Pharmacokinetics

Pharmacology
Pharmacokinetics
Pharmacodynamics
Definitions
PHARMACOKINETICS
What the body does to the drug ?
PHARMACODYNAMICS
What the drug does to the body ?
Three Phases of Pharmacology
Pharmacokinetics
• Time course of drug absorption,
distribution, metabolism, excretion
How the drug

comes and goes ?
Pharmacokinetics
• What the body does to the drug ?
Drug at
Excretion
Absorption Excreted Drug
Site
Absorption
Drug in Body
Distribution
Metabolism
Metabolites
Pharmacokinetics
ADME
 Absorption
Distribution
Metabolism
Elimination
ABSORPTION
Absorption is the transport of a chemical from
the exposed surface to the blood
Ingestion Inhalation Dermal
G. I. Tract Lung Skin
Blood
Factors Affecting
Liberation/Absorption
• Formulation factors • Patient factors
– Tablet disintegration – Absorbing surface
– Inert ingredient / – Blood flow
solvent effects – Environmental pH
– Solubility – Disease states
– Drug pH – Interactions with food,
– Concentration other drugs
Pharmaceutics
• Different dosage forms have different

pharmaceutical properties.
– Drug absorption of various preparations
• Liquids Fastest
• Powders
• Tablets
• Enteric-coated tablets Slowest
Three ways to get in!
• Direct penetration of the membrane
• Protein channels
• Carrier proteins
Lipid Soluble Drugs
(Lipophylicity)
• Lipid soluble drugs are able to dissolve in
the lipid layer of the cell membrane
• No energy expended by the cell
• Passive diffusion
– Oral tablets or capsules must be water soluble
to dissolve in fluids of the stomach and small
intestine
Membranes and Absorption
Hydrophilic
Lipid Bilayer
Heads Hydrophobic
Tails
Small, H2O, urea,
uncharged Swoosh!
CO2, O2, N2
Large, Glucose DENIED!

uncharged Sucrose
Small
charged H+, Na+, K+,
ions Ca2+, Cl-, DENIED!
HCO3-
A real live, actual clinical
question...
Aspirin is an acidic drug. In the

stomach will it exist mostly in ionized
or non-ionized form?
NON-IONIZED
Why?
Moral of the story...
Acidic drugs are best absorbed from

acidic environments
Basic drugs are best absorbed from

basic environments
So...
To  absorption of an acidic drug…

acidify the environment
To  absorption of an acidic drug…

alkalanize the environment...
Bioavailability
• The fraction of the dose of a drug (F) that
enters the general circulatory system,
F= amt. of drug that enters systemic circul.
Dose administered
F = AUC/Dose
Hepatic ‘First-Pass’
Metabolism
• Affects orally administered drugs
• Metabolism of drug by liver before drug
reaches systemic circulation
• Drug absorbed into portal circulation, must
pass through liver to reach systemic
circulation
• May reduce availability of drug
Therapeutic window
Toxic level
Minimum
Cp
therapeutic level
time
DISTRIBUTION
Once absorbed, chemicals move from the blood
to the various organs
Liver Kidney
Blood Other Organs
Brain Fetus
Factors Affecting Distribution
• Rate of perfusion
• Plasma protein (albumin) binding
• Accumulation in tissues
• Ability to cross membranes
– Blood-brain barrier
– Placental barrier
Factor Affecting Protein Binding
• Affinity of protein for the drug

• Number of binding sites on the protein
molecule
• Concentrations of both drug and protein
• Concomitant drug concentrations
• Disease states
• Species differences
Plasma Protein Binding
warfarin (Coumadin) is highly protein

bound (99%). Aspirin binds to the same
site on serum proteins as does
Coumadin. If a patient on Coumadin
also takes aspirin, what will happen?
The available Coumadin will

1) Why?
increase.
2) Why do we care?
BIOTRANSFORMATION
Some chemicals are transformed by the body (metabolized)
to aid excretion
Liver and other organs
Detoxification
Less Toxic Metabolic Product
Kidney Liver Lung
Urine Feces/Bile Expired Air

Metabolism
• The conversion of one chemical species to another by a
biological system
• Enzymes catalyze the chemical reaction
• Enzymes act on “substrates”

– Endogenous substances (e.g. glucose, hormones)
– Xenobiotics (e.g. drugs, herbs)
• Process often referred to as biotransformation

Factors Altering Metabolism
• Genetics
• Use of concurrent drugs or herbal remedies
• Diet
• Environmental pollutants
• Disease-related changes in enzyme levels
• Age
• Gender
Structure of CYP450
Ribbon form Protein Ball & stick form Heme

