PHARMACOLOGY IN ANESTHESIA PART 1

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PHARMACOLOGY IN ANESTHESIAPART 1

• Alexa R. George, PharmD
• With significant contributions by
• Vicente Gonzalez, CRNA, MS and
• Juan E. Gonzalez, CRNA, PhD

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Pharmacokinetics

• Describes the Absorption, Distribution,
  Metabolism, Elimination of drugs (ADME) and their
  corresponding pharmacologic, therapeutic, or
  toxic responses
• Describes relationship b/w dose of drug given
  its observed plasma and/or tissue
• Defined therapeutic range
• What the BODY does to the DRUG

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Pharmacokinetics (PK)

• PK parameters allow the prediction of plasma
  following different dosing regimens (dose
  individualization)
• Ex Volume of distribution (Vd), Clearance (CL)
• Therapeutic Range (TR) the plasma or serum
  concentration range within which a drug is likely
  to produce its therapeutic effects
• Defined by minimum effective conc. (MEC) and
  minimum toxic conc. (MTC)

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Pharmacodynamics (PD)

• Describes relationship b/w drug and the
  response (pharmacological effect)
• Responsible for desired and undesired clinical
  outcomes
• Drug Receptor ? Drug-Receptor Complex ?
  Response
• What the DRUG does to the BODY
• Ex Objective- Changes in BP, HR, PT/INR
• Ex Subjective- Relief of pain, anxiety

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PK PD

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

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Transport

• 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 transports drug molecule to site of
  activity
• Passive diffusion most common, moves down
  concentration gradient
• Facilitated diffusion carrier-mediated process,
  moves down conc. gradient
• Active Transport carrier-mediated, requires
  energy, can move against conc. gradient

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Transport
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Ionization

• Most drugs are salts of weak acids or weak bases
• Absorbed by passive diffusion
• Drugs are preferentially absorbed in their
  unionized form
• Fraction of drug available in unionized form
  depends on the dissociation constant (pKa) of the
  drug and the pH of the environment
• Lipid solubility plays a large role

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Ionization

• pKa pH at which ionized and unionized forms are
  in a 11 ratio
• pH defined as the negative log of H
• Henderson-Hasselbach equation allows calculation
  of degree of ionization
• Weak acids pH pKa log ionized
• unionized
• Weak bases pH pKa log unionized
• ionized

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Ionization, pH, pKa

• 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
• pHpKalog ionized/unionized

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

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More about protein binding

• Most drugs bind to plasma proteins (e.g.,
  albumin)
• Bound drugs (protein-bound) stay in intravascular
  space (IV)
• Free drugs (unbound) cross capillary wall to
  target tissue/cells
• Unbound and unionized (uncharged) drugs cross
  placenta and blood brain barrier
• Pts with hypoproteinemia (hypoalbuminemia) are
  more sensitive to intravenous drugs since protein
  binding is decreased (more than usual free drug
  could get out of IV space and it is distributed
  to tissue/cells (increased Vd) and cause toxicity
• 65-85 of circulating Thiopental is protein-bound

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ADME

• Absorption process by which a drug proceeds from
  the site of administration to the site of
  measurement (usually blood, plasma, or serum)
• Distribution process of reversible transfer of
  drug to and from the site of measurement (between
  blood and tissue)
• Metabolism process by which a drug is
  structurally changed for purposes of
  detoxification and elimination
• Elimination (Excretion) the irreversible loss of
  drug from site of measurement

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PK Concepts Absorption

• Extravascular administration drug must be
  absorbed across biological membranes to reach
  systemic circulation
• PO from GI tract into capillaries
• Transdermal from skin into capillaries
  longer
• Sublingual, rectaI
• IM, SQ injections

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Absorption

• Bioavailability (F) the fraction of administered
  drug that reaches general circulation
• Influenced by gut function, gut perfusion (CHF),
  route of administration, first-pass metabolism
• First-pass effect combined action of intestinal
  and liver enzymes on drugs, or loss of a drug
  given orally, before it reaches systemic
  circulation

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PK concepts Distribution

• Intravascular administration bypasses absorption
  (A)
• Immediate onset of action
• 100 bioavailability (F1)
• Once 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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Distribution

• If unbound drug leaves the bloodstream and
  distributes to tissue
• Drug may become tissue-bound
• Binds to receptor (pharmacologic or toxic
  response)
• Binds to a nonspecific site (no effect)
• Drug may remain unbound in tissue
• Drug may be rendered inactive and/or eliminated
  from the body
• One vs Two-compartment models

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PK concepts Metabolism

• Organs (e.g. liver, GI tract, lung) have enzymes
  that metabolize drugs
• Resulting metabolites may be active (biological
  effect) or inactive (no effect)
• Ex CYP450 system
• (see cytochrome P-450, Table 5, page 122 in The
  Chemistry of Drugs for Nurse Anesthetists)
• 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
• Can also produce inactive metabolites
• Ex oxidation, hydrolysis, reduction
• Phase II reactions
• Inactivate the pharmacologic activity of the
  drug, may make it more prone to elimination by
  the kidney (more water-soluble)
• Ex conjugation reactions- glucuronidation,
  acetylation, sulfation

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PK concepts Elimination

• Occurs by 2 processes Metabolism and Excretion
• Excretion irreversible loss of drug in
  chemically unchanged form
• Kidney is primary site of excretion (of both
  unchanged drug and metabolites)
• Clearance (CL) rate of drug removal at a given
  time
• Measure of the bodys ability to eliminate drug
• Units ml/min
• Calculate patients Creatinine clearance (CLcr)
  to determine dosing regimen (Cockroft-Gault)
• CLcr (140-age) (weight)
• (72 x Scr)

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PK Parameters

• Volume of Distribution (Vd) relates the amount
  of the drug in the body to the concentration of
  the drug in the plasma (Cp)
• Apparent volume --gt hypothetical value that tells
  us about distribution characteristics of a drug
• Calculated from the total dose divided by the
  plasma concentration at zero time
• Vd D/Cp0 where D dose
  of drug
• 
  Cp0 drug in plasma at time 0
• Units liters/kg

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Volume of Distribution
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PK Parameters

• Elimination rate constant (Ke) Fraction of the
  total amount of drug removed per unit of time
• Function of clearance and Vd Ke CL/Vd
• Elimination half-life (t1/2) time required for
  serum drug to be decreased by 50 after
  absorption and distribution are complete
• t1/2 0.693 / Ke
• Plasma reaches Steady State (Css) in 4-5
  half-lives
• Css where rate of infusion rate of elimination

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PK Parameters

• 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)
• Context sensitive half-time the time necessary
  for plasma drug concentration to fall by 50 or
  other percentage after a continuous infusion of
  specific duration
• Time to Recovery how far plasma must decrease
  to reach levels compatible with awakening

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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