Definitions

Pharmacokinetics:

The activity or fate of drugs in the body over a period of time, including the processes of absorption, distribution, localization in tissues, biotransformation and excretion.

“ How the body deals with the drug”

Pharmacodynamics:

The study of the biochemical and physiological effects of drugs and the mechanisms of their actions, including the correlation of action and effects of drugs with their chemical structure; also, the relationship between drug concentration and effect.

“ How the durg deals with the body”

Therapeutic index The therapeutic index (also known as therapeutic ratio) is a comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes toxicity.

The larger the therapeutic index, the safer the drug is. If the TI is small (the difference between the two concentrations is very small), the drug must be dosed carefully and the person receiving the drug should be monitored closely for any signs of drug toxicity.

Bioavailability

the rate and extent of the drug reaching systemic circulation

Drugs that require close monitoring In your textbook p7, 1st paragraph.

Pharmacokinetics

Absorption

Distribution

Metabolism

Excretion

The transfer of a drug from external to internal environment of the body.

GENERAL INFORMATION The first stage for the drugs to reach to their target

organs is known as “absorption”.

In fact, the absorption is the transportation of the drug across the biological membranes

There are different mechanisms for a drug to be transported across a biological membrane:

Passive (simple) diffusion

Active transport

Pinocytosis

Facilitated diffusion

SIMPLE (PASSIVE) DIFFUSION The major role for the transportation of the drugs

across the cell membrane is simple (passive) diffusion.

The substances move across a membrane according to a concentration gradient.

The concentration gradient is the factor that determines the route and rate of the diffusion.

No energy is required.

There is no special transport (carrier) protein.

No saturation.

SIMPLE (PASSIVE) DIFFUSION

The concentration gradient and the lipid solubility of the drug are the two main factors that determine the diffusion rate (speed) of the drug.

Molecular weight of the high lipophilic drugs is not important as much as in the drugs that are soluble in water, BUT MW OVER 1000 is generally restrictive!!!

The simple diffusion of the drugs with high solubility in water occurs via the aqueous pores found on the cell membrane (i.e. caffeine, ascorbic acid, acetylsalicylic acid, nicotinamide).

ACTIVE TRANSPORT The transportation of the drug molecules across the

cell membrane against a concentration or an electrochemical gradient.

It requires energy (ATP) and a special transporter (carrier) protein.

There is «transport maximum» for the substances (the rate of active transport depends on the drug concentration in the enviroment).

FACILITATED DIFFUSION

Ooccurs by the carrier proteins..

Net flux of drug molecules is from the high concentration to low concentration.

No energy is required.

Saturable.

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

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

• 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

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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.

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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.

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21

pH of the medium

100%

50%

0% 1

75%

25%

Role of pH in ionization of a Weak base %

of

Un

ion

ize

d f

orm

14

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

Un

ion

ize

d f

orm

14

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

So...

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To absorption of an basic drug…

acidify the environment

To absorption of an acidic drug…

alkalanize the environment...

This concept is very important in treatment of a drug poisoning