Asmah Nasser, M.D.

Pharmacokinetics

Pharmacokinetics is the quantitative study of drug movement in, through and out of the body

What Happens After Drug Administration?

Absorption

Distribution

Metabolism

Elimination /Excretion

Important factors to know…• Factors affecting absorption

• Concept of ionization , pKa and pH

• Henderson –Hassel Balch equation

• Bioavailability , Bioequivalence , AUC

• Distribution , volume of distribution

(Vd), redistribution

• Plasma protein binding

Important factors to know…• Metabolism (biotransformation) , CYP 450 etc

• Excretion

• First and zero order kinetics of elimination

• Plasma Half life

• Clearance

• Steady state ,loading and maintenance dose

• Therapeutic drug monitoring

• Pharmacokinetic calculations

Absorption

After a drug is administered, how does it reaches site of action?

Absorption… is the transfer of a

drug from its site of administration to

the blood stream. In order to reach

their site of action, a drug has to

pass through several membranes

Transport

A. Passive diffusion: Concentration gradient across membrane is the driving force for movement of drug molecule across the membrane

1. Small size, water soluble drug molecule penetrate through aqueous channels or paracellular spaces …Filtration …few drugs does this

2. Lipid soluble drugs readily pass through membrane by dissolving in membrane ….many drugs does this

B. Active Transport:• Movement occurs against the concentration

gradient and needs energy like ATP

Factors that affects absorption• The particle size – Smaller is better

• concentration gradient

• Surface area and vascularity of that area

• Lipid solubility / Water solubility

• Nature of the drug…acidic or basic

• Ionized or non ionized

• The pH levels on either side of cell membrane

• pKa of the drug

Lipid/Water solubility

Once in solution, drugs exist as a mixture of

two interchangeable forms

1. Water-soluble is the ionized or

electrically charged form…Cannot cross

membrane

2. Lipid-soluble is the non ionized, or

uncharged form….Can cross membrane

Concept of ionization…continued

• We know most of the drugs are either weak acid or a weak base and when dissolved in body fluids, some or all of a drugs molecules become ionized/unionized

10

HA H+ + A-

BH+ B + H+

Concept of ionization…continued

What percentage is ionized /unionized

determined by following factors :

1.Whether the drug was an acid or a base.

2. Whether it is dissolved in an acid or base

medium (Eg: Stomach or intestine ?) i.e pH of

the medium.

3. And also the pKa of the drug.

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Role of pH in ionization of a Weak base

As pH increases, a weak base will become

more and more unionized, lipid soluble and

better absorbed

As pH decreases, a weak base will become

more and more ionized, lipid insoluble, and will

not be absorbed. Also becomes more water

soluble and better excreted.12

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pH of the medium

100%

50%

0%1

75%

25%

Role of pH in ionization of a Weak base %

of U

nion

ized

form

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As pH increases, a weak acid will become more and

more ionized , lipid insoluble and will not be

absorbed. Also becomes more water soluble and

better excreted .

As pH decreases, a weak acid will become more and

more unionized , lipid soluble and better absorbed .

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Role of pH on ionization of a Weak Acid

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pH of the medium

100%

50%

0%1

75%

25%

Role of pH in ionization of a Weak acid%

of U

nion

ized

form

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Question

Aspirin is an acidic drug. In the stomach, is it mostly in the

ionized or unionized form?

Moral of the story...

Acidic drugs are Absorbed best in Acidic environments

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Basic drugs are Best absorbed in Basic environments

Basic drugs are Best absorbed in Basic environments

So...

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To absorption of an basic drug…

acidify the environment

To absorption of an basic drug…

acidify the environment

To absorption of an acidic drug…

alkalanize the environment...

To absorption of an acidic drug…

alkalanize the environment...

This concept is very important in treatment of a drug poisoning

pKa pKa is equivalent to the pH at which 50%

drug is ionized and 50% is

unionized….Remember this point

pKa Is the negative logarithm of acidic

disassociation constant of the weak

electrolyte …not necessary to know19

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pH of the medium

100%

50%

0%1

75%

25%

pKa

% o

f Uni

oniz

ed fo

rm

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Henderson-Hasselbalch equation

The ratio of lipid-soluble form to water-soluble form for a weak acid or weak base is expressed by the Henderson-Hasselbalch equation

The Henderson-Hasselbalch equation relates the ratio of protonated to unprotonated weak acid or weak base to the molecule's pKa and the pH of the medium as follows:

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Henderson-Hasselbalch equation

pH-pKa -2 -1 0 +1 +2

Weak acid: %nonionized

99 90 50 10 01

Weak base: %nonionized

01 10 50 90 99

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Question

1. The pKa of acetylsalicylic acid is 3.5. What percentage of the drug is in an absorbable form in the stomach at pH of 1.5?

A. 0.1%B. 1%C. 10%D. 90%E. 99

Question

The greater proportion of the dose of a drug administered orally will be absorbed in the small intestine. However, on the assumption that passive transport of the nonionized form of a drug determines its rate of absorption, which of the following compounds will be absorbed to the least extent in the stomach?

a. Ampicillin (pKa = 2.5)

b. Aspirin (pKa = 3.0)

c. Warfarin (pKa = 5.0)

d. Phenobarbital (pKa = 7.4)

e. Propranolol (pKa = 9.4)

Summary

• A drug molecule carrying an electrical charge is said to be Ionized

• Lipid-soluble is the non ionized, or uncharged form….Can cross membrane

• Percentage of ionized drug depends on :1.Whether the drug was an acid or a base2. Whether it is dissolved in an acid or base

medium (Stomach or intestine ?) i.e pH3. And also the pKa of the drug

• As pH increases, a weak base will become more and more unionized ,lipid soluble and better absorbed

• As pH decreases, a weak acid will become more and more unionized ,lipid soluble and better absorbed

Summary

pKa is equivalent to the pH at which 50%

drug is ionized and 50% is unionized

For a weak acid if pH –pKa is low it will

be more nonionized and better absorbed

For a weak base if pH –pKa value is high

it will be more nonionized and better

absorbed