Transcript Introduction to Pharmacology

Pharmacokinetics
Ed Bilsky, Ph.D.
Department of Pharmacology
University of New England
Pharmacokinetics vs. Pharmacodynamics
• Pharmacokinetics describes the movement of
the drug (and its metabolites) through the body
during the processes of absorption, distribution
and elimination
– Relates the dose of the drug administered to the
concentration that is achieved at the site of action
– “The actions of the body on the drug”
• Pharmacodynamics describes the relationship
between the concentration of the drug at the
site of action with the observed effect
– “The actions of the drug on the body”
Pharmacokinetics
• Pharmacokinetics processes of absorption, distribution
and elimination will determine how rapidly, in what
concentration, and for how long, the drug will appear at
the target site
• “Standardized” doses may have to be adjusted in
individual patients in response to various factors
– Physiology (age, sex, ethnicity)
– Pathology (diseases of the liver, kidney, etc.)
• For a particular drug, the parameters of clearance and
volume of distribution are especially sensitive to
changes in these factors
Pharmacokinetics
Pharmacokinetic properties of selected drugs:
Drug
Oral
availability
% Urinary
excretion
% Plasma
Binding
Half-life
(hours)
Acetaminophen
88
3
0
2
Diazepam
100
1
99
43
Digitoxin
90
32
97
161
Lithium
100
95
0
22
Morphine
24
4
35
1.9
0
79
25
1.1
Vancomycin
Pharmacokinetics
Administration
Absorption
Routes:
topical
enteral
parenteral
Central Compartment
Plasma free drug
Protei n bound drug
Metaboli sm
(li ver, etc.)
Figure 1. An overview of drug disposition
Eli mination
(ki dney, GI tract)
Distribution
Site of action
Ti ssue reservoi rs
Enteral Absorption
Administration of the drug into the alimentary tract:
1. Oral
– most common route of administration
– important considerations
•
•
•
•
state of consciousness
nausea and vomiting
stomach contents and acid environment affect pharmacokinetics
first pass effect
2. Rectal
– decreased first pass effect
– absorption can be variable
3. Sublingual
Oral administration
Sublingual administration
Buccal
cavity
Venous return from buccal cavity
Hepatic vein
Stomach
Portal vein
Intestine
LIVER
Bile duct
Rectum
Venous return from rectum
Rectal
administration
Vena cava
Parenteral Absorption
Injection of the drug into the skin, muscle or blood:
1. Subcutaneous (under the skin)
– small drug volumes and slow absorption
2. Intramuscular (into the muscle)
– larger drug volumes and faster absorption
3. Intravenous (into the vein)
– quickest delivery route, easier to maintain steady drug
concentrations
Miscellaneous Routes
1. Inhalation/Pulmonary
– typical rapid onset, no first pass effect, targeted
delivery
2. Topical
– Transdermal
• requires the drug to be absorbed across the dermis
• usually a very slow absorption and a prolonged duration of
action (fentanyl patch)
• no first pass effect
– Mucous membranes
– Eye drops
Drug Formulation
Drug formulations can modify the pharmacokinetics
of drug delivery
• sustained release products
– controlled-release theophylline for asthma
• protective coating
– enteric coated aspirin
• selective tissue targeting
– ointments
Drug Formulation
Plasma
Gastrointestinal Tract
Solid dose
forms
Oral
suspension
Release
Dissolution
Oral
solution
Absorption
Arthrotec
Rate of Absorption for Various Preparations
• Liquids
• Suspension solutions
Fastest
• Powders
• Capsules
• Tablets
• Coated Tablets
• Enteric-coated tablets
Slowest
Factors Affecting Drug Absorption
• Chemical properties
–
–
–
–
chemical structure – solubility (structure)
molecular weight (lithium to tPA)
solubility
partition coefficient (lipid solubility– charge
Or no charge)
QuickTime™ and a
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• Physiological variables
– gastric motility – empty vs full stomach
– pH at absorption site – pH at tissue can affect pharmacokinetics/
dynamics – affects ability to get into cell (eg local anesthetics)
– surface area at absorption site – more readily absorbed
– blood flow
– presence or absence of food (affects transit in intestine, what
you eat can affect drugs (chelating)
Factors Affecting Drug Absorption
Process
Outside
Passive diffusion
Drug (D)
Inside
Membrane
D
Facilitated diffusion
D
Active transport
D
ATP/Gradient
Diffusion
• The spontaneous movement of molecules or other
particles in solution to reach a uniform concentration
