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(The General
Pharmacology)
By
Dr. Faraza Javaid
General Pharmacology
The interactions between a drug and the body
are conveniently divided into two classes.
 Pharmacokinetic processes
 Pharmacodynamic processes
Pharmacokinetics
 Pharmaco- Greek word (pharmackon) for
“drug,”, and kinetics from the Greek word
(kinetikos) for “moving,”.
 Pharmacokinetics (PK) is the study of drug
movement into, around, and out of the body
How the human body act on the drugs?
Pharmacokinetics of drugs
(ADME)
 Absorption
 Distribution
 Metabolism
 Excretion of drugs
The Pharmacokinetic Process
Absorption
Absorption is the transfer of a drug from the site
of administration to the bloodstream
Or
Is the passage of drug through cell membranes to
reach its site of action.
Mechanisms of drug absorption
1. Simple/ Passive diffusion.
2. Facilitated diffusion.
3. Active transport.
4. Phagocytosis (Endocytosis & Exocytosis).
Passive Transport
Biological/Cell Membrane
Passive Diffusion
Passive diffusion is the process by which molecules
diffuse from a region of higher concentration to a
region of lower concentration.
Passive diffusion does not involve a carrier, is
not saturable, and shows low structural
specificity.
Vast majority of drugs are absorbed by this
mechanism.
Water soluble drug (ionized or polar) is
readily absorbed via diffusion through
aqueous channels or pores in cell
membrane.
Lipid soluble drug (nonionized or non
polar) is readily absorbed via diffusion
through lipid cell membrane itself.
Facilitated Diffusion
Other agents can enter the cell through specialized
transmembrane carrier proteins that facilitate the
passage of large molecules. These carrier proteins
allow the passage of drugs or endogenous molecules
into the interior of cells. This process is known as
facilitated diffusion.
Active Transport
This mode of drug entry also involves specific
carrier proteins that span the membrane.
Energy dependent
Move drugs against a concentration gradient,
(from a region of low drug concentration to one of
higher concentration)
Carrier-mediated
facilitated diffusion
Active transport
Along concentration gradient
(From high to low)
Against concentration
gradient
(From low to high)
Needs carriers
Needs carriers
Selective, saturable
Selective, saturable
No energy is required
Energy is required
Mechanisms of drug absorption
1. Simple/ Passive diffusion.
2. Facilitated diffusion.
3. Active transport.
4. Phagocytosis (Endocytosis & Exocytosis).
Passive Transport
Endocytosis: Uptake of membrane-bound particles.
Exocytosis: Expulsion of membrane-bound particles.
High molecular weight drugs or
Highly lipid insoluble drugs
Factors Influencing Rate of Absorption
Route of Administration
Drug Concentration
Ph
Molecular Size
Surface Area
Blood Flow
Contact time at the absorption surface
Expression of P-Glycoprotein
Route of Administration
 IV administration-
Immediate and complete absorption.
 Extravascular administered-
Carried through various barriers to reach the
circulation and their site of action.
pH
 Most drugs are weak organic acids or bases, so
they undergo ionization
 Ionization of drugs reduces its ability to
permeate membranes
(REDUCES LIPOPHILICITY…)
A drug is present in solution as both the
Lipid-soluble, diffusible, non-ionized form and
The ionized form - lipid insoluble and poorly
diffusible across a membrane.
The degree of ionization of a drug is determined
by the surrounding pH and pKa of the drug.
Ionization of Weak Acids and Weak Bases;
Henderson-Hasselbalch Equation
 A weak acid - neutral molecule that can reversibly dissociate
into an anion and a proton (a hydrogen ion).
 A weak base; neutral molecule that can reversibly dissociated
into a cation and a proton
HA H+ + A-
Ka
B + H+
BH+
Kb
A drug passes through membranes more readily if it is uncharged
 A drug passes through membranes more readily if it is
uncharged.
 Therefore, the effective concentration of the permeable form
of each drug at its absorption site is determined by the relative
concentrations of the charged and uncharged forms. The ratio
between the two forms is, in turn, determined by the pH at
the site of absorption and by the strength of the weak acid or
base, which is represented by the ionization constant, pKa.
 The pKa is a measure of the strength of the interaction of a
compound with a proton.
 The lower the pKa of a drug, the more acidic it is. Conversely,
the higher the pKa, the more basic is the drug.
Molecular size: The smaller in size-----more
absorption
Concentration of drug- Increase in conc. increases
rate of absorption
Surface area - The more absorptive surface area, the
more absorption.
Brush borders of the intestine -1000-fold SA to that
of the stomach, - Hence EFFICIENT
ABSORPTION….
Blood Flow- The intestines receive much more blood
flow than the stomach, so absorption from the
intestine is favored over the stomach.
 Contact time at the absorption surface: If a drug
moves through the GI tract very quickly (in severe
diarrhea), it is not well absorbed.
