8/21/22
Pharmacokinetics
N926 Pharmacology for Nurse Anesthesia
Nicolette Hooge, DNP, MBA, CRNA
1
Objectives
• Describe the processes of absorption, distribution, metabolism, and excretion and factors that affect each
• Explain key characteristics of drug plasma concentration vs. time curves
• Define: elimination half-life, steady-state, the volume of distribution, clearance, plasma protein binding,
bioavailability, and first-pass effect
• Compare and contrast first-order elimination kinetics to zero-order elimination kinetics
• Describe how elimination half-life relates to steady-state, disappearance of drug from the body, and doseadjustment considerations
• Explain the relationships between common PK parameters; predict how a change in one parameter may
affect another
• Calculate basic PK parameters using hypothetical data
• Distinguish how PK can be used to predict drug actions and interactions and optimize drug therapy
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Purpose of Anesthesia Pharmacology
Class
To provide you with the knowledge of a full spectrum of drugs so you can
create and implement an anesthetic care plan to achieve the desired level
of:
• surgical anesthesia
• analgesia
• amnesia
• muscle relaxation
3
Goal of Anesthesia Pharmacology
To deliver the serum concentration of
drugs that will result in desired effects
while minimizing side effects
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Pharmacology Overview
A schema of clinical
pharmacology divided into dose,
concentration, and effect domains.
The science underpinning the field
can be divided into the disciplines
of Pharmacokinetics, the
Biophase, and Pharmacodynamics.
Triangles represent drug molecules.
PK – pharmacokinetics
PD – pharmacodynamics
5
Pharmacokinetics
Describes what the body does to the drug
Quantitative study of:
Absorption
Distribution
Metabolism
Elimination
Excretion
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Absorption
The passage of a drug from its site of administration into the circulation
7
Factors Affecting Absorption
• Route of Administration
• Drug Formulation
• Physiochemical Properties
• molecular size
• concentration gradient
• drug transporters
• solubility
• ionization
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Route of Administration
9
Route of Administration
Intravenous &
Inhalational
Oral, Sublingual,
Buccal, Nasal,
Transdermal, & Rectal
reach the systemic circulation
almost instantly
initial delay between
administration and appearance of
the drug in the systemic
circulation
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Oral Administration
• Advantages
• most convenient
• inexpensive
• Disadvantages
• emesis caused by irritation of the GI mucosa by the drug
• destruction of the drug by digestive enzymes or acidic gastric fluid
• irregularities in absorption in the presence of food or other drugs
11
First-Pass Hepatic Effect
• Principal site of most drug
absorption = small intestine
• large surface area
• Drug enters portal venous
blood & passes through the
liver before entering the
systemic circulation for
delivery to tissue receptors
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Sublingual, Buccal, & Nasal
Administration
• Rapid onset of drug effect
• bypasses the liver preventing first-pass metabolism
• drugs absorbed from the oral cavity flow into the superior vena cava
• Buccal administration
• alternative to sublingual placement of a drug
• better tolerated
• less likely to stimulate salivation
• Nasal administration
• limited to small volumes
• only high potency & hydrophilic drugs can be administered
• disease conditions of nose impair absorption
13
Transdermal Administration
• Provides sustained therapeutic plasma concentrations of the drug
• Decreases the likelihood of loss of therapeutic efficacy due to peaks and
valleys associated with conventional intermittent drug injections
• Low incidence of side effects
• High patient compliance
• Examples
•
•
•
•
•
•
Scopolamine*
Fentanyl
Clonidine
Estrogen
Progesterone
Nitroglycerin*
*Sustained plasma concentrations provided by transdermal
absorption result in tolerance and loss of therapeutic effect
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Rectal Administration
UNPREDICTABLE
• Administered into the PROXIMAL rectum are absorbed into the superior
hemorrhoidal veins and subsequently transported via the portal venous system to
the liver
• First -pass hepatic metabolism
• Administered into the DISTAL rectum can be absorbed directly into the
systemic circulation, bypassing the liver.
