Professional Documents
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Pharmacokinetics I:
ADME
Marc Imhotep Cray, M.D.
BMS / CK-CS Teacher
http://www.imhotepvirtualmedsch.com/
General Principles of Drug Therapy
Topics Outline
ABSORPTION METABOLISM
Ionization Rates of Metabolism
Molecular Weight Microsomal P450 Isoenzymes
Dosage Form Enzyme Induction and Inhibition
Routes of Administration ELIMINATION
DISTRIBUTION Pharmacokinetic Changes with Aging
Plasma Protein Binding
Selective Distribution
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General Principles of Drug Therapy
Absorption drug in
Distribution
Metabolism
Excretion drug out = Elimination
Movement of drug molecules through various
physiologic compartments drug deposition
Pharmacokinetics Overview
PK what the body
Understanding PK
does to a drug
parameters, enable
design of optimal drug
regimens, including :
route of
administration
(RoA),
dosage,
dosing interval, and
duration of Tx
Modified from: Lippincott Illustrated
Reviews: Pharmacology. 6e. (2014)
General Principles of Drug Therapy
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Enteral Routes
of Administration
General Principles of Drug Therapy
Bioavailability (F)
F is how much of what is ingested makes it into the systemic
circulation
First-pass metabolism
Any substance absorbed through
the intestinal mucosa
(except at end of the rectum)
will drain into the portal system
and be processed by the
liver before reaching the
systemic circulation
Oral Ingestion
• Governed by:
surface area for absorption, blood flow, physical
state of drug, concentration
occurs via passive process
In theory: weak acids optimally absorbed in
stomach, weak bases in intestine
In reality: overall rate of absorption of drugs is
always greater in intestine (surface area, organ
function)
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General Principles of Drug Therapy
Suspensions
Powders
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General Principles of Drug Therapy
For example:
Timed release capsules
dissolve at different rates
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General Principles of Drug Therapy
Effect of Changing
Rate of Gastric Emptying
Ingestion of a solid dosage form with a glass of cold
water will accelerate gastric emptying
accelerated presentation of drug to upper intestine
significantly increases absorption
Ingestion with a fatty meal, acidic drink, or with
another drug with anticholinergic properties, will
retard gastric emptying
Sympathetic output (as in stress) also slows
emptying
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Rectal Administration
Advantages:
Useful when oral administration is precluded by
vomiting or when patient is unconscious
Approx. 50% of drug absorbed from rectum will
bypass liver, thus reducing influence of first-pass
hepatic metabolism
Disadvantages:
Irregular and incomplete absorption
Irritation
Patient aversion
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General Principles of Drug Therapy
Parenteral Routes
of Administration
General Principles of Drug Therapy
Subcutaneous
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General Principles of Drug Therapy
Intramuscular
Rapid rate of absorption from aqueous solution,
depending on the muscle
Perfusion of particular muscle influences rate of
absorption: gluteus vs. deltoid
Slow & constant absorption of drug when injected in
an oil solution or suspension
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General Principles of Drug Therapy
Intra-arterial administration
Occasionally a drug is injected directly into an
artery to localize its effect to a particular
organ, e.g., for liver tumors, head/neck
cancers
Requires great care and should be reserved
for those with experience
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General Principles of Drug Therapy
Intrathecal administration
Necessary RofA if the blood-brain barrier
and blood-CSF barrier impede entrance into
CNS
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General Principles of Drug Therapy
Intraperitoneal administration
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General Principles of Drug Therapy
Pulmonary Absorption
Inhaled gaseous and volatile drugs are
absorbed by the pulmonary
epithelium and mucous membranes
of respiratory tract
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General Principles of Drug Therapy
Topical Application
Mucous membranes
Drugs are applied to mucous membranes of
conjunctiva, nasopharynx, vagina, colon,
urethra, and bladder for local effects
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Oral • Variable; affected by many • Safest and most common, • Limited absorption of some drugs
factors convenient, and economical RofA • Food may affect absorption
• Patient compliance is necessary
• Drugs may be metabolized before
systemic absorption
Intravenous • Absorption not required • Can have immediate effects • Unsuitable for oily substances
• Ideal if dosed in large volumes • Bolus injection may result in adverse
• Suitable for irritating substances effects
and complex mixtures • Most substances must be slowly
• Valuable in emergency situations injected
• Dosage titration permissible • Strict aseptic techniques needed
• Ideal for high molecular weight
proteins and peptide drugs
Subcutaneous • Depends on drug diluents: • Suitable for slow-release drugs • Pain or necrosis if drug is irritating
Aqueous solution: prompt • Ideal for some poorly soluble • Unsuitable for drugs administered in large
Depot preparations: slow and suspensions volumes
sustained
Intramuscular • Depends on drug diluents: • Suitable if drug volume is moderate • Affects certain lab tests (creatine
Aqueous solution: prompt • Suitable for oily vehicles and certain kinase)
Depot preparations: slow and irritating substances • Can be painful
sustained • Preferable to intravenous if patient • Can cause intramuscular
must self-administer hemorrhage (precluded during
anticoagulation therapy)
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General Principles of Drug Therapy
Routes of Administration Summary Table (2)
RofA ABSORPTION PATTERN ADVANTAGES DISADVANTAGES
Transdermal • Slow and sustained • Bypasses the first-pass effect • Some patients are allergic to
(patch) • Convenient and painless patches, which can cause irritation
• Ideal for drugs that are lipophilic and • Drug must be highly lipophilic
have poor oral bioavailability • May cause delayed delivery of drug
• Ideal for drugs that are quickly to pharmacological site of action
eliminated from the body • Limited to drugs that can be
taken in small daily doses
Rectal • Erratic and variable • Partially bypasses first-pass effect • Drugs may irritate the rectal
• Bypasses destruction by stomach acid mucosa
• Ideal if drug causes vomiting • Not a well-accepted route
• Ideal in patients who are vomiting, or
comatose
Inhalation • Systemic absorption may • Absorption is rapid; can have • Most addictive route (drug can
occur; this is not always immediate effects, Ideal for gases enter the brain quickly)
desirable • Effective for patients with respiratory • Patient may have difficulty
Problems, Dose can be titrated regulating dose
• Localized effect to target lungs: lower • Some patients may have
doses used compared to that with difficulty using inhalers
oral or parenteral administration
• Fewer systemic side effects
Sublingual • Depends on the drug: Few • Bypasses first-pass effect • Limited to certain types of drugs
drugs (for example, • Bypasses destruction by stomach acid • Limited to drugs that can be
nitroglycerin) have rapid • Drug stability maintained because taken in small doses
direct systemic absorption the pH of saliva relatively neutral • May lose part of the drug dose if
Most drugs erratically or • May cause immediate pharmacological swallowed 28
incompletely absorbed effects
General Principles of Drug Therapy
Cell Membranes
Passive Properties
Carrier-Mediated Transport
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Facts...
“ADME of a drug all involve its passage across cell
membranes”
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General Principles of Drug Therapy
1. Molecular Size
In general, smaller molecules diffuse more readily across
membranes than larger ones because the diffusion
coefficient is inversely related to the sq. root of the MW
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2. Lipid-Solubility
Oil:Water Partition Coefficient
The greater the partition coefficient, the higher the
lipid-solubility of the drug, and the greater its diffusion
across membranes
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General Principles of Drug Therapy
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30
20
10
1
Other things (MW, pKa) being equal,
absorption of these drugs is 0
barbital secobarbital thiopental
proportional to lipid solubility (pKa 7.8) (pKa 7.9) (pKa 7.6)
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General Principles of Drug Therapy
3. Ionization
• Most drugs are small (MW < 1000) weak electrolytes
(acids/bases)
• This influences passive diffusion since cell membranes are
hydrophobic lipid bilayers that are much more permeable to
the non-ionized forms of drugs
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General Principles of Drug Therapy
Ionization (2)
You can think of properties this way:
ionized = polar = water-soluble
non-ionized = less polar = more lipid-soluble
*For both acids and bases, pKa = acid dissociation constant, the pH at
which 50% of the molecules are ionized.
Example:
weak acid = aspirin (pKa 3.5)
weak base = morphine (pKa 8.0)
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General Principles of Drug Therapy
HA A- B BH+
intracellular
H+ pH H+
* The pH on each side of the membrane determines the equilibrium on each side
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A Useful Concept...
Drugs tend to exist in the ionized form
when exposed to their “pH-opposite”
chemical environment.
Acids are increasingly ionized with
increasing pH (basic environment),
whereas…
Bases are increasingly ionized with
decreasing pH (acidic environment).
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General Principles of Drug Therapy
+
HA acid pH base HB
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Henderson-Hasselbalch Eqn.
[protonated]
log = pKa - pH
[unprotonated]
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if pH = pKa then HA = A-
if pH < pKa, acid form (HA) will always predominate
if pH > pKa, the basic form (A-) will always predominate
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General Principles of Drug Therapy
In a Suspected Overdose...
The most appropriate site for sampling to identify the
drug depends on the drug’s chemical nature
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General Principles of Drug Therapy
total total
HA + A- = 1.001 HA + A- = 252
total total
+ +
HB + B = 502 HB + B = 5
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General Principles of Drug Therapy
Other aspects….
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General Principles of Drug Therapy
Other aspects….
Certain compounds may exist as strong electrolytes
This means they are ionized at all body pH values
They are poorly lipid soluble
Examples:
strong acid = glucuronic acid derivatives of drugs.
strong base = quaternary ammonium compounds such as
acetylcholine
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General Principles of Drug Therapy
Membrane Transfer
ATP
ADP-Pi
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General Principles of Drug Therapy
Facilitated Diffusion
This is a carrier-mediated process that does NOT
require energy
Movement of substance can NOT be against its
concentration gradient
Necessary for transport of endogenous
compounds whose rate of movement across
membranes by simple diffusion would be too slow
Example: Insulin
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General Principles of Drug Therapy
Special carriers
Substances that are important for cell function
and too large or too insoluble in lipid to diffuse
passively through membranes
eg, peptides, amino acids, glucose.
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General Principles of Drug Therapy
MDR1/P-glycoprotein
P-glycoprotein: P-glycoprotein 1
(permeability glycoprotein, abbreviated
as P-gp or Pgp) also known as
multidrug resistance protein 1 (MDR1)
or ATP-binding cassette subfamily B
member 1 (ABCB1) is an important
protein of the cell membrane that
pumps many foreign substances out of
cells.
Active Transport
Occurrence:
neuronal membranes, choroid plexus, renal tubule cells,
hepatocytes
Characteristics:
carrier-mediated
Selectivity
competitive inhibition by congeners
energy requirement *
Saturable
movement against concentration gradient *
Example:
This is the mechanism by which thyroid follicular cells, in
response to TSH, take up thyroglobulin (MW > 500,000).
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Pharmacokinetics
Locus of Tissue
action reservoirs
“receptors”
Bound Free Bound Free
Systemic
circulation
Biotransformation
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General Principles of Drug Therapy
AUC
injected i.v.
AUC
oral
time
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Bioequivalence
Drugs are pharmaceutical equivalents if they contain the same
active ingredients and are identical in dose (quantity of drug),
dosage form (e.g., pill formulation), and route of
administration
Bioequivalence exists between two such products when the
rates and extent of bioavailability of their active ingredient are
not significantly different
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General Principles of Drug Therapy
Distribution
Once a drug is absorbed into the bloodstream, it may be
distributed into interstitial and cellular fluids
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General Principles of Drug Therapy
Phases of Distribution
first phase
reflects cardiac output and regional blood flow
Thus, heart, liver, kidney & brain receive most of the drug during
the first few minutes after absorption
next phase
delivery to muscle, most viscera, skin and adipose is slower,
and involves a far larger fraction of the body mass
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General Principles of Drug Therapy
Drug Reservoirs
Body compartments where a drug can accumulate are reservoirs
Have dynamic effects on drug availability.
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General Principles of Drug Therapy
Pharmacokinetics
Locus of Tissue
action reservoirs
“receptors”
Bound Free Bound Free
Systemic
circulation
Biotransformation
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General Principles of Drug Therapy
Protein Binding
Passive movement of drugs across biological membranes
is influenced by protein binding
Binding may occur with plasma proteins or with non-
specific tissue proteins in addition to the drug’s receptors
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General Principles of Drug Therapy
Plasma Proteins
albumin
- binds many acidic drugs
α1-acid glycoprotein
- binds basic drugs
The fraction of total drug in plasma that is bound is
determined by
1. its concentration
2. its binding affinity
3. the number of binding sites
At low concentration, binding is a function of Kd (dissociation
constant); at high concentration it’s the # of binding sites
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Bone Reservoir
Tetracycline antibiotics (and other divalent metal ion-chelating
agents) and heavy metals may accumulate in bone
They are adsorbed onto the bone-crystal surface and eventually
become incorporated into the crystal lattice
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General Principles of Drug Therapy
Adipose Reservoir
• Many lipid-soluble drugs are stored in fat
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General Principles of Drug Therapy
Thiopental
A highly lipid-soluble i.v. anesthetic
Blood flow to brain is high, so maximal brain concentrations
brain are achieved in minutes and quickly decline
Plasma levels drop as diffusion into other tissues (muscle)
occurs
Onset and termination of anesthesia is rapid
The third phase represents accumulation in fat (70% after 3 h)
Can store large amounts and maintain anesthesia
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General Principles of Drug Therapy
brain
muscle adipose
50
0
1 10 100 1000
minutes
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GI Tract as Reservoir
Weak bases are passively concentrated in stomach from blood
because of large pH differential
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General Principles of Drug Therapy
Redistribution
Termination of drug action is normally by biotransformation /
excretion, but may also occur as a result of redistribution
between various compartments
Particularly true for lipid-soluble drugs that affect brain and heart
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General Principles of Drug Therapy
Placental Transfer
Drugs cross the placental barrier primarily by simple passive
diffusion
Lipid-soluble, nonionized drugs readily enter fetal bloodstream
from maternal circulation
Rates of drug movement across placenta tend to increase
towards term as tissue layers between maternal blood and
fetal capillaries thin
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General Principles of Drug Therapy
Clinical Pharmacokinetics
Fundamental hypothesis:
A relationship exists between the pharmacological or toxic
response to a drug and the accessible concentration of the
drug (e.g., in blood)
Important parameters:
volume of distribution (Vd)
clearance (CL)
bioavailability (F)
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General Principles of Drug Therapy
Volume of Distribution
Volume of distribution (Vd) relates the amount of drug in
the body to the plasma concentration of drug (Cp)
27 liters
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General Principles of Drug Therapy
Example of Vd
• The plasma volume of a 70-kg man ~ 3L, blood volume ~
5.5L, extracellular fluid volume ~ 12L, and total body
water ~ 42L.
• Givens: If 500 mg of digoxin were in his body, Cp would be
~ 0.7 ng/ml
• Dividing 500 mg by 0.7 ng/ml yields a Vd of 700L, a value
10 times total body volume! Huh?
Clearance (CL)
• Clearance is the most important property to consider when a
rational regimen for long-term drug administration is designed
– The clinician usually wants to maintain steady-state drug
concentrations known to be within the therapeutic range
– CL = dosing rate / Css
– CL = rate of elimination / Css
– (volume/time) = (mass of drug/time) / (mass of drug/volume)
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General Principles of Drug Therapy
Clearance (2)
• Clearance does not indicate how much drug is removed but,
rather, the volume of blood (or plasma) that would have to be
completely freed of drug to account for the elimination rate.
– CL is expressed as volume per unit time
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General Principles of Drug Therapy
Clearance (3)
Sum of all process
contributing to
disappearance of drug
from plasma
Drug in plasma at Drug concentration in plasma is less
concentration of 2 mg/ml after each pass through elimination /
metabolism process
Remember:
CL = dosing rate / Css
CL = rate of elimination / Css
Drug molecules disappearing from
plasma at rate of 400 mg/min
CL = 400 mg/min
= 200 ml/min
2 mg/ml
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General Principles of Drug Therapy
Clearance (4)
Example: cephalexin, CLp = 4.3 ml/min/kg
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General Principles of Drug Therapy
Clearance (5)
Example: propranolol, CLp = 12 ml/min/kg or 840
ml/min in a 70-kg man
The drug is cleared almost exclusively by the liver
Every minute, the liver is able to remove the amount of drug
contained in 840 ml of plasma
NB:
Clearance of most drugs is constant over a range of
concentrations
This means that elimination is not saturated and its rate is
directly proportional to the drug concentration:
this is a description of 1st-order elimination
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General Principles of Drug Therapy
CL in a given organ
CL in a given organ may be defined in terms of blood flow and
[drug]
Q = blood flow to organ (volume/min)
CA = arterial drug conc. (mass/volume)
CV = venous drug conc.
rate of elimination = (Q x CA) - (Q x CV) = Q (CA-CV)
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General Principles of Drug Therapy
Further study:
eNotes: GP- General Principles of Drug Action
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