Pharmacokinetics

1. Molecular size and shape

Diffuse readily across cell

2. Degree of ionization

membrane

3. Relative lipid solubility of its ionized and

**Ionized - low lipid solubility

non - ionized forms

c)

4. binding to serum and tissue protein

area of absorbing surface -duodenum



site

of

absorption

because of the villi ABSORPTION

d) mesenteric blood flow

Concerns

e) pre  systemic elimination / first pass

the process of entry of drug into the

systemic circulation

effect

The

-

Liver, stomach, etc.

-

Rapid metabolism of a drug prior to

determinants of absorption are those of drug

permeation Intravascular

administration (eg.IV) does not

reaching the general circulation.

involve absorption, and there is no loss of drug. With

extravascular

administration

(eg.oral,

FACTORS THAT INFLUENCE ABSORPTION

intramuscular, subcutaneous, inhalation) less than

1. Blood flow at the site of administration

100% of a dose may reach the systemic circulation

2. Total Surface area available for absorption

because of variations in bioavailability.

3.

FACTORS

THAT

AFFECT

THE

RATE AND EXTENT OF

DRUG ABSORPTION

1. Dosage form / Drug Formulation a.

Liquid dosage forms are absorbed

2.

Physical

k

The parameter of absorption

k

Function of Time and conc.

k

Measure the rate and extent by w/c a drug

 Chemical Properties k

The fraction of a drug dose that reaches the bloodstream after absorption at any site site of 

b) pH  will determine ionization Lipophilic vs. Hydrophilic Partition Coefficient

Fraction of unchanged drug that reaches the systemic circulation

better absorption.

 

reaches the systemic circulation k

a) Molecular weight  must be smaller for

c)

time at the site of absorption

BIOAVAILABILITY (f )

more efficiently than solid dosage forms.

Contact

administration f = AUCPO

= measure of 

lipophilicity; the greater it is, the more lipid soluble the drug.

AUC IV

Bioequivalence: 

 Lipophilic drugs readily diffuse through the cell membrane (lipid bilayer).   Hydrophilic drugs / charged drugs cannot readily diffuse through the cell

when two related drugs show comparable

bioavailability Therapeutic Equivalence: 

when two similar drugs have comparable efficacy and safety

membrane. 3.

Physiologic Variable

**For bioequivalence to occur between

a) Gastric motility

two

formulations

of

the

same

motility = absorption

compound, they must have the same

Delay transition of drug from stomach

bioavailability and the same rate of 

to intestine (where most of the drug

absorption.

absorption takes place).

plasma levels of the two products will be

occurs,

the

Acidic pH

same dose, by the same mode. Cmax and

Weak Acid =more unionized

Tmax are rate dependent. The faster the

=more lipid soluble

rate of absorption, the smaller the Tmax

Weak base=less unionized=less

and the larger the Cmax, and vice versa.

lipid soluble y

this

super imposable if they are given at the

b) pH at absorptive site y

When

ABSOLUTE VS RELATIVE BIOAVAILABILITY

Basic pH

Absolute Bioavailability  compares the

Weak Acid=less unionized=less

bioavailability of the active drug in systemic

lipid soluble

circulation

Weak

Base=more

unionized=more lipid soluble

following

non-intravenous

administration with the bioavailability of the same drug following IV administration.

**Non-ionized  lipid soluble;

2

Relative Bioavailability  measures the

**IV administration by definition has 100%

bioavailability of a formulation of a certain drug

bioavailability and the most rapid onset

when compared with another formulation of  the same drug, usually an established standard

DISTRIBUTION 

or through administration via a different route.

the systemic circulation and enters the

FACTORS THAT AFFECT BIOAVAILABILITY

interstitial space and/or the cells of the

1. Biopharmaceutical factors  Dosage form ; Physicochemical

process by which a drug reversibly leaves

tissues

properties



once in the blood stream, the drug is distributed to the different tissues



The process of distribution of a drug from the systemic circulation to organs and tissue

involves

permeation

through

membrane barriers and are dependent on its solubility (recall that only non  ionized drugs cross biomembranes), the rate of  blood flow to tissues and the binding of  drug molecules to plasma proteins. FACTORS THAT INFLUENCEDRUG DISTRIBUTION

2.

Physiologic

factors  Gastric Motility ; Pre -

1.

Plasma Protein Binding

systemic metabolism

- Drugs bound to proteins are not readily

3. GIT Contents  Foods, drugs, liquids

distributed and are inactive

4. Disease State

- High protein binding prolongs onset and duration of action

DETERMINANTS OF BIOAVAILABILITY

1.

Plasma

** Many drugs bind to plasma proteins, including

Data

albumin, with equilibrium between bound and free molecules (Recall that only unbound drugs cross

**Tmax  time of maximum drug concentration - Rate of the drug absorption **AUC  Area under the curve; shaded portion - Most

reliable

measure

for

bioavailability - Direct - Extent of the drug absorption - It is directly proportional to the total amount

of

unchanged

drug

that

reaches the systemic circulation

biomembranes). **Competition between drugs-drugs for plasma protein binding sites may increase the free fraction, possibly enhancing the effects of the drug displaced. **Remember that plasma protein binding limits the distribution, intensity of pharmacologic action and elimination rate of drugs.  **Therefore: A highly protein bound drug generally has longer duration, low toxicity, and low biologic effect. PROTEIN BINDING

Albumin  major plasma protein component; reversible drug binding; weakly acidic drugs Alpha -1 Acidic Glycoproteins (AAG) and Globulin  weakly basic drugs Lipoproteins  macromolecular complexes of lipids + proteins; Binding drugs when albumin sites become saturated

2. Urine Data 

maximum urinary excretion rate



time for maximum excretion rate



cumulative amount of drug excreted in

Pharmacologic

Free, unbound drug is the active form of the drug  Drugs bound to proteins are not readily distributed and are inactive 

the urine 3.

RBC  Binding does not significantly affect distribution

effect

3



High protein binding prolongs onset and duration of action

Apparent Volume of Distribution (Vd)

- A kinetic parameter of a drug that correlates 2.

Cardiac

Output and Blood flow to vascular

organ

dose with plasma level at zero time - The higher the Vd, the lower the plasma

-highly vascular organs receive more of the drugs (heart, liver, kidneys, brain) -blood

flow

(perfusion)

is

concentration and vice versa - Vd is low when a high percentage of a drug is

directly

bound to plasma proteins used for calculating

proportional to the drug distribution.

Vd by using the dose only if one knows or can calculate drug concentration.

3.

Permeability and Perfusion

of Membranes

- Tissue binding and accumulation of drugs with

- Capillary wall structure

high

- Drugs pKa and blood pH

displacement by other agents 

- Blood perfusion

pharmacologic activity.

4. Natural barriers

Vd

values

raises

the

possibility

of 

Changes

in

Vd= amount of drug administered

- Placental Barrier  most small molecular

Initial drug concentration

weight drugs cross this barrier, although fetal blood levels are usually lower than

METABOLISM

maternal

process by which a drug is altered chemically

- Blood  brain barrier  permeable only to

into another compound called metabolites

lipid  soluble drugs or those of very low

which may be more active or less active than

molecular weight

the parent drug.

- Blood  ocular barrier

Aka biotransformation

5. Diseases

primarily occurs in the liver

- renal, cardiac failure

can also occur in the stomach, small intestines,

- plasma albumin conc:  in malnutrition,

plasma, kidney, lung, skin, other tissues

hepatic and renal diseases -

Alpha-1-acid glycoprotein conc:  in pregnancy and post MI

VOLUME OF DISTRIBUTION (V) i

the volume of fluid to which a drug is distributed

i

drugs with large volume of distribution will have a longer half-life and duration of action

iotransformation  is the metabolic conversion of  Biotransformation

drugs, generally to less active compounds but sometimes to isoactive or more active forms Two

Phases of  Metabolism:

**remember xenobiotics? Phase

1

Include

oxidation

(especially

the

i

The parameter of distribution

cytochrome

i

Relates the amount of a given drug in the body

mixed function oxidase), reduction, deamination,

to the concentration to the drug in the blood.

and hydrolysis. Reactions that convert the parent

Actually non - physiological or hypothetical

drug to a more polar (water  soluble) or more

volume; is concerned with extent and where a

reactive product by unmasking or inserting a polar

drug is distributed.

functional group such as OH, - SH, -or -NH

i

i

P45-group

of enzymes also called

Defined with respect to blood, plasma, or water (unbound drug), depending on the

Phase 2  synthetic reaction that involve addition

concentration used in the equation

(conjugation) of subgroups to OH, -NH 2and SH

i Can

vastly exceed and physical volume in the

functions on the drug molecule. The subgroups that

body because it is the volume apparently

are

necessary to contain the amount of drug

glutathione, glycine, sulfate, and methyl groups.

homogeneously at the concentration found in

Most of these groups are relatively polar and make

the blood, plasma, or water.

the product less lipid  soluble than the original

i Can

be determined in the blood or by back -

extrapolation

added

include

glucoronate,

acetate,

drug molecule. -

glucuronidation,

sulfation,

glutathione

conjugation, n-acetylation, methylation V = Total amount of drug in the body (A) Plasma

drug concentration (C)

SIGNIFICANCE OF METABOLISM

4



i

defensive mechanism

i

increases polarity of drug molecules 

restricts

penetration

Anions, cations, non  ionized molecules with lipophilic polar groups and those with

thru

MW>500

cellular

membranes



For drugs poorly absorbed in the intestines



reduces distribution



Organic acids and organic bases  active



promotes elimination

transport  

1. Non  Genetic 

extremes

of

age slower :

metabolism due to lack of enzymes, and/or

reduced

availability

of 

essential co-factors.

the

effect

of

3.Mammary 3. Mammary Excretion 

Nursing mothers should avoid taking drugs



Anti-thyroid, lithium, chloramphenicol, ant i-



Extremely

narrow

therapeutic

index

(effective dose) gentamicin, kanamycin 

androgenic 

hormone.



Main organ  kidney

cancer drugs  Do not nurse to





- Via different transport mechanism

Sex

  males have faster metabolism due



recycling

2. Salivary Excretion

Age  



biliary

Enterohepatic Recirculation

FACTORS AFFECTING DRUG METABOLISM 

Considered

Take special care

4.Drug 4. Drug Excretion into sweat

Liver size / function    more functional and inc size=inc

k Passive diffusion of the non-ionized moiety

enzymes=faster absorption.

k

Diet / Nutrition

Non



ionized

compounds:

Alcohol,

Antipyrine, Urea

  Charbroiled food: inhibit CYP 1A

k

Weak Acids: Sulfonamides, salicylic acids

 Grapefruit juice: inhibit CYP 3A

k

Weak Base: Thiamine

k

Metals: I, Br, Hg, Pb

Environmental

5.Drug 5. Drug Excretion into Expired Air 2. Genetics a.

Less soluble anesthetics

Hydrolysis of esters  succinylcholine

Soluble

b. Acetylation of amines  isoniazid in

Other volatile compounds: Alcohol, Ethereal

slow and fast acetylators 

oils

Dependent on the amount of  hepatic n-acetyltransferase.

 Slow

acetylators: at risk for

6.Genital 6. Genital Excretion  Prostate secretions  Seminal

toxicity. 

Caucasians

are slow

phenformin,



Not



dextromethorphan, and

some

dependent

on

enzyme

availability.

Verified by the presence of drugs in the Ex. Doxycycline  renal failure; no need for favored

8.Renal 8. Renal Drug Excretion 

Major route



Non-volatile; water soluble, low MW drugs

EXCRETION 

process by which a drug or its metabolites is eliminated from the body



main organ of elimination is the kidneys



other organ of excretion include the billiary system, GIT, skin and lungs





dose adjustments; intestinal excretion is

tricyclic

antidepressant; poor and extensive 

drugs

GUT lumen after IV administration

Oxidation  debrisoquin, sparteine, metoprolol,

anti-cancer

7.Intestinal 7. Intestinal Excretion

acetylators. c.

fluid:

malformations

Filipinos are fast acetylators whereas

gases

removal of intact drug

PATHWAYS **Remember physio :p

1.Biliary 1. Biliary Excretion 5

CLEARANCE 

Defined as the volume of blood cleared of the drug in unit time.



It represents the relationship between the rate of drug elimination and its plasma level.

HALF





 LIFE (t ½)

the measure of the ability of the body to eliminate the drug

The period of time required for the amount or



the sum of hepatic metabolism and renal excretion

concentration of drug to decrease by one half. 

Related to its duration of action and indicates when another dose should be given



often

used

to

determine

frequency

of 

administration 

determines the time to attain steady-state concentration



Drug needs about 4-5 half lives to be completely eliminated from the body E.g. Paracetamol (ACET) 500 mg half-life 4 hrs

**Higher Vd , lower half life = faster clearance **Lower Vd, higher half life = slower clearance that can lead to toxicity KINETIC ORDER

1. Zero Order Kinetics - constant rate - rate is independent of the amount of drug - linear

st

- active transport

nd

- A constant amount of drug is eliminated per

after 1 4 hrs = 250 mg after 2 4 hrs hrs = 125 mg rd

after 3

unit

4 hrs = 62.5 mg

time;

For

example,

if

80mg

is

th

administered and 10mg is eliminated every

th

4hours, the time course of the drug

after 4 4 hrs = 31.25 after 5 4 hrs = 15. 635

elimination

is

80mg(4hrs)70mg(4hrs)60mg(4hrs)50m g(4hrs)40mg - Drugs with zero elimination include ethanol (except low blood levels), phenytoin (high Vd = volume of distribution

therapeutic doses), and salicylates (Toxic

Cl = Clearance

**0.7 or 0.693 can be use** 

2. First Order Kinetics

The longer the t ½ , the longer the plasma



not uniform

concentration to stay in the therapeutic



proportional to the amount of drug

range.

 Curvilinear

STEADY STATE 

doses)

the point where rate of drug availability



passive diffusion



fraction of drug eliminated is constant



rate is dependent on the amount of drug

equals rate of elimination

undergoing the process



constant drug concentration



point where expect maximum drug effect

administered and its elimination half life =



usually attained after 4-5 half lives

4hrs, the time course of its elimination is



For

example,

if

80mg

of

a

drug

6

is

80mg(4h)40mg(4h)20mg(4h)10mg(4 h)5mg 

st

Most drugs follow 1 order elimination rates.

 ____________End of Transcription  ____________ Come to me all who labor and are heavy laden, and I will give you rest. Matthew 11 :28

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