15
Route of Administration
16
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Drug Formulation
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Drug Formulation
• Dosage Forms
• tablets
• capsules
• solutions
• Drug formulations consist of
the drug plus other ingredients
• formulated to be given by various routes
• Regardless of the route of administration, drugs must be in a solution
to be absorbed
• solid forms (tablets) must be able to disintegrate and dissolve
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Drug
Formulation
19
Physiochemical Properties
Molecular Size | Concentration Gradient | Drug Transporters | Ionization | Solubility
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Drug Transporters
• Transporters can either help drugs get across biological barriers (such as the gut lining) or
work to exclude them from a part of the body (such as the brain)
• Many cell membranes possess specialized transport mechanisms that control entry and exit
molecules
• sugars | amino acids | neurotransmitters | metal ions
Solute Carrier (SLC) Transporters
Adenosine Triphosphate (ATP) –
Binding Cassette (ABC) Transporters
control passive movement of solutes down
their electrochemical gradient
active pumps requiring energy derived from
adenosine triphosphate
21
Ionization
• Ionization: process where an atom or molecule loses an electron,
resulting in two oppositely charged particles
• a negatively charged electron
• a positively charged ion
• Most drugs are weak acids or weak bases
• exist in both ionized and nonionized forms in solution
• acids are usually proton donors
• bases can usually accept a proton
• If a drug is ionized, then it is charged with either a negative or positive
charge
A-
BH+
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Ionization
HA
A-
Ionized = water soluble
Nonionized = lipid soluble
BH+
B
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Degree of Ionization
• Degree of Ionization of a drug depends on
• pH of environment
• pKa
• pKa: pH at which the drug is 50% ionized and 50% nonionized
𝐻𝐴 ⟷ 𝐴! + 𝐻"
𝐵𝐻" ⟷ 𝐵 + 𝐻"
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Degree of Ionization
Weak Acid
!
𝐻𝐴 ⟷ 𝐴 + 𝐻
"
Weak Base
𝐵𝐻" ⟷ 𝐵 + 𝐻"
Local Anesthetics
Opioids
Atropine
Amphetamines
Aspirin
Barbiturates
Cephalosporines
Loop & Thiazide diuretics
25
Degree of Ionization
Acidic Environment
(pH < 7)
Basic Environment
(pH >7)
Acidic Drug
(pH < 7)
Nonionized
Ionized
Basic Drug
(pH > 7)
Ionized
Nonionized
v
v
v
v
Acid drug in acidic environment: nonionized [HA] à absorbed
Acid drug in basic environment: ionized [A-] à cleared
Base drug in acidic environment: ionized [BH+] à cleared
Base drug in basic environment: nonionized [B] à absorbed
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Ionization & Solubility
Most drugs are weak acids or bases that are present in both
ionized and nonionized forms in solution
Ionized
• water soluble (hydrophilic)
• cannot cross cell membrane
• pharmacologically inactive
Nonionized
• lipid soluble (lipophilic)
• can diffuse across cell membranes
• BBB, renal tubular epithelium,
GI epithelium, placenta,
hepatocytes
• pharmacologically active
27
Determinants of Degree of Ionization
• The degree of drug ionization is a function of its dissociation constant
(pKa) and the pH of the surrounding fluid
• pKa = pH à 50% of the drug exists in both the ionized and nonionized
form
• Small changes in pH can result in large changes in the extent of
ionization
• especially if the pH and pKa values are similar
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Determinants of Degree of Ionization
Acidic Drugs
Basic Drugs
Barbiturates
Opioids & Local anesthetics (LA)
• highly ionized at an alkaline pH
• usually supplied in basic solution
to make more soluble in water
• highly ionized at an acid pH
• usually supplied in acidic solution
to make more soluble in water
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Ion Trapping
• The nonionized form of the drug equilibrates across lipid membranes
• When lipid membranes separate fluids with different pHs, a
concentration difference of total drug can develop on the two sides of
the membrane
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Henderson-Hasselbalch
𝑝𝐻 = 𝑝𝐾! + 𝑙𝑜𝑔"#
𝑝𝑂𝐻 = 𝑝𝐾% + 𝑙𝑜𝑔"#
𝐴$
𝐻𝐴
𝐵𝐻 &
𝐵
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Henderson-Hasselbalch
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Dissociation Constant
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pH & pKa