throughout the solvent
– based on random thermal motion of the particles
– does not require the input of external energy
Initial Conditions
A
B
Equilibrium
A
B
Diffusion
Fick’s Law of Diffusion:
DC x A x Perm. Coefficient
Flux
=
(molecules/unit time)
Thickness
• In the case of diffusion across membranes, the
lipid solubility of the compound is a major
determinant of mobility of the drug
Drug pKa
• Most drugs are either weak acids, weak bases or
are amphoteric (both –side groups with both
properties)
• A drug’s pKa value represents the pH at which
50% of the molecules in solution are ionized
• Drugs will tend to exist in the ionized form when
exposed to their pH-opposite environment
– acids are increasingly ionized in a basic environment
– bases are increasingly ionized in an acid environment
Henderson-Hasselbalch Equation
pH = pKa - log
log
[Protonated]
[Unprotonated]
[Protonated]
[Unprotonated]
= pKa -pH
pKa and Drug Diffusion
• Aspirin is a weak acid (pKa=3.0)
– in the stomach, aspirin is roughly in equilibrium between its
ionized and unionized forms
– aspirin is absorbed across the lining of the stomach
stomach environment (pH ~ 2-3)
COO -
COOH
OCOCH
Unionized
3
OCOCH
Ionized
3
+ H+
Drug Ionization as a Function of pH
100
100
Weak Acids:
Aspirin
Phenobarbital
Morphine
Diazepam
75
% Ionized
% Ionized
75
50
50
25
25
0
Weak Bases:
0
3
6
pH of Solution
9
12
0
0
3
6
pH of Solution
9
12
pKa and Drug Diffusion
• Differences in the pH of body fluids can lead to drug
“trapping” in certain compartments
– lead to changes in absorption and/or elimination
Body fluid
Range of pH
Stomach
1.9-2.6
Intestine
6.4-7.6
Urine
5.0-8.0
Breast milk
6.4-7.6
Drug Persistence in the Blood
Once the drug has been absorbed into the blood, a
number of factors can affect bioavailability
1. Drug metabolism by enzymes in the blood
– cholinesterases (succinylcholine duration of action < 8
minutes – mimics Ach/muscle blocker)
2. Binding to blood proteins
– albumin (acidic drugs)
– Alpha-1 acid glycoprotein (basic drugs)
Lipid Solubility
• Affects diffusion and distribution of the drug
– passage across the blood-brain barrier (heroin versus
morphine)
• Highly lipid soluble drugs tend to accumulate in
body fat
– diminishes the effect the drug has on the CNS
– slowly released from the fat over a long period of time
Blood Brain Barrier
capillary in the supraoptic nucleus
capillary in the subfornical organ
Drug Metabolism
• Biotransformation
– modifies the chemical
structures of compounds
– liver >> kidney > other
selected tissues
– in general, makes the
compounds more water
soluble to enhance renal
excretion
– typically inactivates
compounds (important
exceptions)
Biotransformation
• Biological transformation of a drug into:
– a more water soluble compound
– an inactive metabolite
– an active metabolite
Phase I
Phase II
Oxidation
Reduction
Hydrolysis
Chemical reactions
that change the molecule
Conjugation
Addition of
another molecule
(e.g., glucuronidation)
Biotransformation
% Drugs Metabolized by Each
Cytochrome Isozyme
100
75
50
25
0
CYP3A4
CYP2D6
CYP2C9/10
CYP2C19
CYP2E1
CYP1A2
Cytochrome P450 Isozyme
Biotransformation
Formation of Active Metabolites
Drug
Active metabolite
diazepam
desmethyldiazepam
imipramine
desmethylimipramine
Prodrug
Active metabolite
codeine
morphine
sulindac
sulindac sulfide
Factors Affecting Drug Metabolism
• Induction of Enzyme Systems
– alcohol and phenobarbital
• Inhibition of Enzyme Systems
– disulfiram and alcohol
• Sex
– levels and distribution of alcohol dehydrogenase
Metabolic Pathway for Alcohol
Ethanol
CH3CH2OH
alcohol dehydrogenase
CH3CHO
Acetaldehyde
aldehyde dehydrogenase
Acetyl Coenzyme A
energy
CO2
citric acid cycle
H2O
Metabolic Pathway for Alcohol
CH3CH2OH
alcohol dehydrogenase
disulfiram
(Antabuse)
CH3CHO
aldehyde dehydrogenase
Acetyl Coenzyme A
energy
CO2
citric acid cycle
H2O
Enzyme Inducers and Inhibitors
Inhibitors
ethanol
phenobarbital
omeprazole
smoking
Inducers
cimetidine
erythromycin
quinidine
grapefruit juice
First-Pass Metabolism after Oral Administration of a Drug, as
Exemplified by Felodipine and Its Interaction with Grapefruit Juice
Wilkinson, G. R. N Engl J Med 2005;352:2211-2221
First-Pass Metabolism after Oral Administration of a Drug, as
Exemplified by Felodipine and Its Interaction with Grapefruit Juice
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are needed to see this picture.