Food in the stomach -dilutes the drug and slows
gastric emptying.- drug taken with a meal is
generally absorbed more slowly
Expression of P-Glycoprotein
P-glycoprotein is a transmembrane transporter
protein responsible for transporting various
molecules, including drugs, across cell membranes .
It is expressed in tissues throughout the body,
including the liver, kidneys, placenta, intestines,
and brain capillaries, and is involved in
transportation of drugs from tissues to blood.
That is, it “pumps” drugs out of cells. Thus, in
areas of high expression, P-glycoprotein reduces
drug absorption.
 Bioavailability is defined as the fraction of unchanged
drug reaching the systemic circulation, following
administration by any route.
 Expressed as percentage.
 If a 1 gram dose of a drug is administered by mouth,
and half of that reaches the systemic circulation, the
drug is 50% bioavailable.
Determination of bioavailability:
Bioavailability is determined by comparing plasma levels of a drug
after a particular route of administration (for eg; oral administration)
with levels achieved by IV administration.
F =
AUC (oral)
AUC (iv)
x 100
 By plotting plasma concentrations of the drug versus time, the
area under the curve (AUC) can be measured.
 Need for Bioavailability studies- To establish important
pharmacokinetic parameters, dosage regimen, dose labelling.
Also explains why the same dose may cause a therapeutic
effect by one route and same dose may cause a toxic effect by
another route.
Factors affecting Bioavailability
First Pass Metabolism
Solubility of Drug
Chemical Instability
Nature of Drug Formulation
 The elimination of drug that occurs after administration but before it enters
the systemic circulation (eg, during passage through the gut wall, portal
circulation, or liver for an orally administered drug)
 Reduces amount of unchanged drug entering the systemic circulation.
Solubility of the drug:
 Very hydrophilic drugs are poorly absorbed because of
their inability to cross lipid-rich cell membranes.
 Drugs that are extremely lipophilic are also poorly
absorbed, because they are totally insoluble in aqueous
body fluids and, therefore, cannot gain access to the
surface of cells.
Chemical instability:
 Penicillin G -unstable in gastric pH.
 Insulin- destroyed in the GI tract by degradative
enzymes.
Nature of the drug formulation:
Drug absorption may be altered by particle size, salt
form, crystal polymorphism, enteric coatings, and the
presence of excipients (such as binders and
dispersing agents) can influence the ease of
dissolution and, therefore, alter the rate of absorption.
Absorption Pharmacokinetics.pptx

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Absorption Pharmacokinetics.pptx

  • 2. General Pharmacology The interactions between a drug and the body are conveniently divided into two classes.  Pharmacokinetic processes  Pharmacodynamic processes
  • 3. Pharmacokinetics  Pharmaco- Greek word (pharmackon) for “drug,”, and kinetics from the Greek word (kinetikos) for “moving,”.  Pharmacokinetics (PK) is the study of drug movement into, around, and out of the body How the human body act on the drugs?
  • 4. Pharmacokinetics of drugs (ADME)  Absorption  Distribution  Metabolism  Excretion of drugs
  • 5.
  • 7. Absorption Absorption is the transfer of a drug from the site of administration to the bloodstream Or Is the passage of drug through cell membranes to reach its site of action.
  • 8. Mechanisms of drug absorption 1. Simple/ Passive diffusion. 2. Facilitated diffusion. 3. Active transport. 4. Phagocytosis (Endocytosis & Exocytosis). Passive Transport
  • 10. Passive Diffusion Passive diffusion is the process by which molecules diffuse from a region of higher concentration to a region of lower concentration. Passive diffusion does not involve a carrier, is not saturable, and shows low structural specificity. Vast majority of drugs are absorbed by this mechanism.
  • 11. Water soluble drug (ionized or polar) is readily absorbed via diffusion through aqueous channels or pores in cell membrane. Lipid soluble drug (nonionized or non polar) is readily absorbed via diffusion through lipid cell membrane itself.
  • 12.
  • 13. Facilitated Diffusion Other agents can enter the cell through specialized transmembrane carrier proteins that facilitate the passage of large molecules. These carrier proteins allow the passage of drugs or endogenous molecules into the interior of cells. This process is known as facilitated diffusion.
  • 14. Active Transport This mode of drug entry also involves specific carrier proteins that span the membrane. Energy dependent Move drugs against a concentration gradient, (from a region of low drug concentration to one of higher concentration)
  • 15.
  • 16. Carrier-mediated facilitated diffusion Active transport Along concentration gradient (From high to low) Against concentration gradient (From low to high) Needs carriers Needs carriers Selective, saturable Selective, saturable No energy is required Energy is required
  • 17.