Weak Acid
Weak Base
If pKa – pH ≥ 1
If pKa – pH ≥ 1
and
and
• pH lower than pKa à ~100% nonionized
• pH lower than pKa à ~100% ionized
• pH higher than pKa à ~100% ionized
• pH higher than pKa à ~100% nonionized
If pKa – pH < 1 à partially ionized and partially nonionized
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pH of Body Fluids
Fluids
pH
Gastric juice
1.0 – 3.0
Small intestine: duodenum
5.0 – 6.0
Small intestine: ileum
7–8
Large intestine
7–8
Plasma
7.4
Cerebrospinal fluid
7.3
Urine
4.0 – 8.0
n
35
Bioavailability
• Bioavailability: the extent and rate at which the active moiety (drug or
metabolite) enters systemic circulation, thereby accessing the site of
action
• Bioavailability of a drug is largely determined by the properties of the
dosage form
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Causes of Low Bioavailability
• First-pass hepatic metabolism
• Insufficient time for absorption in the GI tract
• Patient-specific factors
• Age, gender, physical activity, genetic phenotype, stress, disorders (malabsorption
syndromes), or previous GI surgery (bariatric surgery)
37
Assessing Bioavailability
• Usually assessed by determining the area under the plasma concentration
curve (AUC)
• AUC most reliable measure of a drug’s bioavailability
• AUC directly proportional to the total amount of unchanged drug that
reaches systemic circulation
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40
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Systemic Absorption of Drugs
• The rate of systemic absorption determines the magnitude of the drug
effect and duration of action
• Changes in the rate of systemic absorption rate may require adjusting the
dose or time interval between repeated drug doses
• Systemic absorption, regardless of the route of drug administration,
depends on the drug’s solubility
• Local conditions at the site of absorption alter solubility, particularly in
the gastrointestinal tract.
• Blood flow to the site of absorption also affects the rate of systemic
transfer
41
Systemic Absorption of Drugs
Drugs must cross the cell membrane to reach the systemic circulation
Passive (simple) diffusion
• most common
• Fick’s law of diffusion
• aqueous or lipid environment
• does not require energy
• drug is transferred based on
concentration gradient
Carrier-mediated membrane transporters
• Active diffusion
• usually faster
• energy-consuming process
• essential for GI absorption and renal &
biliary excretion of many drugs
• enables movement of drugs AGAINST a
concentration gradient
• Facilitated diffusion
• minor role in drug absorption
• does not require energy
• does not enable movement against a
concentration gradient
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Distribution
The disbursement of an unmetabolized drug as it moves through the body’s blood and
tissues
43
Factors Affecting Distribution
• Drugs must cross cell membranes to produce an effect
• Transfer across cell membranes occur more readily with a:
üLow molecular weight
üHigh concentration gradient
üLow degree of ionization
üHigh lipid solubility
üLow degree of protein binding
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Solubility
• Polar drug à water (hydrophilic)
• Nonpolar drug à fat (lipophilic)
• Many anesthetic drugs are highly fat soluble = large volume of distribution (Vd)
• Because fat soluble drugs are preferentially taken up by fat, thus diluting the concentration
of drug available in the plasma
• **Propofol
• large amount is held in the body’s fatty tissues
• Accumulation of drugs in tissues or body compartments à prolonged duration
of action (DOA)
• Because tissues release the accumulated drug as plasma drug concentration decreases
• Storage of drug in fat INITALLY shortens the drug’s effects, but eventually prolongs the
effect
• initial doses distribute into fat leaving a lower concentration bioavailable
• subsequent doses are more bioavailable d/t saturation of the fat compartment
45
Protein Binding
• Most drugs are bound to plasma proteins
• Albumin (most acidic drugs)
• ⍺1-acid glycoprotein (most basic drugs)
• lipoproteins
• Protein binding affects:
• Distribution of drugs
• Potency of drugs
• Only unbound drug is available for passive diffusion to extravascular or tissue
sites where the pharmacologic effects of the drug occur. Therefore, the
unbound drug concentration in systemic circulation typically determines drug
concentration at the active site and thus efficacy.