Wilkinson, G. R. N Engl J Med 2005;352:2211-2221
QuickTime™ and a
decompressor
are needed to see this picture.
Drug Excretion
• Many drugs are excreted via the urine
– blood concentration of the drug determines how much
drug gets filtered by the kidneys --> how much drug is
eliminated (important for first order kinetics)
– some drugs are excreted unchanged in the urine
• Other sites of excretion
– feces
– lungs
– sweat
Drug Excretion
• Urine pH can alter the excretion rate of some
drugs
– varies between 5.0 and 8.0
• Weak acids are excreted more readily in alkaline
urine and more slowly in acidic urine
• Weak bases are excreted more readily in acidic
urine and more slowly in alkaline urine
Phenobarbital (weak acid, pKa 7.2)
nonionized
ionized
Urine pH = 7.2
Urine pH = 8.2
Reabsorption
alkalinize the urine
(sodium bicarbonate)
Bladder
Bladder
Clinical Pharmacology
• A relationship exists between the concentration of a
drug at the site of action and the beneficial and/or toxic
effects produced by that drug
• Application of pharmacokinetic knowledge helps the
clinician to achieve a desired beneficial effect with
minimal adverse effects
• In practice, these applications are most critical when the
therapeutic index of a drug is very low, or when there is a
large variation in response of different patients to a
given dose of a drug
Volume of Distribution
• Relates the amount of drug in the body to the
concentration of the drug in blood or plasma
Vd =
Amount of drug in body
Concentration of drug
• Examples:
– warfarin = 9.8 L/70 kg
– fluoxetine = 2500 L/70 kg
blood
Clearance
• The factor that predicts the rate of elimination
in relation to the drug concentration
CL =
Rate of elimination
Concentration of drug
• May be defined with respect to blood, plasma or
unbound drug in the plasma water
Clearance
• Elimination of a drug from the body is the sum of
all routes of elimination
CL systemic = CL
renal
+ CL liver + CL
• Examples
– Digitoxin, CL = 0.234 L/h/70 kg, t1/2 = 161
– Atenolol, CL = 10.2 L/h/70 kg, t1/2 = 6.1
– Acetaminophen, CL = 21 L/h/70 kg, t1/2 = 2
other
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Volume of Distribution and Clearance
Katzung, 3-2
Rate of Elimination
• For most drugs, clearance is constant over the
plasma or blood concentration range encountered
in clinical settings
– elimination is not saturable
• This is referred to as first-order elimination
Rate of elimination = CL x Concentration
Clinical Example
• Determine rate of elimination for acetaminophen
• Calculate a typical dose for acetaminophen
– oral bioavailability and plasma protein binding
• Determine total body water and concentration
after a typical dose
• Compare calculated concentration with toxic
concentration
– What is the therapeutic index for acetaminophen?
Capacity-Limited Elimination
• Some drugs exhibit capacity-limited elimination
– phenytoin, alcohol, aspirin
CL =
Vmax x C
Km + C
• When C >> Km, the elimination rate becomes
nearly independent of drug concentrations
– zero-order kinetics
Clinical Example
J.B., a 25 year old medical student, ingests typical dosages of
acetaminophen, diazepam and ethanol on three consecutive weekends.
He weighs 100 kg and has a body-fat content of less than 10%
• What are the approximate concentrations attained in the body for
each of these compounds?
• For the ethanol example, what does this come out to on a molar
basis?
• What if a middle-age professor (100 kg, bodyfat >40%) drank the
same amount of alcohol, what would his blood alcohol level be at?
Flow-Limited Elimination
• Some drugs are cleared very readily by the
organ of elimination (e.g., morphine)
– most of the drug is eliminated from the blood during
the first pass of the drug through the organ
• Elimination of these drugs will depend primarily
on the rate of drug delivery to the organ
– rate of elimination will be affected by disease
processes that affect blood flow and the organs
capacity to biotransform the drug
Half-Life
• Half-life (t1/2) is the time required to change
the amount of drug in the body by one-half
during elimination
– simplify by assuming the body is a single compartment
t1/2 =
0.7 x Vd
CL
• Disease states can affect both the volume of
distribution and clearance
Katzung, 3-3
Bioavailability
• Defined as the fraction of unchanged drug reaching the
systemic circulation following administration
Concentration, g/ml
40
To determine Foral:
i.v.
AUC = [drug] x time = mg•hr•ml-1
30
oral
20
1. Measure AUCi.v.
2. Measure AUCoral
10
AUCoral
Foral =
AUCi.v.
0
0
2
4
6
Hours
8
10
For drug given i.v., F = 1.0
For other routes, F < 1.0
Bioavailability
• Extent of absorption
– gut metabolism
– too lipophilic or too hydrophilic
– effects of P-glycoprotein
• First-pass elimination
– portal blood delivers the drug to the liver prior to
distribution to the systemic circulation
• metabolism
• excretion into the bile
Extraction
• The effect of first-pass hepatic elimination on
bioavailability is expressed as the extraction ratio
ER =
CLliver
Q
Q = hepatic blood flow
• The systemic bioavailability of the drug (F) can be
predicted by the extent of absorption (f) and the
extraction ration
F = f x (1 - ER)
Katzung, 3-3
Delayed Drug Effects
• Changes in drug plasma levels are not always an accurate
estimate of changes in drug effect
• Some drug effects are delayed due to the time lag
between the rise in plasma concentrations and the time
needed for the drug to distribute to the site of action
• Other drug effects require changes in gene expression
and protein synthesis to occur before becoming manifest
• Another example is the effects of warfarin on blood
clotting-decreased synthesis of clotting factors occurs
immediately but existing factors are somewhat stable
Dosing Intervals
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TIFF (Uncompressed) decompressor
are needed to see this picture.
Figure 3-6, Katzung
Katzung, 3-3
Dosing Intervals
• Significant differences can occur between
continuous versus intermittent dosing regimens
even though the average steady state levels of
the drug are the same
• Renal toxicity of gentamicin is greater with
continuous infusion versus intermittent dosing
Katzung, 3-3
Target Concentrations
• For most drugs, there are specific target concentration
ranges that will provide a desired therapeutic effect
• The goal of the dosing regimen is to keep drug levels in
the target range for the entire interval between doses
• At steady state, the dosing rate must equal the rate of
elimination
Dosing rate = Rate of elimination = CL x TC
Katzung, 3-3
Maintenance Dose
• If bioavailability is less than 100%, then this must be
taken into account
Dosing rateoral = Dosing rate/Foral
• When giving intermittent doses, the maintenance dose is
calculated as:
MD = Dosing rate x Dosing interval
Katzung, 3-3
Theophylline Example
• A 18 year old female presents to the ER with an acute
asthma attack. The physician wants to administer
theophylline intravenously.
• What are the clearance and target concentration values
for theophylline?
• Dosing rate = CL x TC = 2.8 L/h/70kg x 10 mg/L = 28 mg/h
Katzung, 3-3
Theophylline Example
• The intervention is successful and the physician now wants
to initiate oral therapy and maintain the target
concentration. How would this be accomplished?
• What is the oral bioavailability of theophylline?
• What is the desired dosing interval?
• Maintenance dose = (Dosing Rate/F) x Dosing Interval
• (28 mg/h ÷ 0.96) x 12 hrs = 350 mg
Katzung, 3-3
Loading Dose
• From Figure 3-6, when using maintenance dosings, it takes
4-5 half-lives to reach steady state regardless of if it is
through intermittent dosing or continual infusion
• A faster rate of onset of drug effect may be required,
especially in the case of drugs with long half-lives
Loading Dose = Vd x TC
• The rate of distribution into different compartments may
need to be considered to avoid excessive drug
concentrations and toxicity --> slower infusion rate
Katzung, 3-3