lungs, liver, kidneys, heart, brain (rapid
equilibrium distribution with blood) -Peripheral
Compartment Cannot be usually sampled. Made up
of organs/tissues poorly perfused with blood,
e.g muscle, skin, fat, bone (slow equilibrium
distribution with blood)
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Fluid Composition

• There are basically two water compartments in the
  body
• Extracellular 17 of body weight (12 liters)
• Plasma 4 of body weight (3 liters)
• Interstitial 13 of body weight (9 liters)
• Intracellularly 41 of body weight (28.5 liters)
• Total body water (58 of body weight) or
  (40.5 liters) (based on 70 kg man)

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Definitions

• Volume of Distribution (Vd) volume necessary to
  account for the total amount of drug in the body
  if the drug were present throughout the body in
  the same concentration as in plasma. Absorption
  must be rapid and one assumes there is no
  elimination.
• Vd is the apparent volume in which the drug is
  distributed after it has been introduced into the
  system.
• This hypothetical value is calculated from the
  total dose divided by the plasma concentration at
  zero time.
• Vd Q/CT0 where Q dose
  of drug
• 
  CT0 drug in plasma at time 0
• Units liters/kg

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Definitions

• Clearance (Cl) theoretical volume of plasma that
  is completely cleared of drug at a given time.
  Measure of the bodys ability to eliminate drug.
• Units ml/min
• Elimination Half-Time (T1/2 beta) time it takes
  for the drug in plasma to fall by one half
  (only accounts for time to a 50 decrease in
  central compartment concentration)
• Elimination Half-Life (t1/2) time it takes for
  the total amount of drug in the body to decrease
  by 50 after absorption and distribution are
  complete. Plasma concentration of a drug reaches
  steady state in 4 to 5 half-lives. Elimination
  also takes 4 to 5 half-lives

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References

• The Chemistry of Drugs for Nurse Anesthetists
  (2005)by L.B. Kier C.S. Dowd, AANA Publishing
  , Inc.Available only through AANA Bookstore
  http//www.aana.com/bookstore/books.asp
• http//www.med.howard.edu/pharmacology/handouts/ph
  armacodynamics.htm
• http//cdds.georgetown.edu/programs/guphm/ligand/
• http//pharmacy.creighton.edu/pha443/pdf/Default.a
  sp
• Nagelhout Zaglaniczny Nurse Anesthesia, 3rd
  edition