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Protein Binding
• The degree of protein binding for a drug is proportional to its lipid solubility
• More lipid soluble à More highly protein bound
• Binding sites on proteins is finite
• protein binding can be overcome by adding more agents that compete for the binding
sites
• bond between drug and protein is weak
• dissociation when plasma concentration of the drug declines or a second drug binds to
the same protein
• Drugs that are >90% protein bound will have an unexpected intensification of their
effect
• warfarin, phenytoin, propranolol, propofol, fentanyl and its analogs, diazepam
• Drugs that are <90% protein bound exhibit little change in their effect
47
Protein Binding
• Binding of drugs to plasma albumin is nonselective
• Drugs with similar physicochemical characteristics may compete with each other
and with endogenous substances for the same protein binding sites
• Age, hepatic disease, renal failure, and pregnancy can decrease plasma
protein concentration
• important in drugs that are highly protein bound
• unbound (free) fraction of the drug increases and may increase the
pharmacological effect
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Volume of Distribution (Vd)
Relationship between the administered dose of a drug and the plasma concentration
that results
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Volume of Distribution (Vd)
• The volume in which the drug is distributed after it has been introduced
into the system
𝑉# =
𝑑𝑜𝑠𝑒 𝑜𝑓 𝑑𝑟𝑢𝑔
𝑝𝑙𝑎𝑠𝑚 𝑐𝑜𝑛𝑐𝑒𝑛𝑡𝑟𝑎𝑡𝑖𝑜𝑛 𝑜𝑓 𝑑𝑟𝑢𝑔
• Used to calculate the loading dose of a drug that will achieve a steadystate concentration
• In practice, a patient’s Vd is unknown
• an average volume of distribution is assumed
• used to calculate a loading dose that will attain a therapeutic concentration rather
than a steady-state concentration
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Intracellular Fluid
28 L
𝑉# 70 𝑘𝑔 𝑎𝑑𝑢𝑙𝑡 =
42 𝐿
70 𝑘𝑔
𝑉# 70 𝑘𝑔 𝑎𝑑𝑢𝑙𝑡 = 0.6 𝐿>𝑘𝑔
ECF (14 L)
Total Body Water (42 L)
Volume of Distribution (Vd)
Interstitial Fluid
10 L
Plasma 4 L
51
Volume of Distribution (Vd)
• Vd provides information on how extensively a drug is distributed
throughout the body
• Large Vd (> 0.6L/KG) à widely distributed in the body and likely lipid soluble
• Propofol is quickly distributed to peripheral tissues after induction, which ends its action
much more rapidly than its elimination half-life would predict
• Patient wakes up because of redistribution from the brain (central compartment) to the
peripheral compartment
• However, the patient may feel sleepy for hours because of the long elimination half-life of
the drug from the whole body (11.6 hours)
• Small Vd (< 0.4 L/ KG) à largely contained in the plasma and likely water
soluble
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Compartmental Pharmacokinetic
Models
53
Central Compartment
• IV drugs mix with body tissues and are immediately diluted by mixing
with the “central compartment”
• Central compartment
•
•
•
•
•
venous blood volume of the arm
volume of the great vessels
heart
lungs
upper aorta
• Many of these volumes are fixed regardless of the drug that is given
• Except the Lungs
• First-pass pulmonary uptake
• Highly lipid soluble drugs
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Other Compartments
• Mixing within the myriad of body fluids and tissues is an ongoing
process
• several minutes to mix with the entire blood volume (AKA circulation time)
• may take hours or days for the drug to fully mix with all bodily tissues
• Fat Compartment
• Blood supply is limited
• Gradual absorption and sequestering of drug
• Accounts for a substantial part of the offset of drug effect following a bolus
• Muscle
• intermediate role d/t intermediate blood flow and solubility for lipophilic drugs
55
Tissue Groups Based on Perfusion
VesselRich
Muscle
Fat
VesselPoor
% body weight
10
50
20
20
% cardiac output
75
19
6
0
Perfusion
(mL/min/100 g)
75
3
3
0
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Vessel-Rich Group
• Following bolus injection, the drug initially goes to the tissues that
receive the bulk of arterial blood flow (vessel-rich group)
•
•
•
•
Brain
Heart
Kidneys
Liver
• Rapid blood flow ensures that the tissue drug concentration rapidly
equilibrates with arterial blood
• Highly lipid-soluble drugs, the capacity of the fat to hold the drug greatly
