2. PASSAGE OF DRUG ACROSS CELL MEMBRANE
Ability of drug to cross cell membrane
Molecular size and shape
Solubility at the site of absorption, degree of ionization and
lipid solubility.
Passive diffusion:
Concentration gradient
Depend upon lipid solubility and ionization
Unionized drugs are more lipid soluble.
Filtration:
Water soluble drugs
Through porous membrane
Hydrostatic pressure or osmotic pressure
3. 2. FACILITATED DIFFUSION
Specialized transmembrane carrier proteins
These carrier proteins undergo conformational changes
Allowing the passage of drugs or endogenous.
It does not require energy, can be saturated, and may be
inhibited by compounds that compete for the carrier.
3. Active transport:
involves specific carrier proteins
Energy-dependent active transport is driven by the hydrolysis
of adenosine triphosphate.
It is capable of moving drugs against a concentration gradient.
The process is saturable, selective and may be compete
inhibited by other cotransported substances.
4. 4. ENDOCYTOSIS AND EXOCYTOSIS
This type of absorption is used to transport drugs of
exceptionally large size across the cell membrane.
Endocytosis involves engulfment of a drug by the cell
membrane and transport into the cell by pinching off the
drugfilled vesicle.
Exocytosis is the reverse of endocytosis..
5. ABSORPTION
Absorption is the transfer of a drug from its site of administration
to the blood stream.
Factors affecting drug absorption
1.Solubility:
Higher lipid soluble – greater absorption rate
Aqueous solution rapidly absorbed than those given in oily
solution, suspension or solid form.
2.Degree of ionization:
Greater ionization – less absorption
Lipid soluble are in unionized form – readily absorbed
Water soluble drugs are in ionized form – can be absorbed –
very small molecular size
6. 3.Effect of PH on drug absorption
Most of drug are either weak acid or weak bases
Acidic drug (HA) release proton causing a charged anion to
form
Weak bases (BH+) can also release H+ ion. Protonated form
of basic drug is usually charged.
4. Pharmaceutical preparation:
Solution are better absorbed than suspension
Smaller the particle size of powders the more efficient their
absorption.
5. Route of administration:
Parenteral routs is rapid than oral route
Intramuscular route is rapid than from subcutaneous route
7. 6. Surface area:
Greater surface, larger will be the amount of drug absorbed
7. Concentration of drug:
Greater concentration of the drug, greater will be the
concentration gradient
8. Local blood flow:
Rate of absorption is directly proportional to the local blood
circulation
8. FACTORS MODIFYING ABSORPTION FROM GUT
1.Motility of the Gut:
Helps in dissolution of tablets, increase the motility also increase rate
of absorption
2.Ph of the Gut:
Weak acid are mostly unionized in acid medium- better absorbed
Weak bases are unionized in alkaline medium- better absorbed
3.Disease condition:
Effect rate of absorption
4.Presence of other substance:
9. Plasma half-life:
Time it takes for the plasma concentration or the amount of drug in
the body to be reduced by 50%.
The half-life of a drug depends on its clearance and volume of
distribution
E.g For example, after intravenous administration, if maximum
concentration is 16 mg and the half life is 2 hours, after 2 hours 8 mg
will be left, and so on.
Factors affecting half-life
Clearance decrease
Volume of distribution
10. Steady state:
Steady state concentration of drug occurs when the rate of drug
elimination is equal to the rate of drug administration.
Steady state plasma concentration is directly proportional to rate of
infusion and inversely proportional to the total body clearance of the
drug.
Biological half life:
The biological half-life or terminal half-life of a substance is the time it
takes for a substance to lose half of its pharmacologic, physiologic,
or radiologic activity,
11. BIOAVAILABILITY
The fraction of unchanged drug reaching the systemic
circulation following administration by any route”
or
The percentage of administered drug that reaches the systemic
circulation in a chemically unchanged form”
Thus by definition a drug that is administered by intravenous
route has 100% bioavailability
12. FACTORS AFFECTING BIOAVAILABILITY
1-Rout of administration:
2-First-pass hepatic metabolism:
when a drug is absorbed across GIT, it enters the portal circulation
before entering the systemic circulation.
If the drug is rapidly metabolized by the liver ,the amount of unchanged
drug that gains access to the systemic circulation is decreased
3-Absorption
4-Solubility of the drug:
hydrophobic drug will absorb more so bioavailability will be more
5-Chemical instability:
some drugs are unstable in pH of the gastric contents. Others are
destroyed in GIT by degradative enzymes
6-Particle size: smaller the particle size more absorption will be there.
13. DISTRIBUTION OF DRUGS
Process by which drug reversibly leave blood stream and
enter interstitial and tissue.
Such as plasma, extra cellular and intracellular fluid
depending upon its physicochemical properties.
Substance of high molecular weight almost remain in water
plasma.
Drug that can pass capillary wall but can not pass across the
cell membrane are localized mainly in extra cellular fluid. E.g
mannitol iv administration
Cross cell membrane and do not have specific affinity for
specific tissue are distributed equally. E.g alcohol , urea
Some drugs are concentrated especially in one or more tissue
of the body. E.g. iodide in thyroid gland
14. FACTORS THAT DETERMINE DRUG
DISTRIBUTION
1. Binding of drug to plasma protein and tissues
Binding to plasma protein
Bound to plasma protein to varying extent
Binding of drug to albumin is reversible and may show
low or high capacity
Albumin has the strongest affinity for anionic drugs and
hydrophobic drugs.
Binding to tissue protein
Drug accumulate in tissue leading to higher conc. In
tissue.
As result of binding to lipid, protein or nucleic acid.
Drug may also be actively transported into tissue.
Tissue reservoirs may serve as major source of the drug
and prolong its action
15. BLOOD FLOW
How rapidly drug molecules are delivered to a given tissue
How effectively the conc. Gradient b/w blood and tissue is
maintained
Drug equilibrate rapidly b/w the blood and organs with high
blood flow
Capillary permeability
Capillary structure and chemical nature of drug.
16. LIPOPHILICITY
Lipophilic drug readily move across most biologic
membranes
Dissolved and penetrate entire cell surface
Hydrophilic drug do not readily penetrate cell
membrane and must pas through slit junction.
17. DRUG METABOLISM/BIOTRANSFORMATION
The series of chemical alterations of drug that occurs
within the body
How activity of drug terminated or altered.
Some drug – excrete through kidney – no need of
metabolism.
Lipophilic– promote- biological membrane- site of
action- reduce elimination
Lipophilic drug convert into hydrophilic metabolites-
terminate biological activity and eliminate from the body.
Site of drug metabolism:
liver, kidney, GIT, skin and lungs
18. ENZYME
Cytochrome P-450 system
Drug- elevate level of cytochrome p-450- increase rate of
metabolism– reduce action and duration of the drug.
Drug– inhibit p-450 system and may potentate the action of
other drug that are metabolized by this system
19. PHASES OF METABOLISM
First phase I and than Phase II
Some drug pass through phase II and the phase I
Some drug directly undergo through phase II.
Phase I:
Generally result in loss of pharmacological activity of drug
Increase pharmacologically inactive become active after
metabolism
Conversion of drug to a toxic compound
Reaction include in type I reaction are
Oxidative reaction
Reduction reaction
hydrolysis
.
20. PHASE II REACTION
o Conjugation of the parent compound with certain acid radical or
amino acids
o Metabolite from phase I metabolism is sufficient polar – excreted
by kidneys
o Many metabolite are too lipophilic to be excreted and they must
undergo conjugation reaction with endogenous substrate
o Phase II reaction result in inactivation of the parent drug but not
always
o Phase II reaction
o Glucuronidation
o Acetylation
o Glutathion conjugation
o Sulfate conjugation
o Methylation
o Water conjugation
21. FACTOR AFFECTING BIOTRANSFORMATION
Difference in drug distribution, metabolism and elimination due
to following factor
Individual difference:
Different people have different level of metabolism
Genetic factors:
Influence enzyme levels resulting in difference in drug
metabolism
Diet and environmental factors:
Certain vegetables and fruits induce or inhibit enzymes
affecting the drug metabolism
Age and Sex;
Drug have more effect and more toxicity – young and old
patient due decrease drug metabolism
In newborn the enzyme in the liver are not developed.
Male have more rapid drug metabolism than female.
22. Drug – Drug interaction
Interaction b/w drugs and endogenous compounds
Diseases affecting drug metabolism
Pharmacokinetic factors
23. CLEARANCE OF DRUG
Clearance estimates the amount of drug cleared
from the body per unit of time.
First order kinetics: if a constant fraction of drug is
eliminated per unit time, it is called first order kinetic
e.g. 5% or 10%
Zero order kinetics: if a constant amount of drug is
eliminated per unit time it is called first order
kinetics, e.g. 5mg or 10 mg
24. DRUG CLEARANCE THROUGH METABOLISM
Major route of elimination hepatic metabolism, biliary
elimination and urinary elimination,
Elimination processes decrease plasma concentration.
Constant fraction of drug present is eliminated in given unit of
time
A. Kinetics of metabolism:
First order kinetics: if a constant fraction of drug is eliminated
per unit time, it is called first order kinetic e.g. 5% or 10%
Zero order kinetics: if a constant amount of drug is eliminated
per unit time it is called first order kinetics, e.g. 5mg or 10 mg
25. B: Reaction of drug metabolism:
Kidney can not eliminate lipophilic drug
First metabolized lipid soluble into more polar in the
liver through phase I and phase II.
26. DRUG CLEARANCE BY THE KIDNEY
Polar to be eliminated
Eliminate through kidney
Glomerular filtration
Proximal tubular secretion
Distal tubular reabsorption
27. CLEARANCE BY OTHER ROUTE
Intestine, bile lungs and breast milk
Orally not absorbed directly eliminate through
intestine or into bile eliminate in the faces.
Lung – anesthetic gases
Excretion of most drugs into sweat, saliva, tears,
hair and skin.