  • 18. Mechanisms of drug absorption 1. Simple/ Passive diffusion. 2. Facilitated diffusion. 3. Active transport. 4. Phagocytosis (Endocytosis & Exocytosis). Passive Transport
  • 19. Endocytosis: Uptake of membrane-bound particles. Exocytosis: Expulsion of membrane-bound particles. High molecular weight drugs or Highly lipid insoluble drugs
  • 20.
  • 21. Factors Influencing Rate of Absorption Route of Administration Drug Concentration Ph Molecular Size Surface Area Blood Flow Contact time at the absorption surface Expression of P-Glycoprotein
  • 22. Route of Administration  IV administration- Immediate and complete absorption.  Extravascular administered- Carried through various barriers to reach the circulation and their site of action.
  • 23. pH  Most drugs are weak organic acids or bases, so they undergo ionization  Ionization of drugs reduces its ability to permeate membranes (REDUCES LIPOPHILICITY…) A drug is present in solution as both the Lipid-soluble, diffusible, non-ionized form and The ionized form - lipid insoluble and poorly diffusible across a membrane. The degree of ionization of a drug is determined by the surrounding pH and pKa of the drug.
  • 24. Ionization of Weak Acids and Weak Bases; Henderson-Hasselbalch Equation  A weak acid - neutral molecule that can reversibly dissociate into an anion and a proton (a hydrogen ion).  A weak base; neutral molecule that can reversibly dissociated into a cation and a proton HA H+ + A- Ka B + H+ BH+ Kb
  • 25. A drug passes through membranes more readily if it is uncharged
  • 26.  A drug passes through membranes more readily if it is uncharged.  Therefore, the effective concentration of the permeable form of each drug at its absorption site is determined by the relative concentrations of the charged and uncharged forms. The ratio between the two forms is, in turn, determined by the pH at the site of absorption and by the strength of the weak acid or base, which is represented by the ionization constant, pKa.  The pKa is a measure of the strength of the interaction of a compound with a proton.  The lower the pKa of a drug, the more acidic it is. Conversely, the higher the pKa, the more basic is the drug.
  • 27. Molecular size: The smaller in size-----more absorption Concentration of drug- Increase in conc. increases rate of absorption Surface area - The more absorptive surface area, the more absorption. Brush borders of the intestine -1000-fold SA to that of the stomach, - Hence EFFICIENT ABSORPTION…. Blood Flow- The intestines receive much more blood flow than the stomach, so absorption from the intestine is favored over the stomach.
  • 28.  Contact time at the absorption surface: If a drug moves through the GI tract very quickly (in severe diarrhea), it is not well absorbed. Food in the stomach -dilutes the drug and slows gastric emptying.- drug taken with a meal is generally absorbed more slowly
  • 29. Expression of P-Glycoprotein P-glycoprotein is a transmembrane transporter protein responsible for transporting various molecules, including drugs, across cell membranes . It is expressed in tissues throughout the body, including the liver, kidneys, placenta, intestines, and brain capillaries, and is involved in transportation of drugs from tissues to blood. That is, it “pumps” drugs out of cells. Thus, in areas of high expression, P-glycoprotein reduces drug absorption.
  • 30.  Bioavailability is defined as the fraction of unchanged drug reaching the systemic circulation, following administration by any route.  Expressed as percentage.  If a 1 gram dose of a drug is administered by mouth, and half of that reaches the systemic circulation, the drug is 50% bioavailable.
  • 31. Determination of bioavailability: Bioavailability is determined by comparing plasma levels of a drug after a particular route of administration (for eg; oral administration) with levels achieved by IV administration. F = AUC (oral) AUC (iv) x 100
  • 32.  By plotting plasma concentrations of the drug versus time, the area under the curve (AUC) can be measured.  Need for Bioavailability studies- To establish important pharmacokinetic parameters, dosage regimen, dose labelling. Also explains why the same dose may cause a therapeutic effect by one route and same dose may cause a toxic effect by another route.
  • 33.
  • 34.
  • 35. Factors affecting Bioavailability First Pass Metabolism Solubility of Drug Chemical Instability Nature of Drug Formulation
  • 36.  The elimination of drug that occurs after administration but before it enters the systemic circulation (eg, during passage through the gut wall, portal circulation, or liver for an orally administered drug)  Reduces amount of unchanged drug entering the systemic circulation.
  • 37. Solubility of the drug:  Very hydrophilic drugs are poorly absorbed because of their inability to cross lipid-rich cell membranes.  Drugs that are extremely lipophilic are also poorly absorbed, because they are totally insoluble in aqueous body fluids and, therefore, cannot gain access to the surface of cells. Chemical instability:  Penicillin G -unstable in gastric pH.  Insulin- destroyed in the GI tract by degradative enzymes.
  • 38. Nature of the drug formulation: Drug absorption may be altered by particle size, salt form, crystal polymorphism, enteric coatings, and the presence of excipients (such as binders and dispersing agents) can influence the ease of dissolution and, therefore, alter the rate of absorption.