exceeds the capacity of highly perfused tissues
57
Compartmental Pharmacokinetic
Models
• Compartmental models are theoretic spaces with calculated volumes
used to describe the PK of agents
• useful for prediction of serum concentration and changes in drug concentrations
in other tissues
• One-compartment model
• Two-compartment model
• Multi-compartment model
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One-Compartment Model
• Represents entire body
• Homogeneous distribution
throughout
• Generally, insufficient to
explain the kinetics of lipidsoluble anesthetic drugs
59
Two-Compartment Model
• Central compartment
(vasculature and vessel-rich
tissues)
• 10% of body mass, but 75%
of cardiac output
• Peripheral compartment
(muscle, fat, and bone)
• 90% of body mass, but only
25% of cardiac output
Sum of all volumes = volume of distribution at steady state (Vdss)
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Two-Compartment Model
• Clearance for drugs
permanently removed from
the central compartment is
the “systemic clearance”
• Clearances between the
central compartment and the
peripheral compartments are
the “intercompartmental”
clearances
61
Multi-Compartment Model
Drugs that display multi-compartment models of distribution will move from
the central compartment into peripheral compartments before elimination
Phases of multi-compartment models
• Distribution phase
• Terminal elimination phase
• Steady State
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Multi-Compartment Model
Distribution Phase: following administration plasma drug concentration will initially decline
while the total amount of drug in the body remains the same
• This phenomenon will cause a single drug to have multiple Vd values, which are each timedependent
Terminal elimination phase: Following the distribution phase, the drug will be eliminated
from the central compartment (by the kidneys/liver) causing changes in both amounts of the
drug in the body and plasma drug concentration
Steady-state: Between the distribution & elimination phase, there is a transition point in which
the drug has completed distribution between the central & peripheral compartments and the
net flux of drug between the central & peripheral compartments is 0
• Vdss is generally the most clinically relevant as it is used to determine the loading dose of a drug
63
Compartmental Pharmacokinetic
Model Distribution
• Drugs leave the central compartment in two phases
• distribution into the tissues
• via metabolism and excretion
• After IV bolus
• largest amount of drug delivered to vessel rich group
• highly perfused tissues equilibrate with the initial high serum concentration
• as blood flows through less perfused organs, drug is also deposited into these
tissues
• the concentration rises more slowly
• concentrations will NOT reach the concentration in the vessel-rich group
• Serum concentration decreases d/t distribution
• when serum concentration falls below tissue concentration, drug transfers from tissues to
plasma serum and is redistributed
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Time Course of Drug Effect
• The plasma is NOT the site of drug effect for anesthetic drugs à there
is a time lag between plasma drug concentration and effect site drug
concentration
• This lag is called hysteresis
• The relationship between the plasma and
the site of drug effect is modeled with an
“effect site” model
65
Plasma Concentration Curve
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Loading dose
𝐿𝑜𝑎𝑑𝑖𝑛𝑔 𝑑𝑜𝑠𝑒 = 𝑉# ×
𝐷𝑒𝑠𝑖𝑟𝑒𝑑 𝑃𝑙𝑎𝑠𝑚𝑎 𝐶𝑜𝑛𝑐𝑒𝑛𝑡𝑟𝑎𝑡𝑖𝑜𝑛
𝐵𝑖𝑜𝑎𝑣𝑎𝑖𝑙𝑎𝑏𝑖𝑙𝑖𝑡𝑦
• The higher the Vd, the higher the loading dose
• For IV medications, bioavailability = 1 sine it’s injected directly into the
bloodstream
67
Steady-State
When the amount of drug entering the body is equivalent to the
amount of drug eliminated from the body
(SS) Rate of Administration = Rate of Elimination
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Steady-State
Generally, steady-state is achieved after five half-times
Half-Time
0
1
2
3
4
5
Amount of Drug
Eliminated %
0
50
75
87.5
93.75
96.875
Amount of Drug
Remaining %
100
50
25
12.5
6.25
3.125
69
Metabolism (Biotransformation)
The act of converting pharmacologically active, lipid-soluble drugs into water-soluble
and usually inactive metabolites
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Pathways of Metabolism
4 basic pathways of metabolism
• Oxidation
• Reduction
Phase I
• Hydrolysis
• Conjugation
Phase II
71
Pathways of Metabolism
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Drug Metabolism
• Liver is the principal site for processing xenobiotics, toxins
• Drug molecules converted into water-soluble (hydrophilic) molecules to
facilitate their excretion
• Phase I pathway: oxidation, reduction, hydrolysis
• Phase II pathway: conjugation
• Detoxification: xenobiotic à phase I reaction à primary metabolite à
phase II reaction à secondary metabolite à excretion
• Cytochrome P450 system: major xenobiotic metabolizer in body
• oxidizes substrates, adds oxygen to structures
• First pass effect for pharmaceuticals
73
Hydrolysis
• Enzymes responsible for hydrolysis of drugs do not involve the
CYP enzymes system
• Often occurs outside the liver
•
•
•
•
Remifentanil
Succinylcholine
Esmolol
Ester local anesthetics
Cleared in the plasma and
tissues by ester hydrolysis
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Sites of Metabolism
• Liver (hepatocytes)
• Plasma (Hofmann elimination & ester hydrolysis)
• Lungs
• Kidneys
• GI tract
• Placenta (Tissue esterases)
75
Phase I Enzymes
• Cytochrome P450 (CYP) enzymes
•
•
•
•
•
family of membrane-bound proteins containing a heme cofactor
act as a catalyze for the metabolism of compounds
predominantly hepatic microsomal enzymes
involves both oxidation and reduction steps
CYP3A4 is the most abundantly expressed P450 isoform, comprising 20% to
60% of total P450 activity and metabolizes more than half of all currently
available drugs
• opioids, benzodiazepines, local anesthetics, immunosuppressants, and antihistamines
• Non-CYP enzymes
• Flavin-containing monooxygenase enzymes
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Phase I Enzyme Induction/Inhibition
• Induction occurs through INCREASED expression of the enzymes
• Phenobarbital, Phenytoin, & Dexamethasone induces microsomal enzymes and
thus can render other drugs less effective through increased metabolism
• Inhibition occurs through DECREASED expression of the enzymes
• increasing the exposure to drug substrates
• Grapefruit juice & Aprepitant (Emend) inhibits CYP 3A4 à increasing the
concentration of anesthetics and other drugs
77
Enzyme
Induction
&
Inhibition
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Phase II Enzymes
• Phase II reactions involve conjugation by coupling the drug or its
metabolites to another molecule, such as glucuronidation, acylation,
sulfate, or glicine.
• Glucuronidation is an important metabolic pathway for several drugs used during
anesthesia
• Propofol
• Morphine (yielding morphine-3-glucuronide and the pharmacologically active morphine-6glucuronide)
• Midazolam (yielding the pharmacologically active α1-hydroxymidazolam)
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Excretion
The removal of drugs from the body, either as a metabolite or unchanged drug
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Excretion
• Kidneys are principal organs for
excreting water-soluble substances
• Biliary system contributes to excretion
to the degree that the drug is not
reabsorbed from the GI tract
• Lungs play a large role in the
excretion/exhalation of volatile
anesthetics
81
Clearance
• Clearance is the volume of plasma that is cleared of drug per unit time
Most important clearing organs include:
1. Liver
2. Kidney
3. Organ independent (Hofmann elimination and ester hydrolysis in the
plasma)
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Clearance
• Clearance is the volume of plasma that is cleared of drug per unit time
• Rate of clearance is determined by blood flow to the liver and kidney and their
ability to extract drug from the blood
• Mathematically:
𝐶𝑙𝑒𝑎𝑟𝑎𝑛𝑐𝑒 = 𝑄 ∗ 𝐸
• Clearance = Blood flow * Extraction ratio
• Total clearance is the sum of all organs’ clearance values
• Clearance can change based on altered flow states or changes in extraction ratio
83
Clearance
• CL is directly proportional to drug dose, extraction ratio, and blood flow
to the target organ
• CL is inversely proportional to half-life and drug concentration
• To maintain a steady-state concentration in the plasma, the infusion rate
or dosing interval must equal the rate of drug clearance
• As a general rule, steady-state is achieved after five half-times. If a drug
has a long half life, you can achieve steady state faster by administering a
loading dose.
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Clearance
Directly Proportional
Inversely Proportional
Blood flow to cleaning organ
Half-life
Extraction Ratio
Drug concentration in the central
compartment
Drug Dose
85
Steady-State
(SS) Rate of Administration = Rate of Elimination
To maintain a steady-state concentration in the plasma, the infusion rate or
dosing interval must equal the rate of drug clearance by metabolism and
elimination
86
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Major Determinants of
Hepatic Clearance
• blood flow to the liver (Q)
• fraction of drug not bound to plasma proteins (fu)
• intrinsic clearance (CLint)
• vascular architecture
87
Hepatic Clearance (CLH)
Extraction Ratio
𝑓" 𝐶𝐿#$%
𝐶𝐿! = 𝑄
𝑄 + 𝑓" 𝐶𝐿#$%
Restrictive Hepatic Clearance
fuCLint << Q
then
CLH = fuCLint
CLH limited by protein binding
Extraction ratios < 0.3
Nonrestrictive Hepatic Clearance
fuCLint >> Q
then
CLH = Q
CLH is flow limited
Extraction ratios > 0.7
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Perfusion-Dependent Hepatic Clearance
• Nonrestrictive Hepatic Clearance
• dependent on perfusion
• drugs have a high extraction ratio (0.7 or greater)
• These drugs are referred to as “high-clearance drugs”
• Lidocaine, Fentanyl, Propofol, Sufentanil, Morphine, Ketamine
• Decrease in perfusion equals decreased clearance of the drug
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Capacity-Dependent Hepatic Clearance
• Primarily determined by the liver’s ability to extract drug from the blood
•
•
•
•
dependent on protein binding & hepatic enzymes
drugs have a low extraction ratio (< 0.3)
small amount of drug is removed per unit of time
hepatic perfusion does not have a significant effect
• Diazepam, Rocuronium, Methadone
• Decrease in protein binding leads to an increased clearance of the drug
• Enzyme induction causes a faster elimination
• Enzyme inhibition causes a slow elimination
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Enterohepatic Circulation
• Process where the liver excretes a
substance into the bile, and then
that substance is reabsorbed from
the small intestine and transported
back to the liver
• Drugs that undergo enterohepatic
circulation tend to have a long
duration of effect
• Diazepam & Warfarin
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Renal Clearance
• Kidneys are efficient at removing water soluble molecules
• Actively secreted substances include:
• Morphine, meperidine, furosemide, penicillin, and quaternary ammonium compounds
• Urine pH influences elimination of drugs
• Weak acids are better excreted in alkaline urine
• NaHCO3 will make the urine more alkaline
• Weak bases are better excreted in acidic urine
• NH4Cl or VitC will make the urine more acidic
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Renal Clearance
• Renal Excretion involves
• Passive Glomerular Filtration
• Water soluble metabolites are filtered and
eliminated
• Aminoglycoside antibiotics
• Active Tubular Secretion
• Penicillin
• Passive Tubular Reabsorption
• Lipid soluble molecules are reabsorbed back
into the circulation
• Propofol
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Elimination
The sum of the processes of removing an administered drug from the body
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Elimination
• Rate of elimination is rate of disappearance of active molecules from
bloodstream or body
• Rate of elimination and dosage determine duration of action of a drug
• Drug elimination ≠ drug excretion
• e.g., a drug may be eliminated by metabolism before excretion from body
95
Zero- and First-Order Processes
Zero-Order
Elimination
• Rate of elimination: Constant
regardless of drug concentration
• Constant AMOUNT of drug
eliminated per unit time
• Drug concentration decreases
linearly with time
First-Order
Elimination
• Rate of elimination: Proportional
to drug concentration
• Constant FRACTION of drug
eliminated per unit time
• Drug concentration decreases
exponentially with time
• Constant half-life of elimination
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Zero- and First-Order Processes
97
Zero- and First-Order Processes
Zero-Order
Elimination
First-Order
Elimination
• Alcohol
• Rocuronium
• Aspirin
• Ketamine
• Heparin
• Fentanyl
• Phenytoin
• Etomidate
• Warfarin
• Propofol
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Elimination
Elimination Half-Time
Elimination Half-Life
Time it takes for 50% of
the drug to be removed
from the plasma during the
elimination phase
Time it takes for 50% of
the drug to be removed
from the body after a rapid
IV injection
99
Elimination Half-Life
• Most drugs follow First-Order Kinetics
• It takes the same amount of time to reduce a concentration from 100 mg to 50
mg as it does from 10 mg to 5 mg
• For practical purposes, a drug is considered eliminated when 95% is
removed from the body
• Four to five half-lives
• Frequent dosing can cause accumulation
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Context Sensitive Half-Time
Continuous infusion
• Time required for the
plasma concentration to
decrease by 50% after an
infusion is stopped
• Increases with longer
infusion duration d/t
accumulation in
peripheral tissues
101
References
Flood, P., Rathmell, J., & Urman, R. (2021). Stoelting’s Pharmacology &
Physiology in Anesthetic Practice (6th ed.). LWW.
• Ch. 2 (p.15-38)
Sass, E., Heiner, J. S., & Nagelhout, J. J. (2022). Nurse Anesthesia (7th ed.).
Saunders.
• Ch. 6
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