Transcript Pharmacokinetics

Pharmacokinetics
Dr. SA Ziai
Pharmacokinetics examines the
movement of a drug over time
through the body
Pharmacological as well as
toxicological actions of drugs are
primarily related to the plasma
concentrations of drugs
ADME
The speed of onset of
drug action, the intensity
of the drug’s effect, and
the duration of drug
action are controlled by
four fundamental
pathways of drug
movement and
modification in the body
Pharmacokinetic Principles
• In practical therapeutics, a drug should be able to
reach its intended site of action after administration by
some convenient route
• Drugs:
–
–
–
–
–
The active drug molecule
Prodrug
Absorbed into the blood from its site of administration
Distributed to its site of action
permeating through the various barriers that separate
these compartments
– Eliminated at a reasonable rate by metabolic inactivation,
by excretion from the body, or by a combination of these
processes
ROUTES OF DRUG ADMINISTRATION
• Enteral
– Oral
– Sublingual
• Parenteral
– IV
– IM
– SC
• Other
–
–
–
–
–
–
Inhalation
Intranasal
Intrathecal/Intraventricular
Topical
Transdermal
Rectal
• Oral
– Simple, Reversible
– First-pass metabolism
• Sublingual
– Enteric coated
• Parentral
–
–
–
–
–
–
–
–
Heparin, Insulin
Unconscious patients
Rapid onset of action
Highest bioavailability (IV)
Irreversible, Pain, Infection
Rate of administration (IV)
Depot and suspension (IM)
Pumps, Implants (SC)
ABSORPTION OF DRUGS
Transport of a drug from the GI tract
• IV 100%
• Passive diffusion
–
–
–
–
Concentration gradient
Lipid soluble
Water soluble
Facilitated diffusion (by carrier)
• No energy, Saturated, Inhibited
• Active transport
– ATP
– Saturated
– Moving against concentration
gradient
• Endocytosis and exocytosis
– Vit B12
Permeation
Aqueous Diffusion
• Across epithelial membrane tight junctions
and the endothelial lining of blood vessels
through aqueous pores that—in some
tissues—permit the passage of molecules as
large as MW 20,000–30,000.
• Concentration gradient (Fick's law)
• Bound to large plasma proteins (eg, albumin)
• Electrical fields
BBB
• The capillaries of the brain, the testis
• Drug export pumps (MDR pumps).
Lipid Diffusion
• The lipid:aqueous partition coefficient of a
drug determines how readily the molecule
moves between aqueous and lipid media.
• In the case of weak acids and weak bases
(which gain or lose electrical charge-bearing
protons, depending on the pH), the ability to
move from aqueous to lipid or vice versa
varies with the pH of the medium
• A weak acid is a neutral molecule that can
reversibly dissociate into an anion (a
negatively charged molecule) and a proton (a
hydrogen ion).
• A weak base is a neutral molecule that can
form a cation (a positively charged molecule)
by combining with a proton.
Effect of pH on drug absorption
• More of a weak acid will be in the lipid-soluble
form at acid pH
• More of a basic drug will be in the lipidsoluble form at alkaline pH
The pKa is a measure of the strength
of the interaction of a compound with
a proton
The lower the pKa of a drug, the more acidic it is.
Conversely, the higher the pKa, the more basic is the drug
Determination of how much drug will
be found on either side
of a membrane
Trapping
Body Fluids with Potential for Drug "Trapping"
through the pH-Partitioning Phenomenon.
Body Fluid
Range of pH Total Fluid: Blood
Total Fluid: Blood
Concentration Ratios for
Concentration Ratios
Sulfadiazine (acid, pKa 6.5) for Pyrimethamine
(base, pKa 7.0)
Urine
Breast milk
5.0–8.0
6.4–7.6
0.12–4.65
0.2–1.77
72.24–0.79
3.56–0.89
Jejunum, ileum contents
7.5–8.0
1.23–3.54
0.94–0.79
Stomach contents
1.92–2.59
0.11
85,993–18,386
Prostatic secretions
6.45–7.4
0.21
3.25–1.0
Vaginal secretions
3.4–4.2
0.114
2848–452
Special Carriers
• Peptides, amino acids, sugars
• ABC (ATP-binding cassette) family
– less selective
– P-glycoprotein, multidrug-resistance type 1
(MDR1) transporter, multidrug resistanceassociated protein (MRP)
– the solute carrier [SLC] family, do not bind ATP but
use ion gradients for transport energy
Special Carriers
Transporter
NET
SERT
VMAT
MDR1
MRP1
Physiologic Function
Norepinephrine reuptake from
synapse
Serotonin reuptake from
synapse
Pharmacologic Significance
Target of cocaine and some
tricyclic antidepressants
Target of selective serotonin
reuptake inhibitors and some
tricyclic antidepressants
Target of reserpine
Transport of dopamine and
norepinephrine into adrenergic
vesicles in nerve endings
Transport of many xenobiotics Increased expression confers
out of cells
resistance to certain anticancer
drugs; inhibition increases blood
levels of digoxin
Leukotriene secretion
Confers resistance to certain
anticancer and antifungal drugs
Physical factors influencing
absorption
• Blood flow to the absorption site
– Blood flow to the intestine is much greater than the
flow to the stomach
– Shock severely reduces blood flow to cutaneous
tissues
• Total surface area available for absorption
– Intestine has a surface rich in microvilli, it has a
surface area about 1000-fold that of the stomach
• Contact time at the absorption surface
– Diarrhea, Parasympathetic, Food
BIOAVAILABILITY
• Determination
• Factors that influence
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–
–
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First-pass metabolism
Solubility of the drug
Chemical instability
Nature of the drug
formulation
– Particle size, salt form, crystal
polymorphism, enteric
coatings and the presence of
excipients (such as binders
and dispersing agents) can
influence the ease of
dissolution
DRUG DISTRIBUTION
DRUG DISTRIBUTION
• Drug distribution is the process by which a drug
reversibly leaves the bloodstream and enters the
interstitium (extracellular fluid) and/or the cells
of the tissues.
• The delivery of a drug from the plasma to the
interstitium primarily depends on:
• Blood flow
• Capillary permeability
• Protein binding
• Hydrophobicity of the drug
Capillary permeability
VOLUME OF DISTRIBUTION
VOLUME OF DISTRIBUTION
• The volume of distribution is a
hypothetical volume of fluid into
which a drug is dispersed.
• Water compartments in the body
1. Plasma compartment (6%)
• Size and PB (Heparin)
2. Extracellular fluid (20%)
•
LMW and hydrophil Aminoglycosides
3. Total body water (60%)
•
Ethanol
4. Other sites
•
Fetus
Apparent volume of distribution
• A drug rarely associates exclusively with only one
of the water compartments of the body. Instead,
the vast majority of drugs distribute into several
compartments, often avidly binding cellular
components—for example,
– lipids (abundant in adipocytes and cell membranes),
– Proteins (abundant in plasma and within cells), or
– Nucleic acids (abundant in the nuclei of cells).
• Therefore, the volume into which drugs distribute
is called the apparent volume of distribution, or
Vd
Effect of a large Vd on the half-life of
a drug
• If the Vd for a drug is large, most of the drug is
in the extraplasmic space and is unavailable to
the excretory organs
• Therefore any factor that increases the
volume of distribution can lead to an increase
in the half-life and extend the duration of
action of the drug
BINDING OF DRUGS TO PLASMA
PROTEINS
Albumin has the strongest affinities
for anionic drugs (weak acids)
and hydrophobic drugs
Competition for binding between
drugs
DRUG METABOLISM
DRUG METABOLISM
• Drugs are most often eliminated by
biotransformation and/or excretion into the
urine or bile.
• The process of metabolism transforms
lipophilic drugs into more polar readily
excretable products.
• The liver is the major site for drug metabolism
Reactions of drug metabolism
Phase I reactions utilizing the P450
system
• The Phase I reactions most frequently
involved in drug metabolism are catalyzed by
the cytochrome P450 system (also called
microsomal mixed function oxidase):
Drug + O2 + NADPH + H+ → Drugmodified + H2O + NADP+
Drug
NADP+
CYP
R-Ase
CYP
ePC
Fe+3
Drug
Drug
OH
NADPH
CO
CYP-Fe+2
Drug
Fe+3
CYP
CO
hu
Fe+2
CYP
Drug
Drug
eO2
CYP
O2
Drug
Fe+2
H2O
2H+
Electron flow in microsomal drug oxidizing system
OH
Summary of the P450 system
• Metabolism of many endogenous compounds
(steroids, lipids, etc.) and biotransformation of
exogenous substances (xenobiotics).
• Cytochrome P450, designated as CYP
• Composed of many families of hemecontaining isozymes
Summary of the P450 system
• There are many different genes, and many
different enzymes
• Six isozymes are responsible for the vast majority
of P450-catalyzed reactions: CYP3A4 (60%),
CYP2D6 (25%), CYP2C9/10 (15%), CYP2C19 (15%),
CYP2E1 (2%), and CYP1A2 (2%).
• An individual drug may be a substrate for more
than one isozyme
• Considerable amounts of CYP3A4 are found in
intestinal mucosa
Phase I reactions not involving the
P450 system
• These include:
– amine oxidation (for example, oxidation of
catecholamines or histamine)
– alcohol dehydrogenation (for example, ethanol
oxidation)
– esterases (for example, metabolism of pravastatin
in liver)
– hydrolysis (for example, of procaine)
Phase II
• Conjugation reaction with an endogenous
substrate, such as glucuronic acid, sulfuric acid,
acetic acid, or an amino acid, results in polar,
usually more water-soluble compounds that are
most often therapeutically inactive
• A notable exception is morphine-6-glucuronide,
which is more potent than morphine
• Glucuronidation is the most common and the
most important conjugation reaction
Phase II
• Neonates are deficient in this conjugating
system, making them particularly vulnerable
to drugs such as chloramphenicol
• Drugs already possessing an –OH, –HN2, or –
COOH group may enter Phase II directly and
become conjugated without prior Phase I
metabolism
• The highly polar drug conjugates may then be
excreted by the kidney or bile
Entero-hepatic Recirculation – clinical significance
Oral contraceptive failure when an antibiotic is taken
An antibiotic such as rifampin also induces CYP enzymes that metabolize the contraceptive
hormones and thus reduces their effectiveness even more
DRUG ELIMINATION
DRUG ELIMINATION
• The most important route is through the
kidney into the urine.
• Other routes include the bile, intestine, lung,
or milk in nursing mothers
Renal elimination of a drug
• Glomerular filtration
– The glomerular filtration rate (125
mL/min) is normally about twenty
percent of the renal plasma flow (600
mL/min)
– Lipid solubility and pH do not influence
the passage of drugs into the glomerular
filtrate
• Proximal tubular secretion
– By two energy-requiring active transport
(carrier requiring) systems, one for
anions and one for cations
– Premature infants and neonates have an
incompletely developed tubular
secretory mechanism
Renal elimination of a drug
• Distal tubular reabsorption
– As a general rule, weak acids
can be eliminated by
alkalinization of the urine,
whereas elimination of weak
bases may be increased by
acidification of the urine. This
process is called “ion trapping.”
• For phenobarbital
(weak acid) overdose
we can give
bicarbonate
• For cocaine,
acidification of the
urine with NH4Cl is
useful
Quantitative aspects of renal drug
elimination
• Plasma clearance is expressed as the volume
of plasma from which all drug appears to be
removed in a given time—for example, as
mL/min
• Clearance equals the amount of renal plasma
flow multiplied by the extraction ratio, and
because these are normally invariant over
time, clearance is constant
Total body clearance
• It is not possible to measure and sum these
individual clearances. However, total
clearance can be derived from the steadystate equation
Clinical situations resulting in changes
in drug half-life
• The half-life of a drug is increased by
1. diminished renal plasma flow or hepatic blood flow—for
example, in cardiogenic shock, heart failure, or hemorrhage
2. decreased extraction ratio—for example, as seen in renal
disease
3. decreased metabolism—for example, when another drug
inhibits its biotransformation or in hepatic insufficiency, as with
cirrhosis.
• The half-life of a drug may decrease by
1. increased hepatic blood flow
2. decreased protein binding
3. increased metabolism
Half-Life
• Half-life (t1/2) is the time required to change
the amount of drug in the body by one-half
during elimination (or during a constant
infusion).
• Half-life is useful because it indicates the time
required to attain 50% of steady state—or to
decay 50% from steady-state conditions—
after a change in the rate of drug
administration.
Time required to reach the steadystate drug concentration