Transcript Pharmacokinetics

Basic Pharmacokinetics
The time course of drug action
Collected and Prepared
By
S.Bohlooli, PhD
What is the goal of therapeutics?
To achieve desired beneficail effect with Minimal side
effects Governs dose-concentration part
Rational apporach combines the principles of
pharmacokinetics and pharmacodynamics to clarify the
dose-effect relationship
Governs concentration-effect part
Pharmacokinetics

“How the body handles a drug over
time.”
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The Time-Dependent Roles of Drug
Absorption, Distribution, and Elimination
(Metabolism/Excretion) in Determining
Drug Levels in Tissues.
Pharmacokinetics
Locus of
action
“receptors”
Bound
Tissue
reservoirs
Free
Bound
Free
Systemic
circulation
Absorption
Free drug
Bound drug
Excretion
Metabolites
Biotransformation
Distribution
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Once a drug is absorbed into the
bloodstream, it may be distributed into
interstitial and cellular fluids.
The actual pattern of drug distribution
reflects various physiological factors and
physicochemical properties of the drug.
Factors affecting Distribution

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Size of the organ
Blood flow to the tissue
Solubility of the drug in the tissue
Binding of the drug to macromolecules
Phases of Distribution
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First phase
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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.
Drug Reservoirs
Body compartments where a drug can
accumulate are reservoirs. They have dynamic
effects on drug availability.
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plasma proteins as reservoirs (bind drug)
cellular reservoirs
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Adipose (lipophilic drugs)
Bone (crystal lattice)
Transcellular (ion trapping)
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.
***Only drug that is not bound to proteins
(i.e., free or unbound drug) can diffuse
across membranes.
Plasma Proteins

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albumin
- binds many acidic drugs
a1-acid glycoprotein for basic drugs
The fraction of total drug in plasma that is bound is
determined by its concentration, its binding affinity,
and the number of binding sites.
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.
Bone then can become a reservoir for slow
release of toxic agents (e.g., lead, radium) into
the blood.
Adipose Reservoir
Many lipid-soluble drugs are stored in fat. In
obesity, fat content may be as high as 50%,
and in starvation it may still be only as low as
10% of body weight.
70% of a thiopental dose may be found in fat 3
hr after administration.
Thiopental
•
A highly lipid-soluble i.v. anesthetic. Blood flow
to the 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.
Thiopental concentration
(as percent of initial dose)
100
blood
brain
50
muscle
1
10
100
minutes
adipose
0
1000
GI Tract as Reservoir
Weak bases are passively concentrated in the
stomach from the blood because of the large
pH differential.
Some drugs are excreted in the bile in active
form or as a conjugate that can be hydrolyzed
in the intestine and reabsorbed.
In these cases, and when orally administered
drugs are slowly absorbed, the GI tract serves
as a reservoir.
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.
Placental Transfer
Drugs cross the placental barrier primarily by
simple passive diffusion. Lipid-soluble,
nonionized drugs readily enter the fetal
bloodstream from maternal circulation.
Rates of drug movement across the placenta
tend to increase towards term as the tissue
layers between maternal blood and fetal
capillaries thin.

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