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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

• Pharmacokinetics Principles (dose-concentration)

S Absorption
^Distribution
^Metabolism
^Elimination (Clearance)

• Effects of drugs are related to its concentration at the site of

action
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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

• Monitor medications with a narrow therapeutic index

• Decrease the risk of adverse effects

• Maximize pharmacologic response of medications

• Evaluate PK as a diagnostic tool for underlying disease states

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Dose of drug
administered

Absorption

Drug concentration Distribution Drug m tissues Pharmaco ki n et ics

in systemic circulation of distribution

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

Dose and Effect Relationship

Absorption
• Absorption: is the movement of a drug from its site of administration
into the central compartment and the extent to which this occurs

• Bioavailability: the fractional extent to which a dose of drug reaches its

site of action or a biological fluid from which the drug has access to its
site of action

• Bioavailability: the fraction of unchanged drug reaching the systemic

circulation following administration by any route (affected by incomplete
absorption and first pass metabolism by the liver)

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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

• Factors affecting drug absorption related to patients:

S Route of administration
S Gastric pH
S Contents of GI tract (rate of emptying)
S Surface area of absorption
S Blood flow
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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

• Absorption from subcutaneous and intramuscular sites occurs by simple

diffusion

• Injection into a subcutaneous site is done only with drugs that are not
irritating to tissue

• Vasodilation increases rate of absorption after parenteral injection

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}

• Systematic bioavailability of a drug (F) can be calculated as;

F = f x (1-ER)
• f (extent of absorption)

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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)

• Zero-order absorption - rate of absorption is independent of the amount

of drug remaining in the gut, e.g., controlled-release drug formulation

• First order absorption - if a drug is dissolved in gastrointestinal fluids,

the rate of absorption is usually proportional to the gastrointestinal
concentration

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Distribution
• Membrane permeability - cross membranes to site of action

• Plasma protein binding

Abound drugs do not cross membranes
S malnutrition = reduced albumin = increased free drug

• 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

Amount of Drug in the body

Vd =
C 16

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Distribution
Paediatric Patient
• Body Composition
S increased total body water & extracellular fluid
S reduced adipose tissue & skeletal muscle

• Protein Binding - albumin, bilirubin, a1-acid glycoprotein

• Tissue Binding - compositional changes

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

• indicates that a steady-state concentration eventually will be

achieved when a drug is administered at a constant rate

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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)

• Phase 1 products not eliminated undergo further reactions

^Hydrolysis
S Oxidation
^Reduction
S Demethylation
SMethylation
S Alcohol dehydrogenase metabolism
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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)

• CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2D6, CYP2E1, and

CYP3A4 are the most important forms

• CYP3A4 metabolism of over 50% of the prescription drugs metabolized

by the liver
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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

• Environmental chemicals and pollutants are also capable of

inducing P450 enzymes (benzo[a]pyrene present in tobacco
smoke, charcoal-broiled meat induce CYP1A enzymes)

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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

• The amount of drug entering the tubular lumen by filtration depends on

the glomerular filtration rate and the extent of plasma binding of the
drug; only unbound drug is filtered

• 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

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dose
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Common Terms
Non Linear PK
• Nonlinear = rate of elimination is constant regardless of amount of drug
present

• Dosage increases saturate binding sites and result in non- proportional

increase/decrease in drug levels

Common Terms
Michaelis-Menten Kinetics

• Follows linear kinetics until enzymes become saturated

• Enzymes responsible for metabolism /elimination become saturated resulting in
non-proportional increase in drug levels

—•— phenytoin

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Special Patient Populations

• Renal Disease: same hepatic metabolism, same/increased volume of
distribution and prolonged elimination therefore increase dosing interval

• Hepatic Disease: same renal elimination, same/increased volume of

distribution, slower rate of enzyme metabolism. Reduce dosage and
increase dosing interval

• Cystic Fibrosis Patients: increased metabolism/ elimination, and larger

volume of distribution. Increase dosage and reduce dosage interval

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References

• Pharmacology by Katzung 12th Edition

• Lippincott Pharmacology Illustrated Reviews: 4 th Edition

• Applied Therapeutics - Clinical Uses of Drugs: 9th Edition

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