Pharmacokinetics

Pharmacokinetics
Phases
Onset of action
Peak effect & duration of action
Cell membrane
Membrane and absorption
Factor affecting Absorption
Distribution
BBB
Vd
Factor affecting drug distribution
Metabolism phases
Enzyme induction
Enzyme inhibition
First pass effect
Factor affecting drug metabolism, excretion
Factor influencing drug excretion and drug clearence
Half life
Bioavailability

Pharmacokinetics
Pharmacokinetics is the field of science that deals with the kinetics of drug
absorption, distribution and elimination
• After oral administration:
▪ The drug is absorbed (A) from the site of administration to the systemic
circulation ▪ The drug is distributed (D) to all parts of the body
▪ And the drug is eliminated from the body by metabolism and/or excretion
(ME)

Biological membrane
This is a bilayer of phospholipid and cholesterol molecules, the polar
groups (glyceryl phosphate attached to ethanolamine/choline or hydroxyl
group of cholesterol) of these are oriented at the two surfaces and the
nonpolar hydrocarbon chains are embedded in the matrix to form a
continuous sheet. Extrinsic and intrinsic protein molecules are adsorbed on
the lipid bilayer.
Glycoproteins or glycolipids are formed on the surface by attachment to
polymeric sugars, aminosugars or acids. The specific lipid and protein
composition of different membranes differs according to the cell or the
organelle type. The proteins are able to freely float through the membrane:
associate and organize or vice versa. Some of the intrinsic ones, which
extend through the full thickness of the membrane, surround
fine aqueous pores. Paracellular spaces or channels also exist between
certain epithelial/endothelial cells. Other adsorbed proteins have enzymatic,
carrier, receptor or signal transduction properties. Lipid molecules also are
capable of lateral movement. Thus, biological membranes are highly
dynamic structures.
Absorption
It is the process by which the drug enters the systemic circulation from the
site of administration through the biological membrane is called absorption
of drug.
Drug absorption is determined by the drug’s physicochemical properties,
formulation, and route of administration. Dosage forms (eg, tablets,
capsules, solutions), consisting of the drug plus other ingredients, are
formulated to be given by various routes (eg, oral, buccal, sublingual, rectal,
parenteral, topical, inhalational). Regardless of the route of administration,
drugs must be in solution to be absorbed. Thus, solid forms (eg, tablets)
must be able to disintegrate.
Unless given IV, a drug must cross several semipermeable cell membranes
before it reaches the systemic circulation. Cell membranes are biologic
barriers that selectively inhibit passage of drug molecules. The membranes
are composed primarily of a bimolecular lipid matrix, which determines
membrane permeability characteristics. Drugs may cross cell membranes
by
 Passive diffusion
 Facilitated passive diffusion
 Active transport
 Pinocytosis
Sometimes various globular proteins embedded in the matrix function as
receptors and help transport molecules across the membrane.
Processes of Absorption
1. Simple transport/ passive transport
Simple diffusion/ Passive diffusion
Filtration
2. Specialized transport
Active transport
Facilitated transport
Endocytosis – 1. Phagocytosis , 2. Pinocytosis
Transport of a drug from the Gl tract
Passive diffusion: the drug moves from a region of high concentration to
one of lower concentration. Passive diffusion does not involve a carrier.
The vast majority of drugs gain access to the body by this mechanism.
Lipid-soluble drugs readily move across biologic membranes due to
solubility in the membrane bilayers .
Water-soluble drugs penetrate the cell membrane through aqueous
channels or pores
Weak acids → best absorbed in stomach.
Aspirin, Phenobarbitone, penicillin v
Weak bases → best absorbed in intestine.
Atropine, ephedrine, Chloroquine

Facilitated diffusion: In this process drug molecules enter the cell through
specialized transmembrane carrier proteins that facilitate the passage of
large molecules.
PORE TRANSPORT/ FILTRATION
It involves the passage of ions through Aq. Pores. Low molecular weight
molecules (less than 100 Daltons) eg- urea, water, sugar are absorbed.
Also imp. In renal excretion, removal of drug from CSF and entry of drugs
Active transport: This mode of drug entry involves specific carrier proteins
that cross the membrane. Active transport is energy-dependent. It is
capable of moving drugs against a concentration gradient that is, from a
region of low drug concentration to one of higher drug concentration.
Active Transport characteristics

➤ Relatively unusual.

➤ Occurs against concentration gradient.

> Requires carrier and energy.

> Specific

➤ Saturable.

➤ Iron absorption.

➤ Uptake of levodopa by brain.

Endocytosis
It involves engulfing extracellular materials within a segment of the cell
membrane to form a vesicle (hence also called as corpuscular or vesicular
transport) which is then pinched off intracellularly.
Pinocytosis ("cell-drinking")
Uptake of fluid solute.
A form of endocytosis in which small particles are brought into the cell in
the form of small vesicles which subsequently fuse with lysosomes to
hydrolyze, or to break down, the particles. This process requires energy in
the form of (ATP).
Polio vaccine and large protein molecules are absorbed by pinocytosis.
What is the difference between Active and Passive Transport
Factors affecting drug absorption:
Physicochemical Factors

 Lipid solubility: More lipid soluble and less water soluble drugs will be
absorbed rapidly.

 Dosage form: (Tablets and capsules) rate of disintegration and

dissolution is limiting factor in their absorption. After dissolution,
smaller the particle size, more efficient will be absorption. Moreover,
drug from liquid formulations will absorb efficiently.

 GIT movements or gastric emptying time: Increased peristaltic

activity as in diarrhea reduces drug absorption

 Effect of pH: Most drugs are either weak acids or weak bases.

 Weak acids become less ionized(charged) in an acidic medium and

weak bases become less ionized in an alkaline medium

 Unionized drug is lipid soluble and diffusible

 Acidic drug will absorb more in stomach or intestine

 Lipid soluble(hydrophobic), uncharged, unionized will cross the

membrane rapidly than lipid insoluble(hydrophilic or water soluble),
charged and ionized.
  Basic drug will absorb more from intestine because it becomes
unionized in basic medium. In acidic medium basic drug will become
more ionized and thus no absorption will takes place.
Dosage form and pharmaceutical ingredients
1. Disintegration time
2. Dissolution time
3. Manufacturing variables
4. Pharmaceutical ingredients
5. Nature and type of dosage form
6. Product age and storage conditions

Patient related factors

1. Age
2. Gastric emptying time
3. Gastrointestinal pH
4. Blood flow through GIT
5. Gastrointestinal contents