What can stop this process?
• Enzyme inhibition
– Other drugs
– Combination drugs
– Liver disease
– Impaired blood circulation in person with heart
disease
– Infant with immature livers
– Malnourished people or those on low-protein
diets
Phases of Drug Metabolism
• Phase I
– A polar group is introduced into the molecule
• Increase water solubility
• For example benzene is changed to phenol
– Most importantly prepares the substrate for Phase II
• Phase II
– Conjugation: "conjugate" a water soluble entity such
as acetate or sulfate onto the drug to make it more
soluble.
– For example: Phenol is converted to phenyl sulfate
Orders of kinetics
• First-order kinetics (exponential

elimination): 50% of the free drug is
removed at each time interval. (e.g. most
drugs)
• Zero-order kinetics: drug is eliminated at a
constant rate regardless of concentration.
(e.g. ethyl alcohol)
Comparison
• First Order Elimination • Zero Order Elimination
– [drug] decreases – [drug] decreases linearly
exponentially w/ time with time
– Rate of elimination is – Rate of elimination is
proportional to [drug] constant
– Plot of log [drug] or – Rate of elimination is
ln[drug] vs. time are independent of [drug]
linear – No true t 1/2
– t 1/2 is constant regardless
of [drug]
Revision of pharmacokinetic terms
Plasma
Concn
(Cp) zero
1st
time
1st order elimination

rate of elimination depends on plasma concentration
C = C0e-kt (k= rate constant of elimination)
Half life (t1/2)

time for plasma concentration to fall by 50%
Zero order elimination (pseudo zero order)

rate of elimination is constant and independent of plasma concentration
Excretion
• Refers to the elimination of the drug from
the body
• Requires adequate functioning of the
circulatory system and organs of excretion
– Kidneys
– Bowels
– Lungs
– Skin
Other forms of excretion
• Low concentrations of drugs may be
excreted through:
– Sweat
– Tears
– Saliva
– Breath (e.g. ETOH)
– Bile
Elimination
• Kidneys = primary site
– Mechanisms dependent upon:
• Passive glomerular filtration
• Active tubular transport
– Partial reabsorption
– Hemodialysis
• Renal disease
– Slows excretion
– Prolongs effects
Active Tubular Transport
Probenecid is moved into the urine by

the same transport pump that moves
many antibiotics. Why is probenecid
sometimes given as an adjunct to
antibiotic therapy?
It competes with the

antibiotic at the pump and
slows its excretion.
Urine pH and Elimination
A patient has overdosed on

phenobartital. Phenobarbital is an acid.
If we ‘alkalinalize’ the urine by giving
bicarbonate what will happen to the
phenobarbital molecules as they are
filtered through the renal tubules?
They will ionize...

How will this affect phenobarbital
reabsorption by the kidney?
Non-ionized Ionized
HA H + + A-
Decreased reabsorption
Increased elimination
Elimination
• Other sources
– Feces
– Exhaled air
– Breast milk
– Sweat
Biological Half-life (t 1/2)
• Amount of time to eliminate 1/2 of total

drug amount
• Shorter t 1/2 may need more frequent doses
• Hepatic disease may increase t1/2
A drug has a half life of 10 seconds. You
give a patient a dose of 6mg. After 30
seconds how much of the drug remains?
Time Amount
0 sec 6 mg
10 sec 3 mg
20 sec 1.5 mg
30 sec 0.75 mg
Why is this important?
• Half-life determines how often a drug is

given
– Daily in the morning
– At bedtime
– Q.I.D - four times a day
– T.I.D – three times a day
– Q4 hours – every four hours
– Q 12 hours – 9 am and 9 pm
Dosing interval
MTL
Cp
time
F . Dose
Cavss =
Clearance. T
T = dosing interval
Cavss
Reducing the dose AND reducing the interval

Cavss remains the same but fluctuation in Cp is less
Half life hours steady state
Lignocaine 2 8 hours
Valproate 6 24 hours
Digoxin 32 6 days
Digitoxin 161 28 days

Drug plasma concentration monitoring is
helpful for drugs
 that have a low therapeutic index

 that are not metabolized to active metabolites
 whose concentration is not predictable from the dose
 whose concentration relates well to either the
therapeutic effect or the toxic effect, and preferably
both
 that are often taken in overdose

Pharmacokinetics

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Pharmacology

How the drug

• What the body does to the drug ?

Ingestion Inhalation Dermal

G. I. Tract Lung Skin

• Different dosage forms have different

• Direct penetration of the membrane

Large, Glucose DENIED!

Aspirin is an acidic drug. In the

Acidic drugs are best absorbed from

Basic drugs are best absorbed from

To  absorption of an acidic drug…

To  absorption of an acidic drug…

Blood Other Organs

• Affinity of protein for the drug

warfarin (Coumadin) is highly protein

The available Coumadin will

Less Toxic Metabolic Product

Kidney Liver Lung

Urine Feces/Bile Expired Air

• Enzymes catalyze the chemical reaction

• Enzymes act on “substrates”

• Process often referred to as biotransformation

Ribbon form Protein Ball & stick form Heme

• First-order kinetics (exponential

1st order elimination

Half life (t1/2)

Zero order elimination (pseudo zero order)

Probenecid is moved into the urine by

It competes with the

A patient has overdosed on

They will ionize...

• Amount of time to eliminate 1/2 of total

• Half-life determines how often a drug is

Reducing the dose AND reducing the interval

Digitoxin 161 28 days

 that have a low therapeutic index

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