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Pharmacokinetics
MBCHB3
September 2014
Definition
• Clinical pharmacokinetics: the application of PK principles to
the safe and effective therapeutic management of drugs in an
individual patient
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Definition
• Four parameters describe drug disposition:
S Bioavailability - the fraction of drug absorbed as such into the
systemic circulation
SVolume of distribution - a measure of the apparent space in the body
available to contain the drug based on how much is given versus what
is found in the systemic circulation
SClearance - a measure of the body's efficiency in eliminating drug
from the systemic circulation
SElimination T1/2 - a measure of the rate of removal of drug from the
systemic circulation
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Importance of PK
• Individualize patient drug therapy
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Dose of drug
administered
Absorption
Ei in i nation
Drug metabolized or excreted
Drug concentration
at site of action
Pharmacologic effect
P ha rm acody nannies
Chnicall response
Toxicity Effectiveness
Absorption
• Absorption: is the movement of a drug from its site of administration
into the central compartment and the extent to which this occurs
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Absorption
• Drug characteristics that affect absorption:
S Molecular weight
S Ionization (non-ionized; passive diffusion)
S Solubility (extended-sustained release formulations)
^Formulation
Absorption
Oral Adminstration
• Sublingual Administration - Absorption from the oral mucosa
Transdermal Absorption
• Absorption is dependent on the surface area and lipid solubility e.g., nicotine for
tobacco-smoking withdrawal, scopolamine for motion sickness, nitroglycerin for
angina pectoris, testosterone and estrogen for replacement therapy
Rectal Administration
• rectal absorption can be irregular and incomplete, and certain drugs can cause
irritation of the rectal mucosa
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Absorption
Parenteral Injection
• intravenous, subcutaneous, and intramuscular, intra-arterial, intrathecal
• Injection into a subcutaneous site is done only with drugs that are not
irritating to tissue
Absorption
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Absorption
• Hydrophilic (eg, atenolol) or lipophilic (eg, acyclovir) drugs have low
bioavailability is also due to incomplete absorption
• If too hydrophilic, the drug cannot cross the lipid cell membrane; if too
lipophilic, the drug is not soluble enough to cross the water layer
adjacent to the cell
• The reverse transporter associated with P-glycoprotein (actively pumps
drug out of gut wall cells back into the gut lumen)
• Inhibition of P-glycoprotein and gut wall metabolism, eg, by grapefruit
juice may increased drug absorption
Absorption
First Pass Elimination
• A drug can be metabolized in the gut wall (eg, by the CYP3A4 enzyme
system), portal blood, and the liver
• The effect of first-pass hepatic elimination on bioavailability is expressed
as the extraction ratio (ER):
CL
ER= —; {Q=hepatic blood flow}
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Absorption
• The rate of absorption is determined by the site of administration and
the drug formulation (different from extent of absorption)
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Distribution
• Membrane permeability - cross membranes to site of action
• Lipophilicity of drug
^lipophilic drugs accumulate in adipose tissue
• Volume of distribution
Distribution
Volume of Distribution
• The volume of distribution (Vd) is a proportionality constant that relates
the amount of drug in the body to the serum/plasma (C) concentration
• Vd is used to calculate the loading dose (LD) of a drug that will
immediately achieve a desired serum concentration
• Vd is the volume apparently necessary to contain the amount of drug
homogeneously at the concentration found in the blood, plasma
• Drugs with very high Vd have much higher concentrations in
extravascular tissue than in the vascular compartment, ie, they are not
homogeneously distributed
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Distribution
Paediatric Patient
• Body Composition
S increased total body water & extracellular fluid
S reduced adipose tissue & skeletal muscle
Distribution
Plasma Proteins
• Albumin is a major carrier for acidic drugs; a1-acid glycoprotein binds
basic drugs
• The fraction of total drug in plasma that is bound is determined by the
drug concentration,, the affinity of binding sites for the drug,; and the
number of binding sites
• Plasma binding is a nonlinear, saturable process
• Hypoalbuminemia secondary to severe liver disease or nephrotic
syndrome results in reduced binding and an increase in the unbound
fraction
• Binding of a drug to plasma proteins limits its concentration in tissues
and at its site of action
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Distribution
Tissue Binding
• Many drugs accumulate in tissues at higher concentrations than
those in the extracellular fluids and blood
• Accumulation is a result of active transport and binding; serve as
a reservoir that prolongs drug action (can cause toxicity)
Fat as a Reservoir
• Many lipid-soluble drugs are stored by physical solution in the neutral fat
e.g., 70% barbiturate thiopental is found in body fat 3 hours after
administration
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Distribution
Bone
• The tetracycline antibiotics (and other divalent metal-ion chelating
agents) and heavy metals accumulate in bone by adsorption onto the
bone crystal surface
• Reservoir for the slow release of toxic agents such as lead or radium into
the blood
• Adsorption of drug onto the bone crystal surface has therapeutic
advantages for the treatment of osteoporosis
Redistribution
• Highly lipid-soluble drug that act on organs like the brain and CVS
rapidly accumulate in adipose tissue
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Distribution
Steady State
C Dosing Rate
ss Clearance
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Metabolism
Half-Life
• The h/2 is the time it takes for the plasma concentration to be
reduced by 50%
^ 0.7 xVd
fl / 2 _ cl
• This h/2 reflects the decline of systemic drug concentrations
during a dosing interval at steady-state
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Metabolism
• Phase 1 reactions usually convert the parent drug to a more polar
metabolite by introducing or unmasking a functional group (—OH,
-NH2, -SH)
Metabolism
• In Phase 2 metabolism an endogenous substrate such as glucuronic acid,
sulfuric acid, acedc acid' or an amino acid combines with the newly
incorporated functional group to form a highly polar conjugate (Phase 2)
• Types of reactions
S Glycine conjugation
SGlucuronide conjugation
S Sulfate conjugation
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Metabolism
Human liver p450 enzymes
• There are many P450 isomers in the liver;
S(CYP: 1A2, 2A6, 2B6, 2C8)
S(CYP: 2C9, 2C18, 2C19, 2D6)
S(CYP: 2E1, 3A4, 3A5, 4A11, and 7)
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Metabolism
Enzyme Induction
• Some of the chemically dissimilar P450 substrate drugs, on
repeated administration, induce P450 expression by enhancing
the rate of its synthesis or reducing its rate of degradation
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Metabolism
Enzyme Inhibition
• Cimetidine and ketoconazole bind tightly to the P450 heme iron and
effectively reduce the metabolism of endogenous substrates (eg,
testosterone) or other co-administered drugs through competitive
inhibition
• Some substrates irreversibly inhibit P450s via covalent interaction e.g.
chloramphenicol is metabolized by CYP2B1 to a product that inactivates
P450 protein
• Examples of suicide inhibitors(inactivators that affect the heme or the
protein moiety of CYPs)
S ethinyl estradiol, norethindrone, and spironolactone
Ritonavir, spironolactone 28
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Excretion
• Excretory organs eliminate polar compounds more efficiently than
substances with high lipid solubility
• The kidney is the most important organ for excreting drugs and
their metabolites
• Substances excreted in the feces are principally unabsorbed orally
ingested drugs or drug metabolites excreted either in the bile or
secreted directly into the intestinal tract and not reabsorbed
• Excretion of drugs in breast milk is important not because of the
amounts eliminated, but because the excreted drugs are potential
sources of unwanted pharmacological effects in the nursing infant
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Excretion
Renal Excretion
• Excretion of drugs and metabolites in the urine involves:
S glomerular filtration
S active tubular secretion
S passive tubular reabsorption
• When the tubular urine is made more alkaline, weak acids are largely
ionized and thus are excreted more rapidly and to a greater extent
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Excretion
Renal Excretion
• When the tubular urine is made more acidic, the fraction of drug
ionized is reduced, and excretion is reduced
• In the treatment of drug poisoning, the excretion of some drugs can be
increased by alkalinization or acidification of the urine
• Alkalinization of urine can produce a 4-6-fold increase in excretion of a
relatively strong acid such as salicylate when urinary pH is changed from
6.4 to 8.0
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Excretion
Excretion by Other Routes
• Excretion of drugs into sweat, saliva, and tears is quantitatively
unimportant
• Elimination by these routes depends mainly on diffusion of the non-
ionized lipid-soluble form of drugs through the epithelial cells of the
glands and depends on the pH
• Excretion into hair and skin is quantitatively unimportant, sensitive
methods of detection of drugs in these tissues have forensic
significance
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Excretion
Clearance
• Assuming complete bioavailability, the steady-state concentration of drug
in the body will be achieved when the rate of drug elimination equals the
rate of drug administration
Dosing rate = CL x Css
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Excretion
• Clearance of drug by several organs is additive
• Elimination of drug from the systemic circulation may occur as a
result of processes that occur in the kidney, liver, and other
organs
• Division of the rate of elimination by each organ by a
concentration of drug (e.g., plasma concentration) will yield the
respective clearance by that organ
CLtotal CLliver + CLrenal + CLother
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Common Terms
Loading Dose
• Loading doses allow rapid achievement of therapeutic serum levels
• Same loading dose used regardless of metabolism/elimination dysfunction
w/ bolus
'w/o
bolus
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Common Terms
Linear Pharmacokinetics
• Linear = rate of elimination is proportional to amount of drug present
• Dosage increases result in proportional increase in plasma drug levels
120
100
=
80
'cs
60
40
20
dose
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Common Terms
Non Linear PK
• Nonlinear = rate of elimination is constant regardless of amount of drug
present
Common Terms
Michaelis-Menten Kinetics
—•— phenytoin
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